Introduction
Hürthle cell carcinoma (HCC) is a rare subtype of thyroid carcinoma that arises from Hürthle cells, also known as oncocytic cells. These cells are characterized by abundant granular eosinophilic cytoplasm, a result of increased mitochondrial content. HCC was previously considered a variant of follicular thyroid carcinoma but is now recognized as a distinct clinical and pathological entity due to its unique biological behavior, increased aggressiveness, and reduced sensitivity to radioactive iodine therapy.
Although HCC represents only about 3–5% of all differentiated thyroid cancers, it is clinically significant because of its higher risk of recurrence, metastasis, and resistance to conventional treatments compared with papillary or follicular thyroid carcinoma.
Pathogenesis and Molecular Features
Hürthle cell carcinoma develops from thyroid follicular epithelial cells through oncocytic transformation. This transformation is associated with mitochondrial dysfunction and increased oxidative stress. The exact molecular pathogenesis is not fully understood, but several genetic alterations have been implicated:
- Mitochondrial DNA mutations – Common in HCC and contribute to the oncocytic phenotype.
- Nuclear gene mutations – Including alterations in TP53, NRAS, and PTEN, which may contribute to tumor progression.
- TERT promoter mutations – Associated with aggressive tumor behavior and poor prognosis.
- PI3K/AKT/mTOR pathway activation – Plays a role in oncogenic signaling.
Unlike papillary thyroid carcinoma, BRAF V600E mutations are uncommon in HCC.
Epidemiology
Hürthle cell carcinoma is more frequently diagnosed in:
- Older patients (peak incidence in the 50–70 age range).
- Females, with a female-to-male ratio of approximately 2:1.
- Regions with iodine deficiency, although the exact relationship remains unclear.
Clinical Presentation
Patients with HCC usually present with:
- A thyroid nodule, often unilateral.
- Neck mass or swelling that may be palpable.
- Occasionally, symptoms of compression such as dysphagia, hoarseness, or dyspnea in cases of large tumors.
- Rarely, metastatic disease at initial diagnosis, commonly involving lungs, bones, and lymph nodes.
Diagnostic Evaluation
Physical Examination and Laboratory Tests
- Most patients are euthyroid at presentation.
- Serum markers such as thyroglobulin may be elevated but are less reliable compared with other thyroid cancers.
Imaging
- Ultrasound (US) is the initial imaging modality, showing solid, hypoechoic nodules with irregular margins.
- CT or MRI may be used to assess extrathyroidal extension or distant metastasis.
- PET-CT is useful in identifying metastasis, especially in radioiodine-refractory disease.
Fine-Needle Aspiration Biopsy (FNAB)
FNAB is commonly performed, but distinguishing HCC from Hürthle cell adenoma cytologically is challenging. A definitive diagnosis of carcinoma requires histological evidence of capsular or vascular invasion.
Histopathological Features
- Oncocytic cells with abundant granular eosinophilic cytoplasm.
- Round nuclei with prominent nucleoli.
- Evidence of capsular or vascular invasion confirms malignancy.
- Classified into:
- Minimally invasive HCC – limited capsular invasion, better prognosis.
- Widely invasive HCC – extensive vascular invasion, associated with aggressive disease and poor outcomes.
Treatment
Surgical Management
- Total thyroidectomy is the preferred treatment, especially for tumors larger than 1 cm or with invasive features.
- Lobectomy may be considered for small, minimally invasive tumors without metastasis.
- Neck dissection is performed in cases with clinically evident lymph node metastasis.
Radioactive Iodine Therapy (RAI)
- HCC is generally less responsive to radioactive iodine than papillary or follicular thyroid carcinoma due to reduced iodine uptake by oncocytic cells.
- Selected patients may still benefit, particularly in cases of residual or recurrent disease.
External Beam Radiotherapy (EBRT)
- May be considered in cases of unresectable or recurrent disease, especially for locoregional control.
Systemic Therapy
- Tyrosine kinase inhibitors (TKIs) such as lenvatinib and sorafenib are approved for advanced, radioiodine-refractory thyroid carcinoma and have shown benefit in HCC.
- Clinical trials are ongoing to evaluate novel agents targeting mitochondrial pathways and PI3K/AKT/mTOR signaling.
Prognosis
Prognosis of HCC depends on the degree of invasion and stage at diagnosis:
- Minimally invasive HCC has an excellent prognosis, with a survival rate similar to that of follicular carcinoma.
- Widely invasive HCC has a poorer prognosis, with increased risk of recurrence and distant metastasis.
- Key prognostic factors include:
- Age of the patient
- Tumor size (>4 cm associated with worse outcomes)
- Degree of vascular invasion
- Presence of distant metastasis
Follow-Up and Surveillance
Long-term follow-up is essential, as recurrence may occur even after initial treatment. Follow-up strategies include:
- Neck ultrasound every 6–12 months.
- Serum thyroglobulin monitoring, although less reliable in HCC compared to other differentiated thyroid cancers.
- Cross-sectional imaging (CT, MRI, PET-CT) in high-risk patients or those with rising tumor markers.
Conclusion
Hürthle cell carcinoma is a distinct and clinically important subtype of thyroid carcinoma with unique biological features and reduced responsiveness to conventional radioactive iodine therapy. Early diagnosis, appropriate surgical management, and careful long-term surveillance are essential for improving patient outcomes. Advances in molecular research and targeted therapy are expected to improve prognosis for patients with advanced or refractory disease.
References
- Ganly I, Ricarte-Filho J, Eng S, et al. Genomic dissection of Hürthle cell carcinoma reveals a unique class of thyroid malignancy. J Clin Endocrinol Metab. 2013;98(5):E962–E972.
- Asa SL. The challenging thyroid carcinoma: Hürthle cell carcinoma. Mod Pathol. 2011;24(S2):S44–S50.
- Kushchayeva Y, Duh QY, Kebebew E, Clark OH. Hürthle cell carcinoma of the thyroid: diagnosis and management. Oncologist. 2008;13(5):459–464.
- Liu J, Singh B, Tallini G, et al. Follicular thyroid carcinoma and Hürthle cell carcinoma: molecular features and clinical implications. Endocr Pathol. 2017;28(2):101–110.
