Continuing Education Activity

Differentiated thyroid carcinomas are among the cancers with one of the best survival rates. Historically they have been divided into papillary, follicular, and medullary types. Hurthle cell carcinoma of the thyroid was considered a subtype of follicular thyroid carcinoma. Still, in 2017 it was classified as a distinct tumor type considering the significant histological, clinical, and prognostic differences of the tumor. This activity reviews the clinical and histological features, diagnosis, evaluation, and management of Hurthle cell thyroid carcinoma. It highlights the role of interprofessional teams in recognizing the differences in Hurthle cell carcinoma compared to other differentiated thyroid carcinomas to evaluate and treat the patients with this tumor type properly.

Objectives:

• Describe the pathophysiology of Hurthle cell thyroid carcinomas.

• Review the histological characteristics of Hurthle cell carcinomas of the thyroid.

• Summarize management of Hurthle cell thyroid carcinoma.

• Explain how interprofessional team strategies can contribute to improved patient outcomes in cases of Hurthle cell thyroid carcinoma.

Introduction

Thyroid cancers have historically been divided into four types- papillary, follicular, medullary, and anaplastic. Papillary, follicular, and medullary carcinomas comprised the differentiated type of thyroid neoplasms. Hurthle cell carcinoma (HCC) of the thyroid gland is one of the lesser-known thyroid cancer types. It used to be considered a variant of follicular thyroid cancer. It shares certain similarities with follicular cancer of the thyroid, like clinical presentation and pattern of metastatic spread. However, in 2017 World Health Organization classified it as a distinct tumor type owing to significant histopathological and molecular differences with follicular thyroid cancer. Hurthle cell thyroid cancer is now defined as a follicular thyroid cell “derived” cancer and not a variant of follicular cancer itself.

Etiology

There are no direct causal relationships defined specifically for Hurthle cell thyroid cancer. Exposure to radiation to the head, neck, and chest and family history of thyroid cancer is presently known risk factors for thyroid cancers.

Epidemiology

Hurthle cell carcinoma represents about 5% of all differentiated thyroid carcinomas.[1] It is seen more frequently in females and generally diagnosed after the age of 40.

Pathophysiology

Hurthle cell tumors can be benign in the form of Hurthle cell adenomas. Malignant Hurthle cell carcinomas are characterized by capsular invasion, vascular invasion, infiltration of the thyroid gland and/or distant lymph nodes, and metastatic spread.[2][3]

Germline polymorphisms of the ATPase 6 gene, which helps maintain mitochondrial DNA integrity, are believed to have a role in the pathogenesis of Hurthle cell tumors. Hurthle cell tumors characteristically have been found to have an increased prevalence of mitochondrial DNA common deletions.[4][5]

Histopathology

Hurthle cell neoplasms originate in thyroid follicles from follicular cells (hence they were initially grouped with follicular thyroid tumors) and are characterized by the presence of Hurthle cells, which are eosinophilic oxyphilic cells with round to oval nuclei with prominent nucleoli, and small densely packed mitochondria giving a granular appearance to the otherwise vastly empty cytoplasm.[4][6] 

These Hurthle cells are also known as oncocytes or Askanazy cells. Hurthle cells can be seen in follicular thyroid tumors as well as other types of thyroid disorders, including non-malignant conditions to a varying degree. Thyroid tumors are classified as Hurthle cell neoplasms when more than 75% of the tumor consists of Hurthle cells.[2][4]

History and Physical

Hurthle cell cancers are usually diagnosed when patients present clinically with thyroid nodules or incidental findings on imaging of the neck. Cervical adenopathy is a common presentation in advanced tumors. Distant metastasis can also rarely be the first presenting signs.

Evaluation

Patients with suspicious nodules should have thyroid function checked with thyroid-stimulating hormone (TSH) and thyroxine (T4) levels and confirm nodules with an ultrasound of the thyroid gland with cervical node evaluation. If TSH is low, indicating a functional nodule, this can be confirmed by a radioiodine imaging scan. These functionally hyperthyroid or "hot" nodules are rarely cancerous and require management of hyperthyroidism or thyrotoxicosis.

Non-thyrotoxic thyroid nodules should be evaluated with fine-needle aspiration (FNA) and biopsy. FNA is sufficient to diagnose papillary and anaplastic thyroid cancers. However, FNA cannot distinguish between a benign adenoma and malignant carcinoma for follicular and Hurthle cell tumor types, and this generally requires a thyroid lobectomy or thyroidectomy to perform a surgical pathological evaluation showing capsular invasion, vascular invasion, or infiltration of the thyroid gland to prove invasive cancer.

Molecular studies are increasingly being used to distinguish benign from malignant follicular-derived tumors to help avoid aggressive surgeries. These include testing for BRAF and RAS mutation, mRNA genomic sequencing classifier testing, and microRNA gene expression modalities.[7][8][9]

Some patients may need CT or MRI evaluation for widespread disease depending on presenting symptoms and laryngoscopic evaluation if present with local symptoms like dysphonia or dysphagia.

PET-CT is useful in patients suspected of having metastatic disease.

Treatment / Management

Surgery is the mainstay of treatment of Hurthle cell tumors. Multiple reports and case series have found thyroid lobectomy and total thyroidectomy to have similar outcomes in matched populations for non-invasive Hurthle cell tumors.[10][11] Invasive cancer requires completion of total thyroidectomy. 

Radioactive iodine (RAI) is commonly used in the adjuvant setting for high-risk features like tumor size >2 cm, cervical lymph node metastases, positive margins, microvascular invasion, or postoperative thyroglobulin levels are more than 1 ng/mL. It is estimated that only around 10% of patients with Hurthle cell carcinoma lesions take up radioiodine; hence responses to treatment with RAI are much lower in these patients when compared to other types of thyroid carcinomas.[12][13] Since the majority of Hurthle cell carcinomas are non-iodine avid, a negative post-operative RAI scan may not necessarily rule out distant disease, and it is recommended in patients with high-risk features to undergo an FDG-PET

For patients with de novo or residual cervical disease, neck dissection can be considered if feasible. If surgical resection is not possible or contraindicated, then External beam radiation therapy or intensity-modulated radiation therapy can be considered.[14][15][16]

For metastatic Hurthle cell carcinoma, patients that are asymptomatic with well-differentiated tumors and indolent disease, observation is an acceptable option as long as they do not have brain metastases. For patients with symptoms or rapidly growing metastatic with iodine avid tumor, RAI is a preferable option. If the patient's tumor is not amenable to RAI, systemic therapy with tyrosine kinase inhibitors (TKI) like lenvatinib or sorafenib is considered.[17][18] Given the adverse effect profile, lenvatinib is preferred over sorafenib. Considering the rarity of Hurthle cell tumors, most of the data for the use of TKI in metastatic disease is extrapolated from other types of thyroid carcinomas.

Molecular analysis of these cancers can be helpful as there is data for non-specific use of larotrectinib or entrectinib in cancers with NTRK fusion and pembrolizumab in patients with high tumor mutation burden regardless of the type of cancer.[19][20] Selpercatinib and pralsetinib have been shown to be beneficial in patients with non-small cell lung cancers and thyroid carcinomas which have a RET fusion and can be used as a first-line agent in patients with this mutation.[21][22][23] 

Most of the patients with RET fusions in the study were medullary carcinoma of the thyroid, but the data can be extrapolated to Hurthle cell carcinomas with RET fusion. Cytotoxic chemotherapy has been used in small studies but has not been reported to significantly benefit patients with Hurthle cell carcinoma and is used as a last option.[24]

Differential Diagnosis

Hurthle cell carcinoma shares many clinical and histological features with other types of thyroid cancers, in particular with follicular thyroid carcinoma.

Compared to follicular thyroid carcinoma, Hurthle cell carcinomas tend to be larger, multifocal, have a higher rate of local thyroid invasion, lymph node metastases, and distant metastases.[4][25] As discussed earlier, Hurthle cell carcinomas have characteristic histological features and also have a low tendency to take up radioactive iodine on imaging.

Rapidly growing thyroid carcinomas should always be evaluated for anaplastic thyroid carcinoma as these tumors carry a significantly worse prognosis and need immediate treatment with systemic chemotherapy and sometimes combined with radiation of the neck.

Medical Oncology

Clinical trials are underway to study the molecular aspects of thyroid tumors to better guide surgical therapy and systemic therapy in metastatic patients with certain mutations like NTRK fusion and RET fusion which are amenable to targeted therapy.

Staging

Thyroid cancer staging is done using American Joint Committee on Cancer (AJCC)’s TNM system presently in the 8th edition as of 2017. It uses tumor size and extrathyroidal extension (T), regional cervical, mediastinal, and retropharyngeal lymph node involvement status (N), and distant metastases (M) into account. All different types of thyroid cancers are classified using the same system with a few noteworthy characteristics-

• All patients with differentiated thyroid carcinomas under 55 are considered to have a good prognosis, and even the most widely metastatic tumors get a maximum stage II.
• All anaplastic thyroid tumors are considered to have a poor prognosis and start at a minimum stage of IVA.
• Medullary carcinoma of the thyroid has some differences in tumor (T) definitions for its staging compared to Hurthle cell and follicular carcinomas.

Prognosis

Hurthle cell carcinomas are considered to be more aggressive and carry a higher rate of metastases and lower overall survival than follicular thyroid carcinomas in case reviews.[1][26][27][28]

Older age, larger tumor size at diagnosis, extra-thyroid extension, female sex, and higher stage at diagnosis are considered poor prognostic features for Hurthle cell carcinomas.[28][29]

Complications

Complications of Hurthle cell carcinomas are similar to thyroid neoplasms in general. They can cause complications in the neck by local invasion into the larynx, vocal cords, esophagus, trachea, or mediastinum and by compression of major nerves and vessels in the neck from bulky adenopathy. Metastases tend to occur in lymph nodes, lungs, bone, and infrequently the brain.

Deterrence and Patient Education

Hurthle cell carcinomas can be more aggressive than other differentiated types of thyroid carcinomas. There are no routine screening methods to diagnose thyroid neoplasms recommended by the United States Preventive Services Task Force for use in the general asymptomatic population. Patients with a family history of medullary thyroid carcinomas, multiple endocrine neoplasias and personal history of thyroid cancer, familial adenomatous polyposis syndrome, or exposure to radiation have a high risk of developing thyroid cancer and are suggested to have a high risk of developing thyroid neoplasms and need to be educated to be vigilant about any suspicious signs and symptoms. Patients should be educated on the importance of timely evaluation of any suspicious thyroid nodules or neck masses.

Enhancing Healthcare Team Outcomes

Hurthle cell thyroid neoplasms were until recently considered a variant of follicular neoplasms of the thyroid. WHO has recognized them as a distinct type of thyroid neoplasm because of significant molecular, histological, and prognostic differences. Since the distinction is new, clinicians must recognize the differences between Hurthle cell and follicular neoplasms. The clinical and translational data for Hurthle cell carcinomas are also limited because it was treated as a part of follicular neoplasms due to the low incidence compared to other differentiated thyroid neoplasms.

Health professionals need to recognize this as a distinct neoplasm in reporting cases, outcomes, or complications and designing clinical trials to have quality data reported on Hurthle cell carcinoma in the literature in the future to improve targeted therapy, response rates, and eventually improve patient outcomes.