Reclassifying Papillary, Oncocytic and Chromophobe Renal Tumours Based on the 5 < sup > th < /sup > Who Classification 2022.

OBJECTIVE: The classification of renal tumors is expanding with the addition of new molecular entities in the 5th World Health Organization classification. Apart from this, the major updates in the definition of papillary renal cell carcinoma are that these tumors are no longer subtyped into type 1 and type 2. In oncocytic tumors, the new molecularly defined renal tumors, emerging and novel entities need to be considered in the diagnosis of oncocytic and chromophobe renal tumors. MATERIAL AND METHODS: This is a retrospective study to review and reclassify papillary, oncocytic, and chromophobe renal tumors based on the new WHO classification and correlate with clinical data, gross, microscopic features, and immunohistochemistry markers. RESULTS: A total of thirteen cases were reviewed and the tumor grade was changed for three out of four cases of papillary renal cell carcinoma and a single case was recategorized and graded. In nine cases of oncocytic and chromophobe renal tumors, the diagnoses were modified in 3 cases. CONCLUSION: Newly defined molecular renal tumors require advanced immunohistochemistry markers and molecular tests. This poses diagnostic challenges to pathologists practicing in low resource settings where molecular tests are not available.

Distinguishing Benign Renal Tumors with an Oncocytic Gene Expression (ONEX) Classifier.

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors. PATIENT SUMMARY: Renal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer.

Deep learning based classification of solid lipid-poor contrast enhancing renal masses using contrast enhanced CT.

OBJECTIVE: Establish a workflow that utilizes convolutional neural nets (CNN) to classify solid, lipid-poor, contrast enhancing renal masses using multiphase contrast enhanced CT (CECT) images and to assess the performance of the resulting network. METHODS: In this institutional review board approved study of 143 patients with predominantly solid, lipid-poor, contrast enhancing renal lesions (46 benign and 97 malignant), patients with a pre-operative multiphase CECT of the abdomen and pelvis obtained between June 2009 and June 2015 were retrospectively queried. Benign renal masses included oncocytoma and lipid-poor angiomyolipoma and the malignant group included clear cell, papillary, and chromophobe carcinomas.Region of interests of whole tumor volumes were manually segmented, and CT phase images with the largest cross-section of the segmented tumor in the axial plane were used for assessment. Post-surgical pathological evaluation was used to establish diagnosis.The segmented images of renal masses were used as input to a CNN. The data were augmented and split into training (83.9%) and validation sets (16.1%) to determine the hyperparameters of the CNN. Thereafter. the performance of the resulting CNN was quantified using eightfold cross-validation. RESULTS: The CNN-based classifier demonstrated an overall accuracy of 78% (95% confidence interval: 76-80%), sensitivity of 70% (95% confidence interval: 66-74%), specificity of 81% (79-83%) and an area under the curve of 0.82. CONCLUSION: A CNN-based classifier to diagnose solid enhancing malignant renal masses based on multiphase CECT images was developed. ADVANCES IN KNOWLEDGE: It was established that a CNN-based classifier could be trained to accurately distinguish malignant renal lesions.

Emerging entities in renal cell neoplasia: thyroid-like follicular renal cell carcinoma and multifocal oncocytoma-like tumours associated with oncocytosis.

The list of accepted entities of renal cell neoplasia has burgeoned since the turn of the century through recognition of rare tumour types and the discovery of genetic mutations driving renal neoplasia syndromes. This growth has not finished and in this report we present examples of each of these types which were not included in the 2016 World Health Organization classification of renal neoplasia, but are candidates for inclusion in the next edition of the classification. Thyroid-like follicular renal cell carcinoma is a rare tumour type with a distinctive microscopic appearance resembling follicles of the thyroid gland. Thirty-nine cases have been described and the findings have been reasonably consistent. Oncocytoma-like tumours associated with oncocytosis arise as a result of somatic mutations in the mitochondrial genome. The differential diagnosis is mainly with the renal lesions of the Birt-Hogg-Dubé syndrome, which is the result of germline mutations in the folliculin gene. Patients with oncocytoma-like tumours associated with oncocytosis are at great risk of developing renal failure as the proliferating lesions replace the renal parenchyma. Oncocytoma-like tumours have never been found to metastasise.

Oncocytic Renal Neoplasms on Resections and Core Biopsies: Our Approach to This Challenging Differential Diagnosis.

Distinguishing oncocytomas from their malignant mimics is very challenging. This review highlights our approach to classifying low-grade oncocytic tumors on both resections and biopsies. We also discuss how we use immunohistochemical stains in this challenging differential diagnosis.

Categorizing renal oncocytic neoplasms on core needle biopsy: a morphologic and immunophenotypic study of 144 cases with clinical follow-up.

There is limited literature on renal oncocytic neoplasms diagnosed on core biopsy. All renal oncocytic neoplasm core biopsies from 2006 to 2013 were retrospectively reviewed. Morphologic features and an immunohistochemical panel of CK7, c-KIT, and S100A1 were assessed. Concordance with resection diagnosis, statistical analysis including a random forest classification, and follow-up were recorded. The post-immunohistochemical diagnoses of 144 renal oncocytic core biopsies were favor oncocytoma (67%), favor renal cell carcinoma (RCC) (12%), and cannot exclude RCC (21%). Diagnosis was revised following immunohistochemistry in 7% of cases. The most common features for oncocytoma (excluding dense granular cytoplasm) were nested architecture, edematous stroma, binucleation and tubular architecture; the most common features for favor RCC were sheet-like architecture, nuclear pleomorphism, papillary architecture, and prominent cell borders. High nuclear grade, necrosis, extensive papillary architecture, raisinoid nuclei, and frequent mitoses were not seen in oncocytomas. Comparing the pathologist and random forest classification, the overall out-of-bag estimate of classification error dropped from 23% to 13% when favor RCC and cannot exclude RCC were combined into 1 category. Resection was performed in 19% (28 cases) with a 94% concordance (100% of favor RCC biopsies and 90% of cannot exclude RCC biopsies confirmed as RCC; 83% of favor oncocytomas confirmed); ablation in 23%; and surveillance in 46%. Follow-up was available in 92% (median follow-up, 33months) with no adverse outcomes. Renal oncocytic neoplasms comprise a significant subset (16%) of all core biopsies, and the majority (78%) can be classified as favor oncocytoma or favor RCC.

[Oncocytoma versus chromophobe renal cell carcinoma: Is there something in between?]. / Onkozytom versus chromophobes Nierenkarzinom: Gibt es etwas dazwischen?

The differentiation of oncocytic tumors of the kidneys is often difficult, particularly in renal biopsies. Differential diagnoses are chromophobe renal cell carcinoma (ChRCC), renal oncocytoma (RO), the oncocytic variant of papillary renal cell carcinoma (OPRCC), the eosinophilic variant of clear cell renal cell carcinoma (CCRCC) and hybrid oncocytic chromophobe tumors (HOCT). In difficult cases that cannot be resolved by morphology alone, immunohistochemistry is usually helpful. The RO and ChRCC show positive reactions for CD117, they are negative for vimentin and alpha-methylacyl-CoA racemase (AMACR), while CCRCC are positive for vimentin and OPRCC are positive for AMACR. To distinguish between RO and ChRCC, CK7, claudin-7 (both strongly positive in ChRCC and negative or patchy positive in RO) and epithelial cell adhesion molecule (EpCAM) can be used (positive in ChRCC, negative in RO); however, a diagnosis may remain difficult in some cases even with the use of immunohistochemistry. Thus, numerous new methods are being developed in the field of molecular pathology and computer-based morphometric tumor analysis; however, these new methods have not yet been applied in routine diagnostics.

The diagnostic accuracy of fine-needle cytology of Hurthle cell lesions; A comprehensive cytological, clinical and ultrasonographic experience.

BACKGROUND: Fine-needle cytology (FNC) diagnosis and pre-operative classification of Hurthle cells (HC) lesions may be difficult. Rapid on-site evaluation (ROSE) enhances the efficiency of FNC, mainly when utilized in close combination to clinical and ultrasound (US) data. OBJECTIVE: to describe an experience on HC FNC with contextual clinical,US and ROSE evaluation and assess if this comprehensive approach improves the FNC accuracy of HC lesions. METHODS: FNC of 112 HC lesion were diagnosed and classified, according to the Bethesda system, by clinical, US and ROSE in one year. All the cases were controlled by follow-up and histology when performed. RESULTS: Eighty-five cases were diagnosed HC rich goiter or Hashimoto thyroiditis and were classified THY2; 5 cases were diagnosed hyperplastic nodular goiter and classified THY3A. Eight cases were diagnosed suspect neoplasia and classified THY3B. Two cases were diagnosed suspect HC papillary thyroid carcinoma (PTC) and classified THY4 and 2 cases were diagnosed HC-PTC and classified THY5. THY3B, THY4, THY5 and 1 THY3A were histologically controlled. FNC were confirmed in 14 out of the 17 THY3-THY5 cases. CONCLUSIONS: A comprehensive diagnostic approach that include FNC, clinical data, US and ROSE improves the diagnosis and classification of HC lesions.

Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes.

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

A genomic algorithm for the molecular classification of common renal cortical neoplasms: development and validation.

PURPOSE: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms. MATERIALS AND METHODS: Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization. RESULTS: The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved. CONCLUSIONS: In a clinical diagnostic setting the implementation of genome based molecular classification could serve as an ancillary assay to assist in the histological classification of common renal neoplasms.

Spindle cell oncocytomas and granular cell tumors of the pituitary are variants of pituicytoma.

Pituicytomas are neoplasms that arise from pituicytes, which are specialized glia of the posterior pituitary. Pituicytes have 5 ultrastructural variants: light, dark, granular, ependymal, and oncocytic. Granular cell tumors of the pituitary gland are thought to arise from granular pituicytes. Spindle cell oncocytomas are considered to arise from folliculostellate cells, which are sustentacular cells of the adenohypophysis. Recent data suggest that, whereas pituicytes and all 3 tumor types are positive for TTF-1, folliculostellate cells are negative for TTF-1. We investigated 7 spindle cell oncocytomas, 4 pituicytomas, and 3 granular cell tumors for their genetic (BRAF(V600E) mutation and BRAF-KIAA fusion), immunohistochemical (GFAP, vimentin, S100 protein, olig2, IDH1-R132H, NF, galectin-3, chromogranin-A, CD56, EMA, CAM5.2, CD68, TTF-1, and bcl-2), and ultrastructural features to refine their classification. All tumors had nuclear positivity for TTF-1 and were negative for CAM5.2, chromogranin-A, and NF. GFAP, vimentin, S100, galectin-3, EMA, and CD68 were variably positive in the majority of the 3 tumor groups. Olig2 was only positive in 1 pituicytoma. Whereas granular cell tumors were negative for bcl-2 and CD56, pituicytomas and spindle cell oncocytomas showed variable positivity. All tumors were negative with the IDH1-R132H mutation-specific antibody, and none had evidence of BRAF alterations (BRAF(V600E) mutation and BRAF-KIAA fusion). Diffuse TTF-1 expression in nontumorous pituicytes, pituicytomas, spindle cell oncocytomas, and granular cell tumors indicates a common pituicyte lineage. The ultrastructural variants of pituicytes are reflected in these 3 morphologic variants of tumors arising from these cells. We propose the terminology "oncocytic pituicytomas" and "granular cell pituicytomas" to refine the classification of these lesions.

DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma.

Renal cell carcinoma (RCC) accounts for around 3% of cancers in the UK, and both incidence and mortality are increasing with the aging population. RCC can be divided into several subtypes: conventional RCC (the most common, comprising 75% of all cases), papillary RCC (15%) and chromophobe RCC (5%). Renal oncocytoma is a benign tumor and accounts for 5% of RCC. Cancer and epigenetics are closely associated, with DNA hypermethylation being widely accepted as a feature of many cancers. In this study the DNA methylation profiles of chromophobe RCC and renal oncocytomas were investigated by utilizing the Infinium HumanMethylation450 BeadChips. Cancer-specific hypermethylation was identified in 9.4% and 5.2% of loci in chromophobe RCC and renal oncocytoma samples, respectively, while the majority of the genome was hypomethylated. Thirty (hypermethylated) and 41 (hypomethylated) genes were identified as differentially methylated between chromophobe RCC and renal oncocytomas (p < 0.05). Pathway analysis identified some of the differentially hypermethylated genes to be involved in Wnt (EN2), MAPK (CACNG7) and TGFß (AMH) signaling, Hippo pathway (NPHP4), and cell death and apoptosis (SPG20, NKX6-2, PAX3 and BAG2). In addition, we analyzed ccRCC and papillary RCC data available from The Cancer Genome Atlas portal to identify differentially methylated loci in chromophobe RCC and renal oncocytoma in relation to the other histological subtypes, providing insight into the pathology of RCC subtypes and classification of renal tumors.

Kidney-specific cadherin correlates with the ontogenetic origin of renal cell carcinoma subtypes: an indicator of a malignant potential?

INTRODUCTION AND OBJECTIVES: To evaluate retrospectively kidney-specific cadherin (Ksp-cad) expression in renal cell carcinoma (RCC) subtypes and oncocytoma in correlation with its ontogenetic origin of distal and proximal tubules and to correlate Ksp-cad expression with tumour characteristics. MATERIALS AND METHODS: Membranous and cytoplasmic expression of Ksp-cad was determined in 40 clear cell (ccRCC), 25 papillary (pRCC), 19 chromophobe carcinomas (chRCC), 27 oncocytomas (oncocytomas) (n = 111) and 32 benign kidney parenchyma specimens separated in distal tubules (DT) and proximal tubules (PT) by immunohistochemistry using tissue microarray technique. Staining intensity was quantified as a score ranging from 0 to 12. Comparison of data and correlation with tumour characteristics were done by Wilcoxon/Kruskal-Wallis tests (post hoc Tukey-Kramer analysis). RESULTS: In benign renal tissue, membranous and cytoplasmic expression of Ksp-cad in the DT was significantly higher than that in the PT (12.0 ± 0 vs. 5.2 ± 0.3 and 6.3 ± 0.5 vs. 0.0 ± 0.0, respectively; (P < 0.05)). Membranous KSP-cad expression was significantly higher in chRCC (5.2 ± 0.8) and oncocytomas (3.7 ± 0.4) than that in ccRCC (0.8 ± 0.2) and pRCC (1.4 ± 0.4; P < 0.05), while expression between oncocytomas and chRCC did not differ significantly. In RCC, Ksp-cad expression was significantly associated with higher T stage and the occurrence of synchronous metastasis (P < 0.05). Higher N stages and grading tended to correlate with a lower Ksp-cad expression. CONCLUSIONS: In this cohort, the origin of tumour subtypes-chRCC and oncocytomas develop from DT and ccRCC and pRCC from PT cells-is mirrored by the respective Ksp-cad expression. This raises the question whether DT-derived tumours have a less malignant potential than PT-derived tumours.

Accurate molecular classification of kidney cancer subtypes using microRNA signature.

BACKGROUND: Renal cell carcinoma (RCC) encompasses different histologic subtypes. Distinguishing between the subtypes is usually made by morphologic assessment, which is not always accurate. OBJECTIVE: Our aim was to identify microRNA (miRNA) signatures that can distinguish the different RCC subtypes accurately. DESIGN, SETTING, AND PARTICIPANTS: A total of 94 different subtype cases were analysed. miRNA microarray analysis was performed on fresh frozen tissues of three common RCC subtypes (clear cell, chromophobe, and papillary) and on oncocytoma. Results were validated on the original as well as on an independent set of tumours, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis with miRNA-specific primers. MEASUREMENTS: Microarray data were analysed by standard approaches. Relative expression for qRT-PCR was determined using the ΔΔC(T) method, and expression values were normalised to small nucleolar RNA, C/D box 44 (SNORD44, formerly RNU44). Experiments were done in triplicate, and an average was calculated. Fold change was expressed as a log(2) value. The top-scoring pairs classifier identified operational decision rules for distinguishing between different RCC subtypes and was robust under cross-validation. RESULTS AND LIMITATIONS: We developed a classification system that can distinguish the different RCC subtypes using unique miRNA signatures in a maximum of four steps. The system has a sensitivity of 97% in distinguishing normal from RCC, 100% for clear cell RCC (ccRCC) subtype, 97% for papillary RCC (pRCC) subtype, and 100% accuracy in distinguishing oncocytoma from chromophobe RCC (chRCC) subtype. This system was cross-validated and showed an accuracy of about 90%. The oncogenesis of ccRCC is more closely related to pRCC, whereas chRCC is comparable with oncocytoma. We also developed a binary classification system that can distinguish between two individual subtypes. CONCLUSIONS: MiRNA expression patterns can distinguish between RCC subtypes.

Follicular thyroid neoplasm: clinicopathologic features suggesting malignancy.

Thyroid follicular neoplasms are the most common tumors of the thyroid. The criterion for their malignancy is evidence of capsular or vascular invasion, which makes preoperative diagnosis difficult. The poorly differentiated thyroid carcinoma entity was introduced by World Health Organization in its 2004 classification with an incidence still poorly known. We found 356 follicular neoplasms treated between 1990 and 2006. Among these tumor patients, adenomas were more common in women than in men (3.6:1), but carcinomas differed little with respect to gender (1.2:1). All follicular carcinomas (n=39), atypical adenomas (n=6), and oxyphilic adenomas (n=15) were included in the study, as well as 30 consecutive conventional follicular adenomas. Five tumors were reclassified as poorly differentiated follicular thyroid carcinomas, representing 13% of carcinomas in this unselected material. Predictors of malignancy were high proliferation index (PI) by MIB-1 (p<0.001), large tumor size (p<0.001), and old age (p=0.006). High PI was also a marker of worse prognosis in malignant tumors. Oxyphilic tumor cells were more frequent in carcinomas than in adenomas; however, among carcinomas, they were non-prognostic. Probability for malignancy is thus greater in a male patient with a large oxyphilic follicular neoplasm. The PI requires evaluation in all follicular thyroid carcinomas to identify poorly differentiated tumors with worse prognosis.

Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases.

Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms.

Effect of reclassification on the incidence of benign and malignant renal tumors.

PURPOSE: The incidence of benign renal tumors has increased in recent years. This trend is commonly attributed to the increased use of cross-sectional imaging and minimally invasive surgical approaches. An alternative hypothesis is that recent changes in histological classification are responsible for the increasing incidence. To further investigate the impact of histological reclassification we reexamined all excised renal masses using the 2004 WHO criteria and compared this histological classification to the prior criteria. MATERIALS AND METHODS: We identified 1,101 consecutive partial and radical nephrectomy cases managed at our institution from 1989 to 2003. All histopathological sections were rereviewed by a single pathologist and reclassified according to 2004 WHO criteria. The percentages of benign lesions per year according to the prior histological and current WHO 2004 histological criteria were compared. RESULTS: Of the 1,101 renal masses 132 (12.0%) and 165 (15.0%) were classified as benign using prior and current WHO criteria, respectively. On average the WHO criteria diagnosed more benign tumors per year than the prior criteria (p = 0.004). Linear regression demonstrated a similar, persistent increase in benign diagnoses per year of 0.69% (WHO) and 1.22% (prior) during the 14-year period (p = 0.33). All masses reclassified as benign were oncocytoma (33). CONCLUSIONS: Implementation of the 2004 WHO criteria is contributing to the increase in diagnosis of benign renal lesions, specifically oncocytoma. Changes in histological classification do not account for the entire increase. Other factors, which remain to be delineated, are also contributing to the increase in the diagnosis of benign renal lesions.