Oncocytic neoplasms are not inherently benign or cancerous. They span a spectrum from completely harmless growths to aggressive malignancies, and the answer depends heavily on where in the body the tumor arises and what the pathologist sees under the microscope. A renal oncocytoma in the kidney is almost always benign, while an oncocytic carcinoma of the thyroid (historically called Hürthle cell carcinoma) can metastasize and threaten life. The shared thread is a distinctive cell type stuffed with mitochondria, but the biology and behavior of these tumors vary enormously from one organ to the next.
What Makes a Tumor “Oncocytic”
The term “oncocytic” describes the cells themselves, not whether the growth is dangerous. Oncocytes are cells whose cytoplasm is crammed with mitochondria, the tiny structures that generate energy inside cells. Under a microscope, this gives them a characteristic granular, pink-staining appearance that pathologists recognize immediately.1PubMed. Aneuploidy in oncocytic lesions of the thyroid gland: diffuse accumulation of mitochondria within the cell is associated with trisomy 7 and progressive numerical chromosomal alterations You may also see these cells referred to as oxyphils, Hürthle cells (in the thyroid), or Ashkanazy cells, all of which are essentially different names for the same phenomenon.2PubMed Central. Oncocytic Change in Thyroid Pathology The interchangeable terminology has been a source of confusion in medicine for decades.3PubMed Central. Hurthle Cell Lesion: Controversies, Challenges, and Debates
The mitochondrial buildup appears to be driven, at least in part, by mutations in mitochondrial DNA. In renal oncocytomas, researchers have found that mutations in genes encoding parts of the cell’s energy-producing machinery (specifically complex I of the respiratory chain) are common, effectively crippling normal energy production and triggering the cell to compensate by producing more and more mitochondria.4PubMed. Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma In thyroid oncocytic tumors, similar disruptive mitochondrial DNA mutations have been identified as a hallmark of the oncocytic phenotype.5PubMed Central. Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors The important takeaway is that this mitochondrial overload is the signature of the cell type, not a marker of malignancy. A cell can be oncocytic and perfectly benign, or oncocytic and cancerous.
Renal Oncocytoma: Almost Always Benign
In the kidney, oncocytoma is one of the most common benign solid tumors. A landmark study of 70 renal oncocytomas found that after an average follow-up of nearly five years, 89% of patients were alive with no evidence of disease and another 9% had died of unrelated causes. Only two patients in the entire series experienced metastatic disease, one of whom was alive and stable nearly five years after diagnosis.6The American Journal of Surgical Pathology. Renal Oncocytoma: A Clinicopathologic Study of 70 Cases So while metastasis is technically possible, it is exceptionally rare.
The real problem with renal oncocytomas is not their behavior but their appearance on scans. On CT and MRI, they closely mimic renal cell carcinoma, a potentially lethal kidney cancer. Because imaging alone cannot reliably tell the two apart, many patients end up having surgery for what turns out to be a benign tumor.7PubMed Central. Oncocytoma: A Differential Consideration for an Incidentally Detected FDG-Avid Renal Mass on PET/CT One particularly tricky distinction is between renal oncocytoma and chromophobe renal cell carcinoma, a low-grade kidney cancer. Both tumors can look similar on biopsy and even share some of the same staining patterns on pathology slides.8European Urology Open Science. Differentiating Oncocytic Renal Tumors from Chromophobe Renal Cell Carcinoma: Comparison of Peak Early-phase Enhancement Ratio to Clinical Risk Factors and Rater Predictions
The World Health Organization’s updated classification of kidney tumors now recognizes a broader spectrum of oncocytic renal neoplasms, including newer categories like low-grade oncocytic tumors and eosinophilic vacuolated tumors. These newly defined entities are distinguishable from other oncocytic tumors under the microscope and tend to behave indolently.9PubMed. Renal Oncocytic Neoplasms: Review of Classification Updates, Imaging, and Management The expanding classification reflects a growing understanding that the old binary of “oncocytoma versus cancer” was too simplistic.
Thyroid Oncocytic Tumors: A Wider Range of Outcomes
The thyroid is where the oncocytic spectrum creates the most clinical anxiety. Oncocytic thyroid tumors can be benign adenomas, which are encapsulated and harmless, or they can be carcinomas (the renamed Hürthle cell carcinoma), which are capable of invading surrounding tissue, spreading to lymph nodes, and metastasizing to distant organs. Among differentiated thyroid cancers, oncocytic carcinoma has the highest rate of metastasis: roughly 10 to 20% of patients already have distant spread at the time of diagnosis, and the overall lifetime metastasis rate reaches about 34%.10AACR Journals (Cancer Research). Abstract 5082: Novel TSHR CAR T therapy for targeting oncocytic carcinoma
Distinguishing the benign adenoma from the carcinoma before surgery is frustratingly difficult. A retrospective study comparing the two found that carcinomas tended to be larger (averaging about 4 cm versus about 3 cm on ultrasound) and more likely to show internal blood flow and certain architectural patterns. But standard thyroid ultrasound scoring systems had mixed success. One widely used system did categorize more carcinomas into higher-risk groups, but another performed no better than chance at telling the two apart.11PubMed Central. Differentiating oncocytic carcinoma from oncocytic adenoma: a comprehensive evaluation of preoperative characteristics and diagnostic approaches in a retrospective cohort study On fine-needle aspiration biopsy, the standard first-line test for thyroid nodules, definitive classification is challenging because oncocytic changes appear in both benign and malignant settings.12Diagnostic Cytopathology. A case series of thyroid fine needle aspiration biopsies diagnosed as follicular neoplasm with oncocytic features The upshot is that many patients with oncocytic thyroid nodules end up having surgery partly for diagnostic reasons: the pathologist needs the whole tumor, not just a needle sample, to determine whether capsular or vascular invasion is present.
A further complication is that oncocytic thyroid carcinomas are less responsive to radioactive iodine therapy than other differentiated thyroid cancers, partly because the oncocytic cells tend to take up iodine less efficiently. Despite this, population-level data suggest that radioactive iodine treatment is associated with improved survival for these patients, particularly those with tumors larger than 2 cm or with nodal and distant metastatic disease.13PubMed. Radioactive Iodine Treatment Is Associated with Improved Survival for Patients with Hürthle Cell Carcinoma Guidelines remain inconsistent about when to use it, which means treatment varies from one institution to the next.
Oncocytic Tumors in Other Organs
Oncocytic neoplasms pop up across the body, and each location has its own behavioral tendencies.
In the salivary glands, oncocytomas are rare and overwhelmingly benign. They account for less than 2% of all neoplasms in the oral cavity and have less than a 1% chance of malignant transformation. They predominantly affect the major salivary glands and are more common in women.14PubMed Central. Oncocytoma of the parotid gland: A rare benign tumour The Warthin tumor, another salivary gland tumor rich in oncocytic cells, is similarly benign and arises almost exclusively in the parotid gland.15PubMed Central. Warthin tumor of the oropharyngeal minor salivary gland
In the adrenal glands, oncocytic tumors present a classification challenge of their own. Pathologists use a system called the Lin-Weiss-Bisceglia (LWB) criteria to sort these tumors into three bins: benign oncocytoma, borderline (uncertain malignant potential), or malignant. The major criteria for malignancy include a high rate of cell division, abnormal cell division patterns, and invasion into veins. Minor criteria include large tumor size, necrosis, and invasion into the capsule or sinusoids. A tumor with even one major criterion is classified as malignant, while a tumor with only minor criteria falls into the uncertain category.16AACE Clinical Case Reports. Adrenocortical Oncocytoma With Borderline Malignant Potential Causing Subclinical Cushing Syndrome Imaging is no help here: CT and MRI cannot reliably differentiate benign from malignant adrenal oncocytic tumors using the same criteria that work for other adrenal masses.17PubMed. Oncocytic neoplasms of the adrenal gland Recent research has also raised concerns that the LWB system may not fully capture aggressiveness, since necrosis, currently only a minor criterion, was found to be associated with disease recurrence in tumors classified as borderline.18PubMed Central. Limitation of the current Lin-Weiss-Bisceglia criteria in predicting poor prognosis in oncocytic adrenocortical neoplasms of uncertain malignant potential and oncocytoma diagnosed by the Lin-Weiss-Bisceglia criteria
In the pancreas, a distinct entity called intraductal oncocytic papillary neoplasm (IOPN) straddles the line. A systematic review of over 300 cases found that about half harbored an associated invasive carcinoma at the time of surgical removal. However, these invasive components were typically small and early-stage, and more than 90% of patients were alive after surgery.19PubMed. Comprehensive Characterization of Intraductal Oncocytic Papillary Neoplasm of the pancreas: A Systematic and Critical Review A smaller study of 24 cases found an even lower rate of unequivocal invasion at 29%, noting that these tumors often grew along existing ducts in a way that could mimic invasion without actually being invasive.20PubMed Central. Intraductal Oncocytic Papillary Neoplasms: Clinical-Pathologic Characterization of 24 Cases, With An Emphasis on Associated Invasive Carcinomas The overall prognosis after surgery is good, but the high frequency of associated carcinoma means these pancreatic tumors are managed more aggressively than, say, a salivary gland oncocytoma.
Why Diagnosis Is So Difficult
A recurring theme across every organ is that oncocytic tumors are easier to identify as oncocytic than to classify as benign or malignant. The mitochondria-packed cells look distinctive, but distinguishing a benign growth from a cancer within the oncocytic family often requires the full surgical specimen, not just a biopsy sample. In the thyroid, needle biopsies frequently return an ambiguous “follicular neoplasm with oncocytic features” result that does not resolve the question of malignancy. In the kidney, needle biopsies face their own limitations: for smaller masses under 5 cm, the diagnostic yield and sensitivity of fine-needle aspiration are low enough that the test rarely changes management.21PubMed. Evaluation of fine-needle aspiration cytology for renal masses
Core biopsies, which take a thicker sample than fine-needle aspiration, have improved the picture for renal tumors somewhat. But even with a core biopsy, telling a renal oncocytoma from chromophobe renal cell carcinoma can be impossible on tissue architecture alone, because the two tumors share overlapping microscopic features. Pathologists rely on immunohistochemistry, which involves staining the tissue with antibodies that bind to specific proteins. In the kidney, one particularly useful approach uses a panel of markers. Renal oncocytomas are typically positive for CD117 and negative for CK7, while chromophobe renal cell carcinomas tend to be positive for both CD117 and CK7. Adding markers like EpCAM further sharpens the distinction: homogeneous EpCAM staining points toward chromophobe carcinoma, while oncocytomas are either negative or show only scattered positive cells.22PubMed. Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma: an optimal and practical panel for differential diagnosis Using the right combination of markers, some studies have achieved perfect diagnostic accuracy in separating these tumor types.23PubMed. Oncocytoma versus chromophobe renal cell carcinoma: Is there something in between? In practice, though, borderline cases still exist, and some tumors show hybrid features that resist neat classification.
How Management Differs Across the Spectrum
Treatment depends on what the tumor is and where it is. For confirmed renal oncocytomas, the tide has been shifting toward less aggressive management. Historically, many of these benign tumors were removed surgically because imaging could not distinguish them from kidney cancer. Active surveillance, meaning regular imaging to monitor growth over time, is now considered a viable option, especially when a core biopsy has confirmed the diagnosis. Triggers that might push a doctor toward surgery include tumor size above 3 cm, growth of more than 5 mm per year, or changes in the patient’s clinical picture.24PubMed. Renal Oncocytoma: An Algorithm for Diagnosis and Management When surgery is needed, partial nephrectomy (removing just the tumor and sparing the rest of the kidney) is preferred over removing the entire kidney.25PubMed Central. Bilateral Renal Oncocytoma: Active Surveillance Versus Partial Nephrectomy
For thyroid oncocytic carcinoma, treatment is more intensive. Surgery, usually a total thyroidectomy, is the primary treatment. Radioactive iodine may follow, and external beam radiation or systemic therapy can be added for advanced or metastatic cases. The challenge with systemic therapy is that oncocytic thyroid carcinomas have historically had limited treatment options, particularly once the cancer stops responding to radioactive iodine. Early-stage research is exploring novel approaches, including engineered immune cell therapies targeting a receptor found on oncocytic carcinoma cells, with preliminary results showing anti-tumor activity in laboratory models.10AACR Journals (Cancer Research). Abstract 5082: Novel TSHR CAR T therapy for targeting oncocytic carcinoma These are very early findings, but they hint at a pipeline of more targeted treatments for a cancer that has historically been underserved by drug development.
For adrenal and pancreatic oncocytic tumors, surgery remains the cornerstone. The borderline category in adrenal tumors is particularly uncomfortable for patients, since it means long-term monitoring without a clear answer about whether the tumor could eventually recur.
The Genetics Underneath
Beyond mitochondrial DNA mutations, oncocytic cancers (particularly thyroid) show striking changes in their nuclear chromosomes. Genomic studies of Hürthle cell carcinomas have revealed that a majority carry widespread losses of chromosomal material across most of the genome, leaving the cells with a near-haploid chromosomal content, meaning they have roughly one copy of most chromosomes instead of the normal two.26PubMed Central. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell Carcinoma This pattern of genome-wide loss of heterozygosity appears to give tumors a selective advantage partly through reduced immune infiltration, essentially helping the cancer hide from the immune system.27PubMed Central. Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma These genomic features are quite different from what is seen in other thyroid cancers, which is why Hürthle cell carcinoma is increasingly treated as a distinct molecular entity rather than just a subtype of follicular thyroid carcinoma.
In renal oncocytomas, the chromosomal picture is much quieter. These benign tumors tend to show losses of just one or two chromosomes, rather than the genome-wide upheaval seen in malignant oncocytic tumors of the thyroid. Chromophobe renal cell carcinomas, by contrast, display a characteristic pattern of losses across multiple specific chromosomes, a pattern that DNA-based analysis can detect and that helps distinguish the two tumor types when pathology alone falls short.28PubMed Central. High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas
Artificial Intelligence and the Diagnostic Horizon
Given how much diagnostic difficulty these tumors cause, there is growing interest in using computational tools to help. CT radiomics, which involves extracting hundreds of quantitative features from imaging scans that the human eye cannot perceive, has shown a high degree of accuracy in distinguishing renal oncocytomas from renal cell carcinomas in early studies. A systematic review and meta-analysis concluded that radiomics algorithms have the potential to improve diagnosis in clinical scenarios that have traditionally been ambiguous.29PubMed Central. CT radiomics for differentiating oncocytoma from renal cell carcinomas: Systematic review and meta-analysis These tools are not yet standard in clinical practice, and most have been validated only retrospectively. But the trajectory is toward integrating computational analysis into the diagnostic workflow, potentially sparing some patients from unnecessary surgery by giving clinicians more confidence in a benign diagnosis before the scalpel is ever picked up.
For thyroid tumors, similar machine learning approaches are being explored using ultrasound images. The diagnostic ambiguity of oncocytic thyroid nodules on needle biopsy makes this a natural application for AI-assisted image analysis, though the research is still in its early stages. The combination of molecular testing on biopsy specimens and AI-enhanced imaging may eventually reduce the number of patients sent to surgery for what turns out to be a benign oncocytic adenoma, but that day has not yet arrived for routine clinical care.