Oncocytic (Hürthle Cell) Thyroid Carcinoma

Etiology

Various genetic, environmental, and biological factors influence the development of oncocytic thyroid cancer. This type of cancer originates from specialized follicular thyroid cells called oncocytes, characterized by their abundant eosinophilic cytoplasm and high mitochondrial content. The pathogenesis of oncocytic cancer is associated with specific genetic mutations, particularly in mitochondrial DNA, and changes in nuclear genes. Mutations in oncogenes like BRAF and HRAS and inactivation of tumor suppressor genes (eg, PTEN) have been identified, indicating a disruption of normal cellular signaling pathways that control cell growth and survival.[2]

Environmental factors also play a significant role in the development of oncocytic thyroid carcinoma. Exposure to ionizing radiation, especially during childhood, has been established as a risk factor for various thyroid malignancies, including oncocytic carcinoma. Individuals with preexisting thyroid conditions, such as adenomas or goiter, may have an elevated risk of developing oncocytic cancer. Additionally, genetic syndromes, including multiple endocrine neoplasia type 1 (MEN 1) and familial nonmedullary thyroid cancer, have been associated with an increased incidence of oncocytic carcinoma.[3] 

Epidemiology

The incidence and prevalence of oncocytic carcinoma are less extensively documented in comparison to more prevalent thyroid cancers such as papillary or follicular thyroid carcinoma. This is in part due to its recent identification as a distinct entity. Oncocytic thyroid cancer accounts for approximately 3% to 4% of all thyroid malignancies.[4]

Oncocytic carcinoma is more commonly diagnosed in women, with a ratio of approximately 1.6 to 4.8:1 compared to men, and typically affects middle-aged adults, particularly those aged between 50 and 60 years. Specific populations, particularly those in areas with endemic goiter or iodine deficiency, may exhibit higher rates of oncocytic carcinoma.[4]

Despite its lower incidence compared to other forms of thyroid cancer, the aggressive nature and tendency of oncocytic carcinoma to metastasize contribute to its clinical significance. The 5-year relative survival rates for oncocytic carcinoma can vary widely, influenced by factors including tumor stage, histological characteristics, and the presence of metastases at diagnosis. The overall 5-year relative survival rate is high, with a weighted average of all stages of the disease at 98.5%. Approximately 2100 thyroid cancer deaths occur per year in the United States.[5] Understanding the epidemiological patterns of oncocytic carcinoma is crucial for identifying at-risk populations and informing screening and management strategies.

Pathophysiology

The pathophysiology of oncocytic thyroid cancer entails a complex interplay of genetic, molecular, and cellular mechanisms contributing to its distinct behavior and clinical presentation. Oncocytic thyroid cancer originates from oncocytic cells, variants of follicular thyroid cells distinguished by abundant eosinophilic cytoplasm, high mitochondrial content, and atypical morphology. Consequently, oncocytic thyroid cancer is associated with significant genetic alterations.[2]

The cancer is linked to changes in the mitochondria, driven by mutations in mitochondrial DNA (mtDNA), including small mutations and larger deletions, leading to compromised energy production and subsequent compensatory mitochondrial proliferation within the cell.[6] Furthermore, oncocytic tumors exhibit specific alterations in nuclear DNA, although these are less prevalent compared to other thyroid tumors. For instance, mutations in oncogenes like HRAS and BRAF, commonly observed in other types of thyroid cancer, are rare in oncocytic tumors.[7]

Histopathologically, oncocytic carcinoma is distinguished by a high density of oncocytic cells, often accompanied by vascular invasion and a tendency for extra-thyroidal extension. Thyroid tumors are classified as oncocytic neoplasms when more than 75% of the tumor comprises oncocytic cells.[8] This aggressive behavior stems partly from the tumor's capacity to invade surrounding tissues and metastasize to distant sites such as the lungs and bones.[9] The vascularization of the tumor microenvironment is also crucial, as increased angiogenesis supports the tumor's growth and survival.

Histopathology

Oncocytic carcinoma is histologically characterized by at least 75% oncocytes, distinguished by their large size and well-defined cell borders.[2] The tumor cells display deeply eosinophilic and granular cytoplasm, large nuclei with prominent nucleoli, and a complete loss of cell polarity (see Image. Oncocytic Thyroid Carcinoma). Growth patterns may vary, presenting as follicular, trabecular, solid, or papillary formations. Occasional nuclear grooves or pseudo-inclusions can be observed. Additionally, psammomatous-like calcifications may be present in the lumen of follicles. However, unlike in papillary carcinoma, these calcifications lack the laminated structure typically seen in psammoma bodies within the stroma. Malignant oncocytic carcinoma typically exhibits a thicker capsule than adenomas, a solid or trabecular growth pattern, smaller cells with a high nuclear-to-cytoplasmic ratio, and increased mitotic figures. Poorly differentiated tumors are characterized by a size >4 cm, tumor necrosis, numerous mitoses, and foci of small tumor cells.[1] 

History and Physical

Oncocytic thyroid cancers present similarly to other differentiated thyroid cancers. Patients often present with an asymptomatic thyroid nodule that is incidentally detected during imaging. Symptoms, when present, may include a palpable nodule that has grown over time, dysphagia, voice changes, or signs of recurrent laryngeal nerve injury such as hoarseness. Given the higher likelihood of distant metastases, particularly to the lungs and bones, clinicians should assess for bone pain and new respiratory symptoms.

A comprehensive physical examination should focus on the thyroid gland and cervical lymph nodes. Clinicians should inquire about any previous exposure to radiation, particularly to the head and neck, during childhood, as this is a known risk factor for thyroid malignancies. Family history, including multiple endocrine neoplasia (MEN) and other thyroid cancers, should be discussed, as this may predispose individuals to oncocytic carcinoma.

Evaluation

Patients presenting with thyroid nodules should have thyroid function tests performed at baseline, even though cancers are not hormonally active. A thyroid ultrasound is the initial imaging test of choice. Image-guided fine or core needle biopsies can identify oncocytic thyroid lesions, typically reported as Bethesda 4 lesions. However, needle biopsies cannot make this distinction because the demonstration of capsular and vascular invasion is the most reliable means of distinguishing between adenomas and invasive oncocytic carcinomas. 

Molecular testing with commercially available genetic testing kits (eg, Afirma^® or ThyroSeq^® Genetic Classifier) may be helpful in further evaluating Bethesda 3 and 4 lesions. However, the data on their efficacy in oncocytic carcinoma are limited, and thus far, they have been associated with high false-positive rates (38% to 41%), which limits their utility.[10][11] Ultimately, most patients with oncocytic lesions undergo a diagnostic thyroid lobectomy. On final pathology, the diagnosis of oncocytic thyroid carcinoma can be made.

Patients with clinical features suspicious of high-risk or locally advanced disease, including ultrasound imaging indicating extrathyroidal extension or local invasion, clinical lymphadenopathy, or symptoms of local invasion, including hoarseness, dysphagia, or stridor, should undergo further evaluation. Cervical ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) may be used to stage the disease. If distant metastatic disease is suspected, whole-body positron emission tomography (PET)/CT and bone scans are valuable modalities. Thyroid uptake studies are generally less helpful for oncocytic tumors, as they do not reliably absorb radioactive iodine.[12]

Treatment / Management

Surgical Treatment

The primary treatment for oncocytic thyroid cancer is thyroidectomy, with the specific approach contingent upon the tumor's size, location, and potential metastasis. Total thyroidectomy, involving the complete removal of the thyroid gland, is the most frequently performed procedure. This procedure is recommended for patients with tumors exceeding 4 cm, those displaying invasive characteristics, or in cases where lymph node metastasis is suspected.[4] Total thyroidectomy diminishes the risk of recurrence and enables the postoperative monitoring of thyroglobulin levels, a critical marker for oncocytic carcinoma recurrence.

Thyroid lobectomy is recommended in cases where the cytology suggests a Bethesda 3 or 4 lesion.[12] This procedure also serves a diagnostic purpose, and if the lobectomy specimen indicates oncocytic thyroid carcinoma, a completion thyroidectomy is advised. In certain instances where the tumor is small and confined to 1 lobe of the thyroid, a lobectomy (removal of 1 lobe) may be considered. Nevertheless, due to the aggressive nature of oncocytic carcinoma and the potential for multifocality, total thyroidectomy is often the preferred option.(A1)

Additionally, therapeutic neck dissection of the central and lateral compartments should be performed for clinically positive lymph nodes.[12] (A1)

Medical Treatment

After total thyroidectomy, patients require thyroid hormone replacement, usually with levothyroxine. Levothyroxine is dosed to suppress thyroid-stimulating hormone (TSH) production, potentially reducing the risk of residual cancer growth. The degree of TSH suppression is based on the risk of tumor recurrence. 

Currently, guidelines regarding the postoperative use of radioactive iodine (RAI) are inconsistent. The largest study to date found no improvement in disease-specific or overall survival with the addition of RAI to surgery, even in patients at high risk for recurrence. Occasionally, patients have tumors that concentrate iodine. RAI may be applicable in these patients, and a sodium iodide I 123 or I 131 uptake study can help identify patients who are candidates for ablation. 

For patients with metastatic oncocytic carcinoma who are asymptomatic and have well-differentiated tumors with slow-growing disease, observation is an acceptable option as long as they do not have brain metastases. However, for patients with symptoms or rapidly growing metastatic tumors that respond to iodine treatment, RAI is a preferable option. If the patient's tumor is not suitable for RAI, systemic therapy with tyrosine kinase inhibitors (eg, lenvatinib or sorafenib) is considered.[13][14] Lenvatinib is preferred over sorafenib due to its better adverse effect profile. However, because oncocytic cell tumors are rare, most of the data for using tyrosine kinase inhibitors in metastatic disease is extrapolated from other thyroid carcinomas.[12](A1)

The molecular analysis of these cancers can be beneficial. Larotrectinib or entrectinib can be used for cancers with neurotrophic tyrosine receptor kinase (NTRK) fusion, and pembrolizumab can be used for patients with a high tumor mutation burden, regardless of the cancer type.[15][16] Selpercatinib and pralsetinib are helpful for patients with non-small cell lung cancers and thyroid carcinomas with RET fusions and can be used as a first-line treatment for patients with this mutation.[17][18][19] Most patients with RET fusions have medullary thyroid carcinoma, but the findings can be applied to oncocytic thyroid carcinomas with RET fusions. While cytotoxic chemotherapy has been used in small studies, it has not been shown to benefit patients with oncocytic carcinoma significantly and is typically used as a last resort.[20]

Radiation Treatment

If surgical resection is not possible or contraindicated, particularly if the cancer has spread beyond the thyroid and threatens vital structures, then external beam radiation therapy or intensity-modulated radiation therapy can be considered.[21][22][23][2](B2)

Monitoring and Follow-Up

Regular follow-up care is crucial for patients treated for oncocytic carcinoma. This typically includes physical examinations, neck ultrasounds, and monitoring of serum thyroglobulin levels. Patients should be educated about the signs of recurrence, eg, new lumps in the neck or voice changes. The frequency and type of follow-up imaging and laboratory testing will depend on individual risk factors and the initial treatment approach.

Differential Diagnosis

Differential diagnoses that should be considered when evaluating oncocytic thyroid cancer include:

• Benign oncocytic adenoma
• Follicular thyroid cell carcinoma
• Papillary thyroid carcinoma
• Thyroid lymphoma
• Medullary thyroid carcinoma
• Parathyroid neoplasms
• Anaplastic thyroid carcinoma
• Thyroiditis
• Metastatic disease
• Goiter

Staging

Staging of oncocytic thyroid cancer utilizes the tumor, node, metastasis (TNM) system from the American Joint Committee on Cancer (AJCC), with specific criteria tailored for this subtype. T staging categorizes tumors based on size and local extension: T1 indicates tumors ≤2 cm, T2 for those >2 cm but ≤4 cm, T3 for tumors >4 cm or with extrathyroidal extension, and T4 for any tumor with significant invasion into adjacent structures. N staging assesses regional lymph node involvement, where N0 indicates no nodal involvement, N1a involves level VI (ie, pretracheal and paratracheal) nodes, and N1b includes lateral neck nodes. M staging denotes distant metastasis, with M0 indicating no distant spread and M1 for distant metastasis.

Age also influences the stage of oncocytic thyroid malignancies. Patients 55 or older are classified under a different prognostic category, often leading to a higher stage classification due to their increased risk of aggressive disease. Accurate staging is essential for guiding treatment decisions and predicting outcomes in oncocytic thyroid cancer.[12]

Prognosis

The prognosis of oncocytic carcinoma is influenced by various clinical, pathological, and socioeconomic factors, reflecting its relatively aggressive nature compared to other differentiated thyroid cancers. The 10-year survival rate for patients with oncocytic carcinoma can exceed 90%, especially when detected early and managed effectively.[24] However, prognosis declines significantly for those with advanced disease or unfavorable characteristics.

A key prognostic indicator is tumor size. Tumors larger than 4 cm (classified as T3 or T4) are associated with a higher risk of metastasis and recurrence. Additionally, extrathyroidal extension correlates with poorer outcomes, particularly when involving adjacent structures. Age is also a crucial prognostic factor. Patients diagnosed at age 55 or older face a higher risk of aggressive disease progression, often exacerbated by comorbidities and the effects of biological aging.

Lymph node involvement is another critical consideration. Patients with regional lymph node metastases (ie, N1a or N1b) have increased recurrence risks and lower survival rates. Additionally, vascular invasion—where cancer cells invade blood vessels—significantly predicts poor prognosis and higher rates of distant metastasis.[7] Long-term follow-up is essential due to the potential for late recurrence. The American Thyroid Association (ATA) risk stratification system is commonly used by clinicians postsurgery to predict disease recurrence and guide surveillance.[25][5]

Regular monitoring through ultrasound and serum thyroglobulin levels is vital for early detection of recurrence, which can improve management outcomes. While oncocytic carcinoma presents significant prognostic challenges, timely and personalized treatment approaches can improve outcomes.

Complications

Complications associated with oncocytic thyroid cancer can arise from both the disease and its treatment. A significant concern is local invasion, which may compress surrounding structures such as the trachea, esophagus, or recurrent laryngeal nerve. This compression can lead to symptoms, including difficulty swallowing, breathing problems, or hoarseness. Oncocytic carcinoma also tends to spread through the lymphatic system, resulting in swollen lymph nodes and potential surgical complications if lymph node dissection is necessary. Additionally, the disease can spread to distant sites, such as the lungs and bones, making management and prognosis more challenging.

While often necessary, surgical intervention carries a risk for complications, including bleeding, infection, and damage to adjacent tissues or nerves. Patients may also experience long-term issues related to thyroid hormone management postthyroidectomy, including hypothyroidism and the need for lifelong hormone replacement therapy. The potential for the cancer to come back adds a psychological burden, requiring ongoing monitoring and follow-up, which can contribute to anxiety and uncertainty. Therefore, a comprehensive approach to management is essential to address these multifaceted complications associated with oncocytic thyroid carcinoma.