Oncocytic Thyroid TumorsEdit

Oncocytic thyroid tumors are a distinct group of thyroid neoplasms defined by the predominance of oncocytic (Hurthle) cells. These cells are large, polygonal, with abundant eosinophilic, granular cytoplasm resulting from an accumulation of mitochondria. The spectrum includes benign lesions, typically called Hurthle cell adenomas, and malignant lesions, known as Hurthle cell carcinomas. The oncocytic phenotype can arise in the context of other thyroid neoplasms as well, including rare oncocytic variants of papillary thyroid carcinoma, but the classic dichotomy in this family is adenoma versus carcinoma based on invasion. The topic intersects pathology, surgical management, and clinical follow-up, with ongoing debates about diagnostic criteria and optimal treatment strategies.

Thyroid tumors with oncocytic differentiation account for a minority of thyroid neoplasms, with clinical behavior that ranges from indolent in some adenomas to potentially aggressive in carcinomas. The biology of these tumors is influenced by distinctive cellular metabolism and genetic features, which also shape how clinicians approach diagnosis, staging, and treatment. Because FNA cytology alone often cannot reliably distinguish adenoma from carcinoma in this group, definitive diagnosis usually relies on histopathologic examination after surgical resection, together with an assessment of invasion and other high-risk features. Throughout the literature, the emphasis is on integrating morphology, imaging, and selective molecular data to guide management and prognosis. Papillary thyroid carcinoma Follicular thyroid carcinoma Thyroid cancer

Overview

Oncocytic thyroid tumors are characterized by cells with abundant cytoplasm rich in mitochondria and a granular appearance. They can arise within the thyroid gland as solitary nodules or as part of a broader thyroid disease process. The main subtypes in surgical pathology are:

Hurthle cell adenoma (benign)
Hurthle cell carcinoma (malignant)

In addition, there is a oncocytic variant of other thyroid carcinomas, most notably Papillary thyroid carcinoma; these entities share the cytologic hallmark of oncocytic cells but differ in architectural patterns and behavior. The distinction between adenoma and carcinoma hinges on evidence of invasion: capsular invasion and/or vascular invasion define malignancy in this setting. The terminology and criteria are codified in major reference works such as the World Health Organization classifications and national guidelines like the American Thyroid Association guidelines. Hurthle cell Capsular invasion Vascular invasion

Classification and terminology

Terminology centers on the presence of oncocytic (Hurthle) cells and on invasion. The principal categories are:

Hurthle cell adenoma: a benign lesion composed of Hurthle cells without true capsular or venous invasion.
Hurthle cell carcinoma: a malignant neoplasm showing capsular invasion, vascular invasion, or both.

Some tumors show oncocytic differentiation within a non-Hurthle follicular or papillary architecture; in such cases, the tumor may be categorized primarily by its dominant pattern (follicular- or papillary-type) with an oncocytic histology component. In addition, a small subset of tumors displays oncocytic features within a papillary thyroid carcinoma framework, referred to as the oncocytic variant of papillary carcinoma. The criteria for malignancy in Hurthle cell tumors mirror those used for follicular-pattern carcinomas, emphasizing invasion rather than cytologic atypia alone. For example, the presence of capsular invasion or vascular invasion upgrades a lesion to carcinoma in the appropriate context. Hurthle cell adenoma Hurthle cell carcinoma Papillary thyroid carcinoma Follicular thyroid carcinoma Capsular invasion Vascular invasion

Pathology

Gross pathology: Hurthle cell adenomas and carcinomas typically present as well-circumscribed thyroid nodules. Carcinomas may show irregular margins or invasiveness at the periphery on gross examination.
Microscopic features: Oncocytic cells have abundant granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Architectural patterns may be follicular, solid, or mixed. The decisive pathologic criterion for malignancy is invasion:
- Capsular invasion: tumor cells penetrating the capsule surrounding the nodule.
- Vascular invasion: tumor cells entering blood vessels within or beyond the capsule.
Immunohistochemistry: Tumor cells often express thyroid lineage markers such as TTF-1 and thyroglobulin; the abundant mitochondria can be demonstrated with mitochondrial markers, reflecting the oncocytic phenotype. The histology must be integrated with clinical and radiologic data to determine prognosis and treatment implications. Thyroglobulin TTF-1 Mitochondria

Diagnosis and imaging

Fine-needle aspiration (FNA): While helpful for initial assessment, FNA cytology often cannot reliably distinguish Hurthle cell adenoma from Hurthle cell carcinoma because invasion is a histologic criterion not assessable on FNA. Therefore, definitive classification frequently requires surgical excision and thorough histologic evaluation. Fine-needle aspiration
Core needle biopsy: May aid in sampling architecture in select cases but likewise cannot substitute for invasion assessment.
Imaging: Ultrasound and cross-sectional imaging help characterize nodule size, margins, and extrathyroidal extension, and they guide surgical planning. Nuclear medicine studies assessing iodine uptake can be variable in Hurthle cell tumors and influence decisions about radioactive iodine therapy. Ultrasound Iodine uptake Radioactive iodine therapy

Genetics and molecular features

The oncocytic phenotype is associated with distinctive molecular and metabolic features:

Mitochondrial genome alterations are common in Hurthle cell tumors and relate to the eosinophilic cytoplasm. This mitochondrial proliferation underpins much of the histologic appearance. Mitochondria Mitochondrial DNA
Nuclear gene mutations: RAS family mutations (e.g., NRAS, HRAS) and other alterations can occur in Hurthle cell tumors, with mutational patterns differing from non-oncocytic thyroid cancers. PAX8/PPAR gamma rearrangements have also been reported in a subset of Hurthle cell lesions. The exact frequency and diagnostic utility remain an area of active study. RAS mutation PAX8/PPAR gamma rearrangement
The molecular landscape helps explain why oncocytic tumors can behave differently from classic papillary or follicular thyroid carcinomas, and it informs ongoing debates about risk stratification and targeted approaches. Thyroid cancer

Management and prognosis

Surgical management: The mainstay of treatment for Hurthle cell adenoma is surgical excision, often a lobectomy, while Hurthle cell carcinoma typically requires more extensive surgery, potentially including total thyroidectomy and regional lymph node assessment, depending on invasion, size, and staging. decisions about adjuvant therapy are influenced by risk assessment. Thyroidectomy
Radioiodine therapy: Hurthle cell carcinomas frequently show reduced or absent iodine uptake compared with some other differentiated thyroid cancers, which can limit the effectiveness of radioactive iodine therapy. Nevertheless, selected higher-risk patients may still receive adjuvant or ablative iodine treatment. Follow-up relies on careful thyroglobulin surveillance and imaging as appropriate. Radioactive iodine therapy Thyroglobulin
Prognosis: Prognosis hinges on invasion, tumor size, age, and the presence of metastasis. While some Hurthle cell adenomas behave in a very indolent fashion, Hurthle cell carcinomas carry a risk of local recurrence and distant spread, with outcomes generally favorable in early-stage disease but variable in advanced cases. The literature reflects ongoing refinement of risk stratification comparing oncocytic to non-oncocytic thyroid cancers. Prognosis Lymph node metastasis

Controversies and debates

Malignancy criteria and classification: A central debate concerns whether invasion alone should drive the carcinoma designation in Hurthle cell tumors, given that cytology and encapsulation alone may be insufficient to predict behavior. Some clinicians and pathologists emphasize strict capsular/vascular invasion as the sole criteria, aligning with standards used for follicular-type thyroid carcinomas, while others argue for broader criteria or incorporation of molecular risk features to better predict outcomes. This discussion has practical implications for surgical planning and adjuvant therapy. Capsular invasion Vascular invasion
Role of molecular data: There is ongoing discussion about the incremental value of molecular testing in risk stratification for Hurthle cell lesions. While certain mutations are associated with oncocytic neoplasia, routine testing is not uniformly adopted in all guidelines, and decisions remain individualized. RAS mutation PAX8/PPAR gamma rearrangement
Management variability across guidelines: The approach to imaging, extent of surgery, and use of radioactive iodine therapy can vary by country and by guideline in effect at the time. This reflects evolving evidence about prognosis, iodine uptake, and the biology of oncocytic tumors. Clinicians weigh histology, imaging, and patient factors in shared decision-making under guideline frameworks such as those from American Thyroid Association and other thyroid-focused bodies. American Thyroid Association