Hurthle Cell Carcinoma (Oncocytic Carcinoma) Treatment & Management

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. ^[34]

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. ^{[35, 36]} 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.

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.

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. ^{[37, 38]}

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. ^[39]

Younes et al have studied antivascular therapy in mouse models with bone metastasis from follicular thyroid cancer. ^{[40, 41]} 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.

Surgery is the main treatment for patients with Hürthle cell carcinoma. Surgical treatment is aimed at removal of the entire cancer, which accomplishes the following:

• 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)
• 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. ^[42]

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; check calcium levels at least every 12-24 hours. If hypocalcemia is present, immediately treat the patient.

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

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

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.

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 of  ¹³¹I (>150 mCi) are administered at short intervals
• Mild pancytopenia observed after repeated  ¹³¹I 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 is increased only in patients who have received a high cumulative dose of ¹³¹I (>500 mCi) and in  those who also receive external radiation therapy.

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

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, an ¹³¹I 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.