Diagnosing oncocytic renal tumours on renal mass biopsy; pathological concordance and the impact of evolving classification

Abstract

Aims

Renal tumours with oncocytic morphology are among the most difficult to classify at renal mass biopsy (RMB), and a number of emerging entities with low‐grade oncocytic morphology have been recently described. This study aimed to evaluate pathological concordance between RMB and subsequent nephrectomy or repeat biopsy for oncocytic renal neoplasms and to identify pathological factors contributing to diagnostic discordance, including the impact of evolving tumour classification.

Methods and results

We retrospectively reviewed 145 cases of oncocytic renal neoplasms diagnosed on RMB, including 114 with subsequent nephrectomy and 31 with repeat biopsy only. Overall concordance was 92.9% between RMB and nephrectomy and 96.7% between initial and repeat RMB. Concordance for oncocytoma at nephrectomy was lower (81.4%), likely reflecting selection bias, but was 100% in cases with repeat biopsy. Review of discordant cases (n = 9) revealed that 55% (5/9) were reclassified as emerging tumour entities, specifically low‐grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT). Additional discordant cases were due to heterogeneous tumour morphology in chromophobe renal cell carcinoma (ChRCC) and incomplete immunohistochemical work‐up leading to misclassification of rarer renal cell carcinoma subtypes.

Conclusions

Despite inherent diagnostic challenges, there was overall good concordance between RMB and nephrectomy or subsequent biopsy for the diagnosis of oncocytic tumours. Recognition of emerging tumour entities may reduce diagnostic uncertainty, improve classification in challenging cases, and further improve diagnostic concordance over time. Nonetheless, limitations of RMB, particularly related to tumour heterogeneity, highlight the importance of integrating pathological, clinical, and radiologic data to inform patient management.

Overall, there was good concordance between renal mass biopsy and subsequent diagnosis at nephrectomy or repeat biopsy in oncocytic renal neoplasms. Some discordant cases were reclassified as emerging tumour entities (LOT, EVT), indicating that greater recognition of these entities may help reduce diagnostic uncertainty and improve biopsy classification.

Abbreviations

CAIX

carbonic anhydrase IX

CCRCC

clear cell renal cell carcinoma

ChRCC

chromophobe renal cell carcinoma

EVT

eosinophilic vacuolated tumour

IHC

immunohistochemistry

LOT

low‐grade oncocytic tumour

NOS

not otherwise specified

RCC

renal cell carcinoma

RMB

renal mass biopsy

SDHB

succinate dehydrogenase subunit B

Introduction

Renal mass biopsy (RMB) is increasingly recognized as an important tool in the evaluation and management of renal masses. ¹ While 10%–30% of small renal masses (≤4 cm) are benign, ² , ³ , ⁴ imaging studies alone cannot reliably distinguish benign from malignant neoplasms in most cases. RMB can play an important role in aiding risk stratification and reducing overtreatment of benign tumours. ⁵

Oncocytic renal neoplasms are recognized as a source of diagnostic complexity in urologic pathology. ⁶ The main differential in this category of tumours is between the established entities of oncocytoma and chromophobe renal cell carcinoma (ChRCC). This distinction is clinically important given that oncocytoma is a benign neoplasm which may be managed with surveillance, while patients with ChRCC are more likely to undergo treatment. There are also tumours which demonstrate hybrid or indeterminate features as well as new emerging entities of low‐grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT). ⁷ , ⁸

Diagnosing tumours with oncocytic morphology on biopsy samples can be particularly challenging due to variable and, in some cases, overlapping histologic features. These complexities have raised concerns about the reliability of RMB for diagnosing oncocytic tumours, with guidelines advising caution against making definitive diagnoses of oncocytoma on RMB. ⁴ , ⁷ , ⁹ Although studies have shown pathological concordance rates between biopsy and surgical resection exceeding 90%, ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ sample sizes are limited, as many oncocytomas are managed conservatively. Similarly, concordance with repeat biopsy has been observed but is based on small case series. ¹¹ Importantly, these studies have not investigated the pathologic factors contributing to diagnostic discrepancies or the influence of evolving tumour classifications and the recognition of new entities. A better understanding of these factors could refine diagnostic accuracy and help inform the appropriate work‐up and categorization of tumours with oncocytic features at RMB.

In this study, we examined an institutional series of oncocytic renal tumours diagnosed on RMB, comparing initial biopsy findings with subsequent diagnoses from repeat biopsies and/or final surgical pathology. Our objectives were to determine the rate and nature of discordant findings and to evaluate the impact of evolving tumour classification on pathologic concordance.

Methods

Cases were identified from the Institutional Laboratory Information System (CoPath) between 2002 and 2023 and comprised localized tumours with initial RMB and at least one subsequent RMB and/or nephrectomy. At our institution, diagnostic RMB is performed on clinically localized renal masses to guide treatment options following shared decision‐making with the patient. While RMB is primarily performed on small renal masses (≤4 cm), it is also used as a diagnostic tool to guide clinical management of larger tumours depending on clinical, imaging, and patient factors. All cases were routinely reported by subspecialized urologic pathologists, and immunohistochemistry (IHC) was performed as required based on the morphological features. The study cohort included all tumours with RMB and/or nephrectomy diagnosis or differential diagnosis of oncocytoma, ChRCC, LOT, EVT, or oncocytic tumour not otherwise specified (NOS). The latter included tumours with overlapping or hybrid features and emerging entities. All ChRCC cases were included, not only those labelled as eosinophilic variant, given that eosinophilic components can be variably represented in RMB samples. Tumours with high grade or papillary features, or those meeting criteria for other established entities with eosinophilic morphology, were not included.

The original diagnoses at RMB and nephrectomy were recorded. Concordance was based on the original reported diagnosis. Cases were considered discordant when the original RMB was consistent with or favoured a specific diagnosis and there was an alternate diagnosis at nephrectomy or repeat biopsy. Cases where the initial RMB did not commit to a specific diagnosis, e.g., oncocytic tumour NOS/indeterminate, including those where a differential was given that incorporated the subsequent/final diagnosis, were not regarded as discordant.

All discordant cases and those reported as oncocytic tumour NOS/indeterminate were jointly reviewed by a urological pathology fellow (SAQ) and a urological pathologist (SP). Each case was reclassified based on the 2022 WHO classification. ⁷ Reclassification was primarily based on a thorough re‐review of the original biopsy specimens, integrating histomorphological assessment and immunohistochemical analysis, with confirmation of findings at subsequent resection where applicable. Pathological factors contributing to discordance, including recognition of emerging entities, were documented.

Results

A total of 145 cases were included (Table 1). This comprised 114 RMB with subsequent nephrectomy and 31 with repeat biopsy only. Repeat RMB was performed at clinician discretion while on surveillance in 24/31 (77%) and at the time of ablation in 7/31 (23%) cases. Median tumour size was 3.5 cm (1.2 cm – 16 cm). Overall, 61% (88/145) of tumours were ≤4 cm and 39% (57/145) were >4 cm. The initial RMB diagnosis was ChRCC/favour ChRCC in 59.3% (86/145); oncocytoma/favour oncocytoma in 34.4% (50/145), oncocytic neoplasm NOS (indeterminate) in 5.52% (8/145), and LOT/favour LOT in 0.69% (1/145).

Table 1.

Reported initial RMB and subsequent (nephrectomy or repeat RMB) diagnoses

Initial RMB diagnosis	Nephrectomy diagnosis
Oncocytoma (n = 27)	Oncocytoma (n = 21) EVT (n = 1) ChRCC (n = 2) Oncocytic neoplasm NOS (n = 1) RCC with low‐grade morphology, not further classified (n = 1) SDH‐deficient RCC (n = 1)
ChRCC (n = 81)	ChRCC (n = 78) Oncocytoma (n = 1) LOT (n = 1) CCRCC (n = 1)
Oncocytic neoplasm NOS (n = 5)	Oncocytic neoplasm NOS (n = 3) ChRCC (n = 2)
LOT (n = 1)	LOT (n = 1)

Initial RMB diagnosis	Repeat RMB diagnosis
Oncocytoma (n = 23)	Oncocytoma (n = 23)
ChRCC (n = 5)	ChRCC (n = 4) LOT (n = 1)
Oncocytic neoplasm NOS (n = 3)	Oncocytic neoplasm NOS (n = 3)

The overall concordance between initial RMB and final surgical pathology was 92.9% (106/114), and overall concordance between initial RMB and subsequent RMB was 96.7% (30/31).

Concordance between RMB and Nephrectomy

Of the 114 cases which underwent nephrectomy, the initial RMB diagnosis was ChRCC/favour ChRCC (81/114, 72%), oncocytoma/favour oncocytoma (27/114, 23.7%), oncocytic tumour NOS (5/114, 4.4%), and LOT (1/114, 0.88%). The initial RMB diagnosis was discordant with the final surgical pathology report in eight cases (7.0%), see Table 2. The concordance for cases with initial diagnosis of oncocytoma/favour oncocytoma was 81.4% (22/27), and for cases with initial diagnosis of ChRCC/favour ChRCC was 96.2% (78/81). Of the five discordant cases with RMB diagnosis of oncocytoma/favour oncocytoma, the reported nephrectomy diagnosis was ChRCC (n = 2), succinate dehydrogenase deficient renal cell carcinoma (SDH‐ deficient RCC) (n = 1), renal cell carcinoma (RCC) with low‐grade morphology, not further classified (n = 1), and EVT (n = 1). Of the three discordant cases with RMB diagnosis of ChRCC/favour ChRCC, the reported nephrectomy diagnosis was clear cell renal cell carcinoma (CCRCC) (n = 1), LOT (n = 1), and oncocytoma (n = 1). Overall, four cases (3.5%) changed from benign to malignant diagnosis at resection, and two cases (1.5%) changed from malignant to benign diagnosis at resection.

Table 2.

Features of discordant cases

Discordance between RMB and nephrectomy
Case	Original biopsy diagnosis	Original nephrectomy diagnosis	Final diagnosis after re‐review	IHC done on RMB at initial reporting	Contributing factor for discrepancy
1	Oncocytoma	ChRCC	ChRCC	Yes	Eosinophilic ChRCC with heterogeneous morphology and reduced CK7 expression
2	Favour oncocytoma	ChRCC	LOT	Yes	Emergence of new entities
3	Favour oncocytoma	SDH‐deficient RCC	SDH‐deficient RCC	Yes but did not include SDHB	Incomplete immunohistochemical panel
4	Oncocytoma	RCC‐NOS	RCC‐NOS	No	Incomplete immunohistochemical panel
5	Oncoctyoma	EVT	EVT	Yes	Emergence of new entities
6	ChRCC	Oncocytoma	EVT	Yes	Emergence of new entities
7	Favour ChRCC	Favour LOT	LOT	Yes	Emergence of new entities
8	Favour ChRCC	CCRCC grade 3	CCRCC	Yes, but did not include CAIX	Incomplete immunohistochemical panel

Discordance between initial and repeat RMB
Case	Initial RMB diagnosis	Repeat RMB diagnosis	Final diagnosis after re‐review	IHC done on RMB at initial reporting	Contributing factor for discrepancy
1	ChRCC	LOT	LOT	Yes	Emergence of new entities

Concordance with Repeat RMB

Of the 31 cases that had repeat RMB, the initial RMB diagnosis was oncocytoma (23/31, 74.1%), ChRCC (5/31, 16.1%), and oncocytic tumour NOS (3/31, 9.6%). One case (1/31, 3.2%) was considered discordant as the original RMB favoured ChRCC and the repeat RMB favoured LOT. All of the cases with an initial RMB diagnosis of oncocytoma (n = 23) were concordant with the subsequent RMB.

Review of Discordant Cases

Table 2 outlines the discordant cases and contributing factors. Discordance was due to classification as a new emerging entity (LOT/EVT) in 4/8 (50%) cases with paired RMB and nephrectomy (Figures 1, 2). This included two cases that were reclassified only on re‐review. Furthermore, recognition of a new entity (LOT) accounted for the only case with discrepant findings between initial and repeat RMB.

Figure 1.

Discordant case, which was reclassified on review as LOT. (A) H&E 5×. (B) H&E 10×. (C) Diffuse CK7 expression. (D) Negative CD117 in tumour cells.

Figure 2.

Discordant case, which was reclassified on review as EVT. (A) H&E 5×. (B) H&E 10×. (C) Cathepsin K‐positive.

Overall, 3/27 (11%) of cases with an initial diagnosis of oncocytoma/favour oncocytoma showed RCC at resection. This included an SDH‐deficient RCC and an RCC with low‐grade morphology not further classified, where misclassification at biopsy was partly due to an incomplete immunohistochemical panel at RMB. For the SDH‐deficient RCC, succinate dehydrogenase subunit B (SDHB) IHC was not performed on initial RMB assessment. The final discordant case in this category was an eosinophilic subtype of ChRCC (Figure 3). This tumour showed heterogeneous morphology, including areas mimicking oncocytoma, and reduced CK7 expression.

Figure 3.

Eosinophilic ChRCC with admixed small oncocytic cells (*) together with cells showing more typical features of ChRCC (arrow). (A) H&E 10×. (B) H&E 20×. (C) Diffuse CD117 expression. (D) Reduced (single cell) CK7 expression.

One RMB favoured ChRCC, but the subtype was revised to CCRCC on resection; an incomplete immunohistochemical panel was also a contributing factor to misclassification at resection in this example as carbonic anhydrase IX (CAIX) IHC was not available at the time of reporting.

Based on the original RMB classification, five cases changed from a benign to malignant diagnosis between RMB and nephrectomy; this number reduced to three on re‐review as two cases were classified as benign/likely benign emerging entities.

Oncocytic Tumour, NOS

For the purpose of this study, these tumours were considered non‐discordant as a definitive diagnosis was not given on the initial biopsy, but a focused review of these cases was performed. Among eight cases without a definitive diagnosis on RMB (oncocytic tumour NOS), five underwent nephrectomy and three had a repeat biopsy (see Table 1). The reported subsequent diagnoses were ChRCC (n = 4), oncocytoma (n = 1), and oncocytic tumour NOS (n = 3). On retrospective re‐review, two of these cases were reclassified as LOT. Both of these cases had the relevant IHC performed at the time of the initial biopsy; however, the biopsy predated the recognition of LOT as an entity.

Discussion

RMB increasingly plays an important role in the management of localized renal masses, particularly small renal masses, to guide management options including surveillance, non‐surgical treatment (e.g., ablation), and resection. The classification of oncocytic tumours remains challenging due to overlapping histological features and evolving tumour classification. While prior studies have reported high concordance rates between RMB and final diagnosis, ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ none have specifically evaluated the impact of emerging oncocytic tumour entities on pathologic concordance. To the best of our knowledge, this is the first series to evaluate how evolving tumour classification and other pathologic factors contribute to diagnostic discordance.

In our cohort, we observed a high overall concordance rate of 92.9% between initial RMB and subsequent nephrectomy, and 96.7% between initial and repeat RMB. These findings are consistent with prior reports ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ and support the overall good reproducibility of RMB diagnoses. However, when focusing specifically on cases with an initial RMB diagnosis of oncocytoma, the concordance rate at nephrectomy was lower at 81%. This finding is also in keeping with prior studies ¹² , ¹⁸ and likely reflects the smaller denominator and selection bias, as oncocytomas proceeding to surgery may represent a subset with atypical imaging or clinical features. To further address this, we assessed concordance with repeat biopsy, where all cases initially diagnosed as oncocytoma (n = 23) were concordant on repeat RMB, providing additional reassurance regarding diagnostic reliability.

Review of discordant cases revealed that a subset was reclassified as emerging tumour entities, specifically LOT and EVT, accounting for 50% (4/8) of cases with discrepant RMB and nephrectomy findings and the only case (100%) with discrepant findings on repeat biopsy. These tumours were not identified at the time of many initial diagnoses and exhibit features that overlap between oncocytoma and ChRCC, contributing to diagnostic uncertainty. For example, the morphologic features of LOT closely resemble oncocytoma, but diffuse CK7 positivity is a feature of ChRCC, leading to variable classification prior to formal recognition. ⁸ Recognition of these entities can reduce ambiguity and support more confident biopsy interpretation. We also found that a proportion of tumours labelled as oncocytic tumour NOS on biopsy were reclassified as LOT on review, again enabling more confident categorization. Increased awareness and routine consideration of these entities may further improve concordance rates over time. As both LOT and EVT have demonstrated indolent clinical behaviour in published series, ¹⁹ , ²⁰ , ²¹ it may be appropriate to group them with oncocytoma for management purposes.

One of the concerns regarding the use of RMB is that ChRCC can exhibit intratumoural heterogeneity, with areas morphologically similar to oncocytoma. ²² This has led to recommendations against rendering a definitive diagnosis of oncocytoma on RMB. ⁴ , ⁷ , ⁹ In this series, we identified one case where misclassification occurred, as the biopsy favoured oncocytoma while the nephrectomy revealed an eosinophilic subtype of ChRCC. The resected tumour contained areas resembling oncocytoma, similar to what was sampled in the biopsy, but also demonstrated admixed regions with morphologic features of ChRCC. Additionally, the tumour showed reduced CK7 expression, as can occur in eosinophilic ChRCC, ²³ which further contributed to misclassification on RMB. Although uncommon in our series, this case underscores the need for pathologists and treating clinicians to be aware of the diagnostic limitations of RMB in this setting.

It is also important for pathologists to be aware of other RCC subtypes, including rare subtypes, which can morphologically mimic oncocytoma on RMB. Two additional cases in our series were reclassified as RCC on resection, including one SDH‐deficient RCC and one RCC with low grade morphology‐NOS. Our series spans a large timeframe during which pathology practice, the availability of immunohistochemical stains, and the recognized morphologic spectrum of RCC subtypes have evolved, and it is possible that these cases would not have been misclassified in contemporary practice. Nevertheless, our findings highlight the importance of careful morphologic assessment and judicious use of IHC when evaluating oncocytic tumours in contemporary practice. We advocate performing CD117 and CK7 with additional stains as required based on morphology and initial results.

Other rare eosinophilic RCC subtypes may also enter the differential diagnosis; however, misclassified examples of these entities were not identified in this study. FH‐deficient RCC with low‐grade morphology is a recently recognized but exceedingly rare potential mimic within the oncocytic tumour spectrum. Although it can resemble oncocytoma, published experience suggests greater morphologic overlap with other solid oncocytic tumours. ²⁴ FH IHC was not routinely performed in this cohort, representing a limitation and meaning that FH‐deficient RCC cannot be entirely excluded. However, review of discordant cases and those classified as oncocytic tumour NOS did not reveal morphologic or immunohistochemical patterns (including CD117/CK7 profiles) suggestive of FH‐deficient RCC, making missed examples unlikely.

Strengths of the present study include the relatively large cohort and detailed review of discordant cases, including reclassification in light of evolving tumour categories. Limitations include the retrospective design and the inherent selection bias that arises because many oncocytomas are managed conservatively without surgical resection. Correlation with repeat biopsy was assessed to help address this, although this still represents only a subset of cases. The study also reflects real‐world pathology practice over a broad timeframe, during which immunohistochemical stain availability and diagnostic criteria have evolved. Despite these limitations, the findings provide important insights into diagnostic challenges and support strategies to further optimize RMB interpretation for oncocytic tumours.

Conclusion

This study demonstrates overall good concordance between RMB and subsequent diagnosis in oncocytic renal neoplasms. A proportion of discordant cases were reclassified as emerging tumour entities, suggesting that increased recognition may help reduce diagnostic uncertainty and improve biopsy classification. Nonetheless, the limitations of RMB remain important considerations, underscoring the need to integrate pathologic interpretation with clinical and imaging findings to guide management decisions.

Author contributions

Conception and design: Shifaa' Al Qa'qa' and Susan Prendeville. Data collection: All authors. Data analysis: Shifaa' Al Qa'qa' and Susan Prendeville. Writing – original draft preparation: Shifaa' Al Qa'qa' and Susan Prendeville. Writing – review and editing: all authors.

Funding information

The authors have nothing to report.

Conflict of interests

The authors declare no competing interests.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.