Acta Cytologica 2025;69:501-511 DOI: 10.1159/000545715
Oncocytic Adrenal Tumors: A Tri-Focal Review with Integrated Cytopathological, Pathological, and Molecular Perspectives
Vincenzo Condelloª Massimo Bongiovannib C. Christofer Juhlina, c
aDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; bDepartment of Pathology and Cytology, UNILABS, Lausanne, Switzerland; “Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
Keywords
Oncocytic lesions . Adrenocortical carcinoma . Tumor . Molecular markers · Review
Abstract
Background: Oncocytic lesions of the adrenal gland pose several diagnostic challenges as they can be associated with both functional and non-functional adrenal disorders and may be either benign or malignant. Summary: Oncocytic tumors are predominantly (>90%) composed of oncocytic cells, characterized by bulky, eosinophilic cytoplasm due to an abundance of mitochondria. Notably, the conventional histopathological criteria for diagnosing adrenal cortical carcinoma (ACC), such as the Weiss criteria, are not rec- ommended for oncocytic tumors, and separate classification algorithms have been proposed for this entity. In addition to their unique cytopathology and histopathology, oncocytic adrenal cortical neoplasms share many driver gene alter- ations with conventional adrenal tumors, albeit at lower frequencies. However, these tumors also exhibit some dis- tinct genetic changes, particularly deletions of mitochon- drial DNA, which are consistent with patterns seen in on- cocytic lesions of other endocrine organs. Interestingly, the presence of oncocytic features may correlate with prognosis in ACCs, making this morphological distinction clinically significant. Some studies suggest that oncocytic features
could be linked to either a more favorable or unfavorable outcome, depending on other molecular markers. This highlights the importance of accurate diagnostic work-up for these lesions and underscores the critical role of endocrine pathologists in their management. While cytology is not part of the routine work-up for primary adrenal tumors, fine-needle aspiration cytology may still be useful in distinguishing primary adrenal tumors from metastases. Key Messages: This review examines the his- tological and molecular characteristics of oncocytic adrenal cortical lesions, highlighting their clinically relevant differ- ences from conventional adrenal tumors. It clarifies the limited role of cytology in diagnosing primary adrenal tu- mors while recognizing its usefulness in distinguishing adrenal metastases. Finally, it underscores the need for a tailored diagnostic approach to effectively manage this complex entity.
@ 2025 The Author(s). Published by S. Karger AG, Basel
Introduction
In endocrine pathology, oncocytic differentiation is associated with various physiological and neoplastic conditions and is generally believed to result from the aberrant accumulation of mitochondria in the cytoplasm [1, 2]. Oncocytic metaplasia can occur as a reactive
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C. Christofer Juhlin, christofer.juhlin@ki.se
phenomenon in thyroid follicular epithelium, particularly in chronic lymphocytic thyroiditis [3]. Additionally, oncocytic tumors of the pituitary, parathyroid, thyroid, and adrenal glands are well-recognized entities that may exhibit distinct genetic and clinical features [4-7].
Histopathologically, oncocytic cells are characterized by their large size, often polygonal shape, and well- defined cell borders. They typically possess volumi- nous, granular, and eosinophilic cytoplasm. The nuclei are frequently large and hyperchromatic, with occasional prominent macronucleoli [2, 8]. Despite their striking morphology, oncocytic tumors in endocrine organs often share the immunohistochemical profile of their con- ventional counterparts. For example, oncocytic thyroid tumors are typically positive for TTF1, PAX8, and thy- roglobulin, while oncocytic adrenal cortical tumors often express SF1 [9]. This immunophenotypic overlap facil- itates the accurate identification of primary tumors and helps prevent misdiagnosis with metastatic oncocytic tumors originating from non-endocrine organs, such as renal cell carcinoma or breast carcinoma. However, differences in biological behavior can be significant. For instance, oncocytic thyroid carcinoma carries a higher risk of lung metastases compared to follicular and pap- illary thyroid carcinomas, and oncocytic adrenal cortical carcinoma may potentially be less aggressive than their conventional counterparts, differences that may stem from distinct genomic alterations [10, 11].
In adrenal cortical tumors, determining malignant potential is particularly challenging as the distinction between adrenal cortical adenoma and carcinoma relies on multi-parameter scoring systems rather than single morphological attributes. This distinction becomes even more complex in oncocytic adrenal cortical neoplasms, where conventional criteria may be less reliable. A thorough understanding of oncocytic differentiation in adrenal cortical lesions is therefore essential for accurate diagnosis and appropriate clinical management. As re- ported in Figure 1, this review aimed to address current gaps in knowledge by exploring the cytopathological, histopathological, and molecular characteristics of these enigmatic tumors, providing insights into their diagnostic and prognostic significance.
Cytopathological Hallmarks of Oncocytic Adrenal Cortical Tumors
Fine-needle aspiration biopsy (FNAB) of the adrenal gland is relatively rare and is most commonly performed for staging metastatic diseases, particularly pulmonary
small and large cell carcinomas. FNAB is not suitable for diagnosing primary adrenal tumors as the distinction between different primary entities requires careful his- topathological investigation of large tumor areas. The use of FNAB for evaluating incidental adrenal masses (“in- cidentalomas”) is therefore uncommon. However, some studies report adrenal FNAB to be effective in diagnosing lesions with high accuracy and negative predictive value, achieving an accuracy rate of 97.6% in distinguishing benign from malignant lesions [12]. Adrenal gland FNAB is typically performed under ultrasound or computed tomography guidance through the abdominal skin. In cases where the lesion is located on the right side, the liver may be traversed before reaching the adrenal gland, which can lead to the presence of hepatocytes in the biopsy [13]. Multiple passes are usually performed to ensure adequate sampling. Rapid on-site evaluation can be used to assess sample quality and guide appropriate specimen management [14, 15]. The biopsied material can be smeared onto slides for alcohol fixation, air-dried, or placed directly into a fixative. Dedicated passes for cell block preparation are highly recommended as they allow for immunostaining.
Among oncocytic adrenocortical adenomas and car- cinomas, the proportion of oncocytic cells in an FNAB can range up to 100%, with more than 90% required for a lesion to be classified as truly oncocytic. Adrenal onco- cytic cells resemble those found in oncocytic lesions of other organs. Smears typically show a population of dispersed, discohesive cells or small aggregates. These cells are cuboidal or polygonal, medium-to-large in size, with abundant granular cytoplasm and eccentrically lo- cated large nuclei, often featuring prominent macro- nucleoli. Samples can be hypercellular and exhibit cy- tological atypia, which may lead to diagnostic pitfalls and a mistaken diagnosis of malignancy. Differentiating be- tween oncocytic adenoma and carcinoma based on cy- topathology alone is usually not possible, and this pro- cedure is therefore reserved for histopathological evaluation.
Cytopathologically, oncocytic adrenal cortical lesions are composed of small-to-medium-sized cells, although occasional isolated cells with more pleomorphic nuclei may be present. The nuclei are typically small and uni- form, with no significant mitotic activity or necrosis. Oncocytic adrenal cortical carcinomas, which are less common than adenomas, are composed of medium-to- large cells with greater pleomorphism than those found in benign lesions.
Grading of oncocytic adrenal carcinoma is not possible based on cytopathology alone. However, the presence of
Hallmarks of oncocytic adrenal cortical tumors
IMAGING
· Often PET avid (may mimic ACC)
HORMONAL WORK-UP
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· Heterogenous on CT scans
· 70% non-producing (incidentalomas)
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· 30% produce androgens, cortisol or both
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· Aldosterone is exceedingly rare
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CYTOLOGY
HISTOLOGY
· Safe and sensitive procedure if image-guided
· >90% oncocytic cells
· Data regarding FNAC of oncocytic lesions is scarce
· Characterized by cells with abundant granular and eosinophilic cytoplasm
· Verify adrenal cortical origin via IHC in non-functional tumors
MOLECULAR GENETICS
RISK ASSESSMENT
· “Common deletion” of mitochondrial DNA
· Rarity of lesions makes comparisons to conventional adrenal cortical tumors hard
· Lin-Weiss-Bisceglia algorithm
· Helsinki algorithm
· Reticulin algorithm
necrosis and a high mitotic count is typically indicative of high-grade tumors and suggests carcinoma rather than adenoma [16, 17]. Other features of malignancy, such as capsular and vascular invasion, cannot be assessed cy- topathologically. In uncertain cases, the lesion should be diagnosed as an “oncocytic adrenal neoplasm.” Figures 2 and 3 illustrate the cytomorphological characteristics of cells obtained by FNAB in patients with oncocytic adrenal cortical tumors.
For challenging cases, a panel of immunostains on cell block preparations is recommended. Adrenal oncocytic cells are positive for SF1 (the most reliable marker), synaptophysin and inhibin alpha (both also expressed in pheochromocytomas), and Melan A. Cytokeratins, CEA, EMA, and other epithelial markers are usually negative [9]. The differential diagnosis should include metastatic tumors with oncocytic features, such as metastatic mel-
anoma, metastatic thyroid carcinoma, metastatic breast carcinoma, metastatic renal cell carcinoma, and meta- static lung neuroendocrine tumors.
Histopathology of Oncocytic Adrenal Cortical Lesions
Histopathological evaluation of a resected adrenal cortical lesion remains the diagnostic cornerstone for patients with adrenal nodules, and this holds true for oncocytic tumors as well. Preoperative imaging is often inconclusive as oncocytic adrenal cortical tumors can appear heterogeneous on CT scans and frequently demonstrate high uptake on fluorodeoxyglucose-positron emission tomography, mimicking malignant lesions [18, 19]. As previously discussed, preoperative biopsies of adrenal masses are rarely performed and are generally
inadequate for distinguishing between benign and ma- lignant primary adrenal cortical tumors. Consequently, accurate diagnosis relies heavily on morphological as-
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sessment of the resected specimen, often complemented by immunohistochemical analyses. This integrated ap- proach is essential for establishing a definitive diagnosis and guiding appropriate clinical management for patients with oncocytic adrenal cortical tumors.
Oncocytic adrenal cortical tumors are defined by the presence of >90% oncocytic cells, a strict criterion that many tumors may not meet. In reality, most adrenal cortical tumors exhibit a mixture of cells with vacuolated cytoplasm, resembling zona fasciculata cells, and compact (eosinophilic) cells, resembling zona reticularis cells (Fig. 4). It is essential to avoid overdiagnosing lesions as “oncocytic” based solely on a high proportion of eosin- ophilic cells as these do not meet the established histo- pathological threshold for true oncocytic differentiation. In surgical pathology practice, it is not uncommon to see misclassified compact cell-rich conventional adrenal cortical carcinoma mistaken for oncocytic adrenal cor- tical carcinoma.
Oncocytic adrenal cortical tumors produce hormones in 30% of cases and are more commonly detected as incidentalomas. When functional, these tumors are pri- marily associated with hyperandrogenism, followed by hypercortisolism [20]. Aldosterone-producing oncocytic tumors are extremely rare. While identifying the primary site may have limited clinical value in hormone- producing tumors - specifically those secreting cortisol, androgens, or aldosterone - it becomes critically im- portant in non-producing tumors. Misdiagnosing an adrenal metastasis as a primary adrenal cortical lesion can have severe, even fatal, clinical consequences. Therefore, pathologists are strongly encouraged to confirm the adrenal origin of non-producing tumors using SF1 im- munohistochemistry as SF1 is the most specific and re- liable marker for this purpose. Oncocytic adrenal cortical tumors, like their conventional counterparts, are also typically positive for alpha-inhibin, calretinin, Melan A, and/or synaptophysin, albeit at variable frequencies [21-24]. These markers, while less specific than SF1, can still provide valuable diagnostic support in verifying the adrenal origin of the tumor.
Oncocytic Adrenal Cortical Adenoma
Oncocytic adrenal cortical adenoma is a rare subtype of adrenal cortical adenoma characterized by the pre- dominant presence of oncocytic cells (Fig. 5a, b). Clin- ically, these tumors are similar to conventional adrenal cortical adenomas, showing no significant differences in patient age, sex distribution or hormone production.
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Histopathologically, oncocytic adenomas are primarily composed of oncocytic cells arranged in solid sheets, with well-defined cell borders, hyperchromatic nuclei, and occasional macronucleoli. In contrast, conventional ad- enomas typically display a mix of vacuolated zona fasciculata-like cells and compact zona reticularis-like cells. Immunohistochemically, oncocytic adrenal corti-
cal adenomas share the same expression profile as con- ventional adenomas, including markers such as SF1, alpha-inhibin, calretinin, Melan A, and synaptophysin (Fig. 5c, d). In terms of clinical outcome, oncocytic ad- renal cortical adenomas are benign, similar to their conventional counterparts. However, their distinct his- topathological features can sometimes complicate the
| Tumor types | Weiss | Lin-Weiss-Bisceglia | Helsinki | Reticulin |
|---|---|---|---|---|
| conventional | oncocytic | conventional or oncocytic | conventional or oncocytic | |
| Parameters | · Nine histological parameters, one point each: - High nuclear grade - Mitotic rate ≥5 per 10 mm2 - Atypical mitoses - Clear cells comprising 25% or less of the tumor - Diffuse architecture (in >30% of tumor volume) - Necrosis - Venous invasion - Sinusoidal invasion - Capsular invasion | · Three major criteria: - Mitotic rate ≥5 per 10 mm2 - Atypical mitoses - Venous invasion · Four minor criteria: - Large size (>10 cm and/or >200 g) - Necrosis - Capsular invasion - Sinusoidal invasion | · Two histological parameters plus Ki-67 labeling index: - Mitotic activity ≥5 per 10 mm2 (3 points) - Necrosis (5 points) - Ki-67 index (%), numerical value | · Reticulin plus three histological parameters: |
| - Reticulin network architecture disruption - Mitotic activity ≥5 per 10 mm2 - Necrosis - Venous invasion | ||||
| Threshold for malignancy | ≥3 parameters | ≥1 major criterion | >8.5 points | Altered reticulin network plus ≥1 histological criteria |
| Other | · 1-4 minor criteria: - Tumor of uncertain malignant potential | |||
| Limitations | High false-positive rate in oncocytic tumors | Not to be used for non- oncocytic adrenal cortical tumors | Limited validation outside specialized centers | Limited validation outside specialized centers |
differentiation from oncocytic adrenal cortical carcino- mas. Accurate diagnosis relies on careful evaluation using established histopathological criteria.
Oncocytic Adrenal Cortical Carcinoma
The Weiss scoring system is the most commonly used algorithm to differentiate adrenal cortical adenomas from carcinomas. This multi-parameter system assesses several histopathological features (Table 1). When applied to oncocytic adrenal cortical tumors, the Weiss system may inherently bias the results toward carcinoma as it assigns points for eosinophilic cell dominance and solid growth patterns - features frequently present in these tumors. This predisposition underscores why the Weiss score is not recommended for evaluating oncocytic adrenal cortical lesions. Instead, the Lin-Weiss-Bisceglia model is the preferred approach, specifically designed to assess the malignant potential of oncocytic adrenal neoplasms
(Table 1) [25]. This model evaluates tumors based on three major criteria and four minor criteria. The presence of any major criterion - defined as >5 mitoses per 10 mm2 atypical mitoses, or venous invasion - classifies the tumor as an oncocytic adrenal cortical carcinoma. If any minor criterion is present (large tumor size, tumor necrosis, sinusoidal invasion, or capsular invasion), the tumor is categorized as having “uncertain malignant potential.” In contrast, the absence of all criteria supports a diagnosis of oncocytic adrenal cortical adenoma.
The Lin-Weiss-Bisceglia model thus provides a more accurate and tailored framework for assessing oncocytic adrenal tumors, reducing the risk of overestimating malignancy. It should be noted, however, that newer diagnostic algorithms, such as the Helsinki and reticulin algorithms, are available for both conventional and on- cocytic adrenal cortical tumors. These models incorpo- rate immunohistochemical or histochemical analyses alongside various histopathological parameters. From the authors’ perspective, using multiple algorithms may
enhance diagnostic robustness by providing comple- mentary insights. However, this approach can also create challenges when a tumor is classified as a carcinoma by one algorithm but as an adenoma by another. To address these discrepancies, future comparative studies on ret- rospective cohorts with long-term patient follow-up will be essential to evaluate the reliability and clinical rele- vance of these diagnostic models.
In terms of patient characteristics, there appears to be significant overlap between conventional adrenal cortical carcinoma and oncocytic adrenal cortical carcinoma, with no clear differences observed in patient age, sex, ethnicity, laterality, or hormone production [26]. On- cocytic adrenocortical carcinomas have rarely been found to produce non-cortical hormones, such as parathyroid hormone, though such occurrences are considered ex- ceedingly rare [27]. While some studies suggest that patients with oncocytic adrenal cortical carcinoma may have longer survival compared to those with conventional carcinoma, other studies have not confirmed this asso- ciation. These discrepancies might be attributed to the rarity of oncocytic tumors, which limits the statistical power of studies, as well as variability in histopathological assessment and differences in clinical follow-up dura- tions. Figure 6 shows the gross and microscopic char- acteristics of an oncocytic adrenal cortical carcinoma.
Differential Diagnoses
In rare cases, other adrenal cortical or non-adrenal lesions may exhibit oncocytic morphology, making ac- curate diagnosis critical to avoid significant clinical consequences, such as misdiagnosing an adrenal me- tastasis as a primary adrenal tumor, or misidentifying a rare genetic condition. For example, primary pigmented nodular adrenocortical disease (PPNAD), a variant of bilateral micronodular adrenocortical disease, can pres- ent with multiple, sub-centimeter nodules with compact cells, displaying an eosinophilic cytoplasm which is often pigmented [2]. These nodules may potentially be con- fused with oncocytic tumors. PPNAD is frequently as- sociated with Cushing syndrome and typically occurs in children and young adults. PPNAD is often linked to Carney complex, a hereditary syndrome caused by germline mutations in the PRKAR1A gene. This syn- drome is characterized by features such as hyperpig- mentation, cardiac myxomas, cutaneous myxomas, and PPNAD. Recognizing this condition is crucial as it is associated with a hereditary syndrome where early de- tection can provide significant clinical benefits. Addi-
tionally, intra-adrenal paraganglioma (also known as pheochromocytoma), which originates in the adrenal medulla, can exhibit granular eosinophilic cytoplasm reminiscent of oncocytic tumors. Distinguishing primary adrenal pheochromocytomas from primary adrenocor- tical tumors with oncocytic features is critical for ensuring accurate diagnosis and appropriate treatment planning. Moreover, epithelioid angiomyolipomas of the adrenal gland (adrenal PEComa) may also mimic an oncocytic adrenal cortical neoplasm [28], especially if the immu- nohistochemical work-up is restricted to Melan A (which is usually positive in PEComas and adrenal cortical tu- mors alike). In these instances, SF1 immunostaining is crucial to distinguish these entities [9].
Metastases to the adrenal glands are frequently en- countered in clinical practice, largely due to the rich vascular supply of these organs. Renal cell carcinoma, which may occasionally display eosinophilic or oncocytic features, is a well-recognized tumor with a propensity for metastasizing to the adrenal glands. Moreover, metastases from hepatocellular carcinoma and oncocytic neuroen- docrine tumors may also cause diagnostic confusion. In these instances, immunohistochemical validation is recommended.
Molecular Landscape of Oncocytic Adrenal Cortical Tumors
The molecular landscape of oncocytic adrenocortical tumors is less characterized than the conventional type, primarily due to its rarity. However, recent studies and case reports are starting to shed light on key aspects of their molecular and genetic profiles.
In conventional adrenal cortical adenomas, there is a well-established correlation between the type of genetic mutations and hormone production. Aldosterone- producing adrenal cortical adenomas are driven by mutations in various ion channels, which ultimately lead to membrane depolarization, CYP11B2 (aldosterone synthase) expression, and cellular proliferation [29]. These mutations thus effectively mimic the physiological response of angiotensin II binding to the AT2 receptor under normal conditions. In contrast, cortisol- producing adenomas are typically driven by genetic aberrations in the protein kinase A signaling pathway, the primary pathway activated by ACTH in normal physiology [29]. While many studies do not specify whether subsets of the included aldosterone- or cortisol- producing adenomas exhibit oncocytic morphology, the rarity of oncocytic adrenal cortical neoplasms suggests
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that the number of oncocytic cases analyzed for mu- tations in ion channel or protein kinase A pathway genes is likely very limited. This highlights the need for de- tailed studies specifically focusing on hormone- producing oncocytic adrenal cortical neoplasms. Nev- ertheless, given the overall scarcity of aldosterone- producing oncocytic adrenal cortical tumors, the prevalence of ion channel mutations in these tumors is expected to be exceedingly low, if present at all. To our knowledge, only a single oncocytic tumor associated with hyperaldosteronism has been assessed for ion channel hotspot mutations, with negative results [30].
In conventional ACC, recent investigations have pinpointed multiple genes implicated in sporadic adre- nocortical tumor development, including IGF2, CTNNB1, and TP53 [29, 31, 32]. Moreover, advanced genomic profiling of ACC has uncovered additional candidate driver genes, such as ZNRF3 and TERT, and revealed distinct molecular subgroups with varying clinical out- comes [29, 33-36]. Furthermore, germline variants in these genes are associated with hereditary conditions such
as Beckwith-Wiedemann syndrome, familial adenoma- tous polyposis coli, and Li-Fraumeni syndrome, which are linked to an increased risk of adrenocortical neoplasia [11, 34].
In 2016, The Cancer Genome Atlas (TCGA) project provided a comprehensive molecular characterization of 91 adult ACCs, offering critical insights into their genomic, transcriptomic, epigenomic and proteomic landscapes. The study identified several novel mutated genes, including PRKARIA, RPL22, TERF2, and CCNE1, which may play significant roles in the de- velopment of ACC. Additionally, genome-wide DNA copy-number analysis revealed a frequent pattern of substantial DNA loss followed by whole-genome dou- bling, a feature strongly associated with aggressive clinical behavior, suggesting its potential as a key marker of disease progression [11]. Although this study did not specifically target the oncocytic variant (only four oncocytic cases were included in the entire cohort), its findings contribute to a broader understanding of ACC molecular biology. Manual inspection of these
four oncocytic ACC using the cBioPortal database (https://www.cbioportal.org) for the sake of this review revealed mutation counts ranging from 45 to 138, which is notably higher than the median (27 mutations) for the entire TCGA cohort [37]. None of these oncocytic cases harbored mutations in the CTNNB1, ZNRF3, or TP53 genes, which are collectively relatively common in conventional ACC. Instead, shared genetic alterations were observed, including mutations in Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) at either positions L24V and L26V in three out of the four oncocytic carcinomas. Interestingly, LRIG1 mu- tations are not exclusive to oncocytic tumors and identical mutations have also been identified in con- ventional adrenal cortical carcinomas, suggesting a potential common genetic event of interest [38]. LRIG1 functions as a negative regulator of receptor tyrosine kinase signaling by enhancing receptor ubiquitination and promoting accelerated intracellular degradation [39]. This shared mutation may highlight a possible avenue for further research into its role in the patho- genesis of adrenal cortical tumors.
Oncocytic tumors typically show a high mitochon- drial content coupled with notable mitochondrial dys- function [1]. The most frequent mitochondrial alter- ation observed in these rare tumors is called “common deletion,” a 4977-bp deletion of mitochondrial DNA that disrupts essential genes encoding components of the electron transport chain [40]. This disruption impairs energy production and increases the generation of re- active oxygen species, exacerbating cellular stress and potentially contributing to tumor development. Notably, this deletion has been identified in approximately 50% of oncocytic adrenocortical carcinomas, as reported by Duregon and collaborators in 2011 [41]. This intriguing study revealed the deletion to be slightly more prevalent in pure oncocytic tumors and in cases classified as be- nign or of uncertain malignant potential. Furthermore, the authors suggested that this alteration is likely not clonally transmitted to all neoplastic cells but instead represents an early event in mtDNA, maintained only within a subpopulation of oncocytes. Rather than driving malignant progression, it may act as a tumor- suppressive mutation by impairing mitochondrial function and limiting the proliferative capacity of af- fected cells [42].
Due to its rarity, a more comprehensive investigation of the molecular profile of these tumors is warranted. Our current understanding is limited, primarily derived from small-scale studies, which leaves significant gaps in our knowledge of their molecular drivers.
Discussion
Oncocytic adrenal cortical tumors represent a rare and distinct subset of adrenal neoplasms, posing significant challenges in both diagnostic and prognostic contexts due to their infrequent occurrence and diverse biological behavior. Their rarity in scientific literature underscores the need for comprehensive characterization from cy- topathological, histopathological, immunohistochemical, and genetic perspectives. While the cytopathological and histopathological features of these tumors often overlap with those of conventional adrenal cortical neoplasms, their unique oncocytic morphology adds a layer of complexity to accurate diagnosis.
To firmly diagnose primary adrenal tumors, histo- pathology is required, and the introduction of the Hel- sinki and reticulin algorithms marks a significant ad- vancement in assessing the malignant potential of on- cocytic adrenal tumors. These tools address some of the limitations inherent in the Lin-Weiss-Bisceglia model by incorporating the Ki-67 labeling index and reticulin framework disruptions into the evaluative criteria. However, while these algorithms may improve diagnostic precision, their application remains constrained by the limited availability of data on oncocytic tumors, and comparative studies are largely lacking.
Immunohistochemical profiling offers valuable in- sights into the diagnosis of oncocytic adrenal cortical tumors, often highlighting markers such as SF1, alpha- inhibin, and melan A. However, the expression patterns of these markers can vary, requiring a cautious and in- tegrative approach to interpretation, particularly when evaluating non-functional oncocytic tumors. This com- plexity is further compounded by the high incidence of metastatic lesions to the adrenal glands, some of which may exhibit eosinophilic or purely oncocytic features, posing additional diagnostic challenges.
Genetic studies, although limited, have begun to shed light on potential pathways involved in the tumori- genesis of oncocytic adrenal cortical neoplasms. However, large-scale investigations are needed to identify reliable molecular biomarkers for diagnostic and prognostic applications. Notably, the so-called “common deletion” of mitochondrial DNA appears to be overrepresented in oncocytic adrenal cortical tumors. Yet, it remains unclear whether this phe- nomenon acts as a driver event in tumorigenesis or simply represents a genetic aberration contributing to mitochondrial accumulation. Further research is re- quired to clarify its role and significance in these rare neoplasms.
In conclusion, the rarity of oncocytic adrenal cortical tumors continues to challenge clinicians and pathologists alike. The adoption of new diagnostic frameworks like the Helsinki and reticulin algorithms is a step forward, but the need for robust molecular investigations remains critical. Future research efforts should focus on ex- panding our understanding of these enigmatic tumors to optimize diagnostic accuracy and patient management.
Conflict of Interest Statement
All the authors have no conflict of interest and nothing to disclose.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
V.C. contributed to writing, reviewing, and editing the man- uscript, with a primary focus on the molecular aspects; M.B. contributed to writing, reviewing, and editing the manuscript, with a primary focus on the cytological aspects; and C.C.J. conceived and supervised the project, contributing to writing, visualization, and manuscript revisions, with an emphasis on the histopatho- logical aspects. All authors critically reviewed and approved the final manuscript.
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