Hurthle Cell Carcinoma (Oncocytic Carcinoma) Guidelines

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) ^[43]
• National Comprehensive Cancer Network (NCCN) ^[44]
• European Society for Medical Oncology (ESMO) ^[45]
• American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA) ^[46]  (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. ^{[43, 44, 46, 45]}

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. ^{[43, 44, 46, 45]} AACE/AME/ETA indications for FNAB according to size are as follows ^[46] :

• 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) ^[43]
• >1 cm in diameter (ESMO) ^[45]
• ≥1 cm if suspicious sonographic features are present; ≥1.5 cm for moderately suspicious nodules and ≥2.5 cm for mildly suspicious nodules (NCCN) ^[44]

NCCN, ATA AACE/AME/ETA guidelines recommend radionuclide imaging in patients with a low TSH level. ^{[43, 44, 46]}

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. ^[43]  

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)

The 2019 ESMO guidelines recommends pathological diagnosis of all thyroid tumors be made according to the 2017 WHO classification. ^[45]

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 ^[47] :

• 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. ^[43]

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. ^[43]

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 ^[43] . 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. ^[43]

The NCCN recommends FNAB as 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) ^[44] :

• 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

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. ^[43]

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. ^[43]

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. ^[9]

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. ^[44]

While ESMO guidelines consider thyroidectomy to be standard of care for other thyroid tumors, they recommend proposing active ultrasound surveillance of every 6–12 months for unifocal papillary microcarcinomas (≤10 mm) with no evidence of extracapsular extension or lymph node metastases. Lobectomy (instead of total thyroidectomy) may be proposed for selected low-risk (T1a–T1b–T2, N0) tumors. ^[45]

Radioiodine Therapy

NCCN guidelines recommend radioiodine (¹³¹I) therapy if any of the following are present ^[44] :

• 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 ^[44] :

• 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: ^[44]

• 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: ^[43]

• 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. ^[43]

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. ^[43]

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  ^{[43, 44]} :

• 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