Low Grade Oncocytic Tumors of the Kidney: A Clinically Relevant Approach for the Workup and Accurate Diagnosis - Beyond the Abstract

Progressive sub-classification of renal tumors has continued over the past decade, particularly for low grade oncocytic tumors (tumors composed predominantly of cells with finely granular eosinophilic cytoplasm), which has helped to reduce the proportion of unclassified lesions at this end of the spectrum. In 2021 the Genitourinary Pathology Society (GUPS) provided a comprehensive update regarding renal neoplasia, with incorporation of emerging and provisional renal entities,^1,2 many of which are codified in the recently published WHO classification.³ This included not only well-established chromophobe RCC and benign oncocytoma, but also difficult to classify tumors in the spectrum between these two, other distinct entities with low grade eosinophilic morphology, and low grade eosinophilic tumors associated with familial renal neoplastic syndromes.⁴ These new entities have generally been supported by astute histologic observations and validated by ultrastructural, cytogenetic, immunohistochemical, and/or molecular data (KEY POINTS). While these developments represent a promising academic advance, what is the clinical relevance?

The relevance of identifying familial low grade oncocytic tumors is not debatable.^1,2,4 Such well-defined entities have been found in association with SDHB and FH-deficient phenotypes, Birt-Hogg-Dubé syndrome, and tuberous sclerosis.  Identification of such lesions should lead to genetic counseling that can benefit the patient and family members.  One clear example is the identification of renal tumors suggestive of SDHB-deficient syndrome, which would indicate an increased risk for pheochromocytoma. 

More controversial is the further subdivision of non-familial entities beyond the spectrum of typical oncocytoma and chromophobe RCC. Some of these are unique and well-defined, such as eosinophilic and vacuolated renal tumor (EVT) and low grade oncocytic tumor (LOT), and we can anticipate the identification of additional entities in this domain in the near future.^1,2,4 However, given that all such tumors appear to be either benign or of extremely low malignant potential, is there clinical value in this exercise? Identification and differentiation of such lesions often require very subtle histologic interpretation that can vary from pathologist to pathologist, even among major academic centers. The special tools required to support these diagnoses, e.g. contemporary immunohistochemical antibodies, are not available in many labs. Many such tumors are uncommon or rare, further complicating the situation.³ In the end low grade oncocytic tumors will typically be prioritized for active surveillance, thermal ablation, or partial nephrectomy dependent on patient age, comorbidities, renal functional status, and patient preferences, decisions that will not hinge on further histologic subclassification.^5,6

Amin and colleagues⁴ provide a comprehensive review of these developments including an algorithm for classification of low grade oncocytic tumors with emphasis on clinical utility (Figure 1).  If distinctive features such as irregular nuclear membranes and perinuclear clearing (perinuclear halo) are identified, then a diagnosis of chromophobe RCC (eosinophilic variant) can be rendered. A minority of chromophobe tumors (2-5%) will have sarcomatoid or rhabdoid features, or other high grade features, and are thus not pertinent to this discussion. The next branch point relates to evaluation for distinctive features for oncocytoma, such as round regular nuclei, and if present, the diagnosis of benign oncocytoma can be provided.  Most of the remaining tumors can be classified as oncocytic renal neoplasm of low malignant potential (ORNLMP), although if other atypical features are evident, the diagnosis of “RCC, low risk oncocytic type” or “unclassified oncocytic neoplasm, low-grade” may be more appropriate. As indicated in Figure 1, further work to differentiate EVT, LOT or other emerging entities would then only be pursued for academic reasons, given lack of compelling clinical utility.⁴

Figure 1. Algorithm for Evaluation and Classification of “Low Risk” Oncocytic Tumors of the Kidney.³

Written by: Steven C. Campbell, MD, PhD, Professor of Surgery, Section of Urologic Oncology, Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic

Co-Authors: Mahul B. Amin¹ Jesse K. McKenney² Guido Martignoni^3,4 Sumanta Pal⁵ and Satish K. Tickoo⁶

1. Department of Pathology and Laboratory Medicine, University of Tennessee Health Science, Memphis, TN, USA.
2. Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
3. Department of Diagnostic and Public Health, Section of Pathology, University of Verona, Verona, Italy.
4. Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy.
5. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
6. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

1. Trpkov K, Williamson SR, Gill AJ, Adeniran AJ, Agaimy A, Alaghehbandan R, et al.: Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol 34, 1167–1184 (2021).
2. Trpkov K, Hes O, Williamson SR, Adeniran AJ, Agaimy A, Alaghehbandan R, et al.: New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol 34, 1392–1424 (2021).
3. WHO Classification of Tumors Editorial Board. Urinary and Male Genital Tumours. WHO classification of tumours series, 5th ed.; vol.8. Lyon (France): International Agency for Research on Cancer, 2022.
4. Amin MB, McKenney JK, Martignoni G, Campbell SC, Pal S, Tickoo SK: Low grade oncocytic tumors of the kidney: a clinically relevant approach for the workup and accurate diagnosis. Modern Pathology, 2022; https://doi.org/10.1038/s41379-022-01108-5.
5. Campbell SC, Clark PE, Chang SS, Karam JA, Souter L, Uzzo RG: Renal mass and localized renal cancer: evaluation, management, and follow-up: AUA Guideline Part I.  J Urology, 206; 199-2008, 2021.
6. Campbell SC, Uzzo RG, Karam JA, Chang SS, Clark PE, Souter L: Renal mass and localized renal cancer: evaluation, management, and follow-up: AUA Guideline Part II. J Urology, 206:209-218, 2021.