Hürthle cells are enlarged thyroid cells packed with an unusual number of mitochondria, giving them a distinctive granular, pink appearance under a microscope. Finding them in a thyroid biopsy can mean anything from harmless inflammation to an aggressive cancer, which is exactly what makes them so frustrating for patients and pathologists alike. The context in which they appear matters far more than the cells themselves, and sorting out that context has become one of thyroid medicine’s more persistent puzzles.
What Makes a Hürthle Cell Different
Normal thyroid follicular cells contain a modest number of mitochondria, just enough to keep the cell’s energy supply humming. Hürthle cells, by contrast, are stuffed with them. Under an electron microscope, these mitochondria can be oval, rod-shaped, or elliptical, with internal structures (cristae) that sometimes take on a finger-like or net-like pattern rather than the usual neat stacks.1PubMed. Scanning electron microscopy of the interior of cells in Hürthle cell tumors The mitochondria themselves often show abnormalities in size, shape, and internal content.2PubMed. Hürthle-cell lesions of the thyroid: a combined study using transmission electron microscopy, scanning electron microscopy, and immunocytochemistry This mitochondrial overload is why Hürthle cells are technically classified as “oncocytes,” a broader term for any cell crammed with excess mitochondria regardless of which organ it appears in.
The sheer volume of mitochondria gives Hürthle cells their trademark look: large, polygonal cells with abundant granular cytoplasm that stains bright pink on standard tissue slides. A pathologist spotting them can recognize them at a glance. The challenge is figuring out what they mean in a given patient, because these cells show up in an unexpectedly wide range of thyroid conditions.
Why These Cells Accumulate So Many Mitochondria
The mitochondrial buildup in Hürthle cells is not random. Research points to a defect in the cell’s ability to clear out damaged mitochondria through a quality-control process called mitophagy. Normally, when a mitochondrion becomes damaged, a protein called Parkin tags it for destruction. In Hürthle cell tumors, Parkin expression is reduced and its function is impaired, sometimes due to a specific mutation that cripples its ability to tag defective mitochondria. The result is that broken mitochondria pile up instead of being recycled.3PubMed. Dysregulation of Parkin-mediated mitophagy in thyroid Hürthle cell tumors
On top of this recycling failure, the mitochondria themselves carry an unusual burden of DNA mutations. Every Hürthle cell tumor studied in one investigation harbored a relatively high percentage of mitochondrial DNA deletions, and tumors with certain mutations in genes responsible for energy production (particularly those in complex I and complex IV of the electron transport chain) were especially affected.4PubMed Central. Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors More recent genomic work confirmed that mutations knocking out complex I function were present in about half of Hürthle cell carcinomas studied, suggesting these mutations are not bystanders but actual drivers of the disease.5Cancer Cell. Genomic Dissection Reveals a Distinct Molecular Profile in Hürthle Cell Carcinoma of the Thyroid
The picture that emerges is a double hit: the mitochondria are damaged, and the cell’s cleanup crew is broken. The cell compensates by making even more mitochondria, perhaps trying to keep up with its energy needs, which only amplifies the distinctive oncocytic appearance.
When Hürthle Cells Are Not a Sign of Cancer
One of the most important things to understand is that Hürthle cells frequently appear in completely benign conditions. The most common setting is Hashimoto’s thyroiditis, the autoimmune condition that is the leading cause of hypothyroidism in many parts of the world. Chronic inflammation from Hashimoto’s triggers a process called Hürthle cell metaplasia, where normal thyroid cells transform into oncocytic cells.6PubMed Central. Malignancy risk for solitary and multiple nodules in Hürthle cell-predominant thyroid fine-needle aspirations: A multi-institutional study This transformation is also common in hyperplastic nodules, the lumpy overgrowths that develop when the thyroid is chronically stimulated.
This creates a real clinical headache. A needle biopsy of a thyroid nodule in someone with Hashimoto’s can yield a sample dominated by Hürthle cells, and the pathologist has to determine whether those cells represent the background inflammatory condition or an actual neoplasm sitting within it. Sometimes a focal nodule of Hürthle cell hyperplasia in Hashimoto’s thyroiditis looks almost identical to a Hürthle cell neoplasm on cytology.7PubMed Central. A focal nodular Hürthle cell hyperplasia in Hashimoto’s thyroiditis: A diagnostic dilemma on fine needle aspiration The cells themselves look the same in both situations, so a pathologist relies heavily on the overall pattern: are there mixed inflammatory cells and colloid in the background (suggesting Hashimoto’s), or is it a monotonous sheet of Hürthle cells with architectural atypia (suggesting a neoplasm)?
The Diagnostic Gray Zone
Even among experienced pathologists, Hürthle cell specimens generate significant disagreement. Fine-needle aspiration of the thyroid is the standard first-line diagnostic tool, but when the sample is dominated by Hürthle cells, the diagnostic accuracy drops and interobserver variability climbs.8PubMed Central. Challenges in Cytology Specimens With Hürthle Cells The core problem is that Hürthle cells can look essentially identical whether they come from a benign adenoma, a carcinoma, or an inflamed thyroid gland. Preoperative classification is genuinely difficult.9PubMed. The diagnostic accuracy of fine-needle cytology of Hurthle cell lesions; A comprehensive cytological, clinical and ultrasonographic experience
Under the Bethesda System for Reporting Thyroid Cytopathology, many Hürthle cell-predominant biopsies fall into indeterminate categories (categories III and IV), meaning they are neither clearly benign nor clearly malignant. This puts patients in a frustrating limbo: the biopsy cannot rule out cancer, but it also cannot confirm it. Historically, the only way to get a definitive answer was surgery, which meant many patients underwent thyroid operations only to learn afterward that their nodules were benign.
Telling Benign from Malignant After Surgery
The definitive distinction between a Hürthle cell adenoma and a Hürthle cell carcinoma can only be made by a pathologist examining the entire excised tumor. The critical features are capsular invasion and vascular invasion. A Hürthle cell adenoma is encapsulated and shows no invasion into surrounding tissue. If the tumor shows invasion of its capsule or blood vessels, it is classified as carcinoma.10PubMed Central. Thyroid Hürthle Cell Carcinoma: Clinical, Pathological, and Molecular Features The degree of invasion matters for prognosis: minimally invasive carcinomas have fewer than four foci of capsular or vascular invasion, while widely invasive carcinomas show extensive invasion. To qualify as a Hürthle cell tumor in the first place, the mass must be composed of more than 75% oncocytic (Hürthle) cells.11PubMed. Prognostic factors of recurrence in encapsulated Hurthle cell carcinoma of the thyroid gland: a clinicopathologic study of 50 cases
This reliance on capsular and vascular invasion explains why needle biopsy alone cannot make the call. A needle samples a tiny sliver of the tumor and cannot assess the capsule’s integrity or look for blood vessel involvement. The question of benign versus malignant is fundamentally an architectural one that requires the whole specimen.
What Genomics Has Revealed
Until recently, Hürthle cell carcinoma was grouped with follicular thyroid carcinoma, essentially treated as a variant. Landmark genomic studies published in 2018 upended that view. Researchers found that the majority of Hürthle cell carcinomas harbor a strikingly unusual chromosomal landscape: widespread losses of entire chromosomes, resulting in a near-haploid state (where the cell has lost one copy of most chromosome pairs) in over half of cases.12PubMed Central. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma This pattern of genome-wide loss of heterozygosity is essentially unique to Hürthle cell carcinoma among thyroid cancers.13Cancer Discovery. Hürthle Cell Carcinomas Exhibit Widespread Loss of Heterozygosity
A parallel study confirmed these findings and added another distinctive feature: whole-chromosome duplications of chromosomes 5 and 7, along with copy-number-neutral events where both copies of a chromosome come from a single parent.14PubMed Central. Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes These genomic features do not resemble what is seen in papillary thyroid cancer or conventional follicular thyroid cancer. The World Health Organization responded by reclassifying Hürthle cell (oncocytic) carcinoma as its own distinct tumor type in the 2022 classification of thyroid tumors, rather than treating it as a subtype of follicular carcinoma.15PubMed. The 2022 WHO classification of thyroid tumors: novel concepts in nomenclature and grading
The near-haploid state itself appears to carry prognostic significance, with tumors showing this pattern associated with worse outcomes. This genomic work has begun reshaping how clinicians think about Hürthle cell carcinoma’s biology and may eventually influence treatment decisions.
How Molecular Testing Helps (and Where It Struggles)
Molecular testing on needle biopsy specimens has transformed the management of indeterminate thyroid nodules over the past decade, often sparing patients from unnecessary surgery. For Hürthle cell nodules specifically, current molecular tests have shown a high rate of benign results, which strengthens their value in helping patients avoid operations they do not need.16PubMed. Diagnostic performance of molecular testing in indeterminate (Bethesda III and IV) thyroid nodules with Hürthle cell cytology
However, Hürthle cell predominance has historically been a weak spot for molecular classifiers. One study comparing earlier versions of two widely used tests found that the gene expression classifier flagged about two thirds of Hürthle cell-predominant nodules as “suspicious,” compared with under half of non-Hürthle cell nodules, yet the actual malignancy rate in the surgically removed Hürthle cell nodules was lower (around 16%) than in the non-Hürthle cell group (around 33%).17PubMed. Hurthle cell predominance impacts results of Afirma gene expression classifier and ThyroSeq molecular panel performance in indeterminate thyroid nodules In other words, the test was more likely to raise a red flag for Hürthle cell nodules, but those red flags were less likely to correspond to actual cancer. The unique biology of Hürthle cells, particularly their chromosomal alterations, complicated the algorithms. Newer test versions have been refined to account for this, though clinicians interpreting molecular results for Hürthle cell nodules still need to factor in this history.
Treatment and the Surgery Question
For confirmed Hürthle cell carcinoma, surgery is the primary treatment. The traditional recommendation has been total thyroidectomy for carcinomas and lobectomy (removing half the thyroid) for adenomas. Because the distinction between the two often cannot be made before or during surgery, surgeons have generally recommended a more aggressive approach for larger nodules. Data have shown that tumor size predicts malignancy: for neoplasms larger than 4 centimeters, definitive resection involving both thyroid lobes should be considered because the probability of malignancy is substantially higher.18PubMed Central. Hürthle cell neoplasms of the thyroid: are there factors predictive of malignancy?
More recent evidence has begun to challenge the reflexive total thyroidectomy approach. A matched cohort analysis found that hemithyroidectomy (removing only the affected lobe) did not worsen recurrence-free survival or overall survival compared with total thyroidectomy for Hürthle cell carcinoma.19Surgical Oncology Insight. Hürthle cell (Oncocytic) carcinoma – Is hemithyroidectomy enough? This finding aligns with a broader trend in thyroid surgery toward more conservative operations for low-risk differentiated cancers, though the decision still depends on tumor size, invasion extent, and patient-specific factors.
One complication particular to Hürthle cell carcinoma is its tendency to be less responsive to radioactive iodine therapy than other differentiated thyroid cancers. Hürthle cell carcinomas often do not concentrate iodine efficiently, which limits the usefulness of the post-surgical radioactive iodine treatment that is standard for many thyroid cancers. However, these tumors do show intense uptake on FDG-PET imaging, a metabolic scan that detects glucose-hungry cells. PET imaging has been shown to improve disease detection and management in Hürthle cell carcinoma compared with anatomic imaging or iodine scans alone.20PubMed. 18F-FDG PET of patients with Hürthle cell carcinoma This inverse relationship, where iodine imaging is weak but PET imaging is strong, is a clinically useful feature that helps guide surveillance.
Prognosis and What Drives It
Overall, Hürthle cell carcinoma carries a prognosis that is somewhat less favorable than the most common thyroid cancers (papillary and follicular) but still far better than many other solid tumors. A population-based study of over 4,600 patients found ten-year overall survival of about 78% and disease-specific survival (deaths from the cancer itself, excluding other causes) of roughly 92%.21PubMed. Prognostic factors and survival analysis of Hurthle cell carcinoma: A population-based study An earlier analysis reported five-year survival around 85% and ten-year survival around 71%, with increasing age at diagnosis, male sex, and larger tumor size emerging as statistically significant predictors of worse outcomes on multivariate analysis.22Archives of Otolaryngology–Head & Neck Surgery. Survival and Prognosis in Hürthle Cell Carcinoma of the Thyroid Gland
The spread in survival figures between studies likely reflects differences in patient populations and time periods. What both analyses agree on is that the widely invasive subtype carries significantly worse outcomes than minimally invasive disease. This is why the pathological distinction between minimally and widely invasive disease, based on those foci of capsular and vascular invasion described earlier, has real consequences for patients and their follow-up schedules.
Targeted Therapy for Advanced Disease
For the minority of patients whose Hürthle cell carcinoma progresses despite surgery and is not responsive to radioactive iodine, targeted therapies have become an option. Tyrosine kinase inhibitors such as lenvatinib and sorafenib, originally approved for radioactive-iodine-refractory differentiated thyroid cancer broadly, have shown activity in Hürthle cell carcinoma specifically. In one documented case, a patient who progressed on sorafenib was switched to lenvatinib and experienced radiological stability with some shrinkage of lung metastases, along with declining tumor markers.23PubMed Central. Lenvatinib-induced multiorgan adverse events in Hurthle cell thyroid cancer: A case report These drugs are not curative for advanced disease, but they can slow progression substantially. Research into more precisely targeted therapies, guided by the distinctive genomic features like mitochondrial complex I mutations and near-haploid chromosomal states, is ongoing.
Hürthle Cells in Children and Younger Patients
Thyroid nodules are uncommon in children compared to adults, and Hürthle cell tumors specifically account for fewer than 5% of thyroid neoplasms in the pediatric population. Case reports exist of Hürthle cell neoplasms in patients as young as 12 years old.24PubMed. Report of a hürthle cell neoplasm in a peripubertal girl While thyroid nodules in children carry a higher risk of malignancy overall compared to adults, the rarity of Hürthle cell tumors in this age group means the evidence base is thin, consisting mainly of isolated case reports rather than large studies. The same diagnostic challenges that make Hürthle cell lesions difficult in adults apply in pediatric cases, compounded by the general unfamiliarity most pediatric specialists have with these uncommon tumors.
Oncocytic Cells Beyond the Thyroid
The oncocytic transformation that defines Hürthle cells is not unique to the thyroid. The same mitochondria-packed cell type appears in tumors of the kidney, salivary glands, adrenal cortex, and parathyroid glands.25International Journal of Surgical Pathology. Oncocytic lesions of the thyroid, kidney, salivary glands, adrenal cortex, and parathyroid glands What these organs have in common is a relatively low cellular turnover rate, which may create conditions favorable for the gradual accumulation of mitochondrial defects over time. In the kidney, oncocytic tumors (oncocytomas) are typically benign, while in the salivary glands, the behavior can range from benign to malignant, mirroring the spectrum seen in the thyroid. The term “Hürthle cell” is reserved specifically for thyroid oncocytes by convention, even though the underlying biology is shared across organs. Understanding this broader pattern has helped researchers see Hürthle cell transformation as a general cellular response to mitochondrial dysfunction rather than something peculiar to the thyroid alone.