The category of "oncocytic renal tumors'' includes well-recognized entities, such as renal oncocytoma (RO) and eosinophilic variant of chromophobe renal cell carcinoma (eo-ChRCC), as well as a group of "gray zone" oncocytic tumors, with overlapping features between RO and eo-ChRCC that create ongoing diagnostic and classification problems. These types of renal tumors were designated in the past as "hybrid oncocytoma-chromophobe tumors". In a recent update, the Genitourinary Pathology Society (GUPS) proposed the term "oncocytic renal neoplasm of low malignant potential, not further classified", for such solitary and sporadic, somewhat heterogeneous, but relatively indolent tumors, with equivocal RO/eo-ChRCC features. GUPS also proposed that the term "hybrid oncocytic tumor" be reserved for tumors found in a hereditary setting, typically arising as bilateral and multifocal ones (as in Birt-Hogg-Dubé syndrome). More recent developments in the "gray zone" of oncocytic renal tumors revealed that potentially distinct entities may have been "hidden" in this group. Recent studies distinguished two new entities: "Eosinophilic Vacuolated Tumor" (EVT) and "Low-grade Oncocytic Tumor" (LOT). The rapidly accumulated evidence on EVT and LOT has validated the initial findings and has expanded the knowledge on these entities. Both are uniformly benign and are typically found in a sporadic setting, but rarely can be found in patients with tuberous sclerosis complex. Both have readily distinguishable morphologic and immunohistochemical features that separate them from similar renal tumors, without a need for detailed molecular studies. These tumors very frequently harbor TSC/MTOR mutations that are however neither specific nor restricted to these two entities. In this review, we outline a proposal for a working framework on how to classify such low-grade oncocytic renal tumors. We believe that such framework will facilitate their handling in practice and will stimulate further discussions and studies to fully elucidate their spectrum.

Department of Pathology and Laboratory Medicine Cumming School of Medicine University of Calgary and Alberta Precision Laboratories Calgary AB Canada

Department of Pathology Charles University and University Hospital Plzen Plzen Czech Republic

Zobrazit více v PubMed

Perrino, C. M. et al. Morphological spectrum of renal cell carcinoma, unclassified: An analysis of 136 cases. Histopathology 72, 305–319 (2018). PubMed DOI

Chen, Y. B. et al. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat. Commun. 7, 13131 (2016). PubMed DOI PMC

Andeen, N. K. et al. Clinical utility of chromosome genomic array testing for unclassified and advanced-stage renal cell carcinomas. Arch. Pathol. Lab. Med. 143, 494–504 (2019). PubMed DOI

Trpkov, K. et al. Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod. Pathol. 34, 1392–1424 (2021). PubMed DOI

Trpkov, K. & Hes, O. New and emerging renal entities: A perspective post-WHO 2016 classification. Histopathology 74, 31–59 (2019). PubMed DOI

Williamson, S. R. et al. Report from the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer. Am. J. Surg. Pathol. 44, e47–e65 (2020). PubMed DOI PMC

Trpkov, K. 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). PubMed DOI

Williamson, S. R. et al. Diagnostic criteria for oncocytic renal neoplasms: A survey of urologic pathologists. Hum. Pathol. 63, 149–156 (2017). PubMed DOI

Hes, O. et al. Oncocytoma. In WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4. (eds. Moch, H. et al.) 43–44 (Lyon, IARC, 2016).

Paner, G. et al. Chromophobe renal cell carcinoma. WHO Classification of Tumours of the Urinary System and Male Genital Organs. (eds Moch, H. et al.) 27–28 (Lyon, IARC, 2016).

Ng, K. L. et al. Differentiation of oncocytoma from chromophobe renal cell carcinoma (RCC): Can novel molecular biomarkers help solve an old problem? J. Clin. Pathol. 67, 97–104 (2014). PubMed DOI

Ng, K. L. et al. A systematic review and meta-analysis of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma. J. Clin. Pathol. 69, 661–671 (2016). PubMed DOI

Skala, S. L. et al. Next-generation RNA sequencing-based biomarker characterization of chromophobe renal cell carcinoma and related oncocytic neoplasms. Eur. Urol. 78, 63–74 (2020). PubMed DOI PMC

McGillivray, P. D. et al. Distinguishing benign renal tumors with an Oncocytic Gene Expression (ONEX) Classifier. Eur. Urol. 79, 107–111 (2021). PubMed DOI

Mai, K. T., Dhamanaskar, P., Belanger, E. & Stinson, W. A. Hybrid chromophobe renal cell neoplasm. Pathol. Res. Pract. 201, 385–389 (2005). PubMed DOI

Petersson, F. et al. Sporadic hybrid oncocytic/chromophobe tumor of the kidney: A clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases. Virchows Arch. 456, 355–365 (2010). PubMed DOI

Hes, O., Petersson, F., Kuroda, N., Hora, M. & Michal, M. Renal hybrid oncocytic/chromophobe tumors—a review. Histol. Histopathol. 28, 1257–1264 (2013). PubMed

Pavlovich, C. P. et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am. J. Surg. Pathol. 26, 1542–1552 (2002). PubMed DOI

Gobbo, S. et al. Renal cell neoplasms of oncocytosis have distinct morphologic, immunohistochemical, and cytogenetic profiles. Am. J. Surg. Pathol. 34, 620–626 (2010). PubMed DOI

Srigley, J. R. et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am. J. Surg. Pathol. 37, 1469–1489 (2013). PubMed DOI

Moch, H., Humphrey, P. A., Ulbright, T. M. & Reuter, V. E., eds. WHO Classification of Tumours of the Urinary System and Male Genital Organs. (Lyon, IARC, 2016).

Trpkov, K. et al. High-grade oncocytic tumour (HOT) of kidney in a patient with tuberous sclerosis complex. Histopathology 75, 440–442 (2019). PubMed DOI

Lerma, L. A., Schade, G. R. & Tretiakova, M. S. Co-existence of ESC-RCC, EVT, and LOT as synchronous and metachronous tumors in six patients with multifocal neoplasia but without clinical features of tuberous sclerosis complex. Hum. Pathol. 116, 1–11 (2021). PubMed DOI

Ruiz-Cordero, R. et al. Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma. Mod. Pathol. 32, 1698–1707 (2019). PubMed DOI

Mohanty, S. K. et al. Oncocytic renal neoplasms with diffuse keratin 7 immunohistochemistry harbor frequent alterations in the mammalian target of rapamycin pathway. Mod. Pathol. 35, 361–375 (2022). PubMed DOI

Amin, M. B. et al. Chromophobe renal cell carcinoma: Histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am. J. Surg. Pathol. 32, 1822–1834 (2008). PubMed DOI

Przybycin, C. G. et al. Chromophobe renal cell carcinoma: A clinicopathologic study of 203 tumors in 200 patients with primary resection at a single institution. Am. J. Surg. Pathol. 35, 962–970 (2011). PubMed DOI

Hakimi, A. A. et al. TCEB1-mutated renal cell carcinoma: A distinct genomic and morphological subtype. Mod. Pathol. 28, 845–853 (2015). PubMed DOI PMC

Shah, R. B. et al. “Renal Cell Carcinoma With Leiomyomatous Stroma” harbor somatic mutations of TSC1, TSC2, MTOR, and/or ELOC (TCEB1): clinicopathologic and molecular characterization of 18 sporadic tumors supports a distinct entity. Am. J. Surg. Pathol. 44, 571–581 (2020). PubMed DOI

Stewart-Merrill, S. B. et al. Oncologic surveillance after surgical resection for renal cell carcinoma: a novel risk-based approach. J. Clin. Oncol. 33, 4151–4157 (2015). PubMed DOI

Ohashi, R. et al. Loss of CDKN1A mRNA and protein expression are independent predictors of poor outcome in chromophobe renal cell carcinoma patients. Cancers 12, 465 (2020). DOI PMC

Alaghehbandan, R. et al. Comprehensive review of numerical chromosomal aberrations in chromophobe renal cell carcinoma including its variant morphologies. Adv Anat Pathol 28, 8–20 (2021). PubMed DOI

Thoenes, W. et al. Chromophobe cell renal carcinoma and its variants—a report on 32 cases. J Pathol 155, 277–287 (1988). PubMed DOI

He, H. et al. “High-grade oncocytic renal tumor”: Morphologic, immunohistochemical, and molecular genetic study of 14 cases. Virchow Arch. 473, 725–738 (2018). DOI

Chen, Y. B. et al. Somatic mutations of TSC2 or MTOR characterize a morphologically distinct subset of sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm. Am. J. Surg. Pathol. 43, 121–131 (2019). PubMed DOI PMC

Kapur, P. et al. Eosinophilic vacuolated tumor of the kidney: A review of evolving concepts in this novel subtype with additional insights from a case with MTOR mutation and concomitant chromosome 1 loss. Adv. Anat. Pathol. 28, 251–257 (2021). PubMed DOI PMC

Gupta, S. et al. Renal Neoplasia in Tuberous Sclerosis: A study of 41 patients. Mayo Clin. Proc. 96, 1470–1489 (2021). PubMed DOI

Trpkov, K. et al. Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): A distinct entity? Histopathology 75, 174–184 (2019). PubMed DOI

Kravtsov, O. et al. Low grade oncocytic tumor of kidney (CK7-positive, CD117-negative). A single institution experience with incidence and clinicopathologic characteristics. Hum. Pathol. (2021). Online ahead of print.

Guo, Q. et al. Characterization of a distinct low-grade oncocytic renal tumor (CD117-negative and cytokeratin 7-positive) based on a tertiary oncology center experience: The new evidence from China. Virchows Arch. 478, 449–458 (2021). PubMed DOI

Akgul, M., Al-Obaidy, K. I., Cheng, L. & Idrees, M. T. Low-grade oncocytic tumour expands the spectrum of renal oncocytic tumours and deserves separate classification: A review of 23 cases from a single tertiary institute. J. Clin. Pathol. (2021). Online ahead of print.

Kapur, P. et al. Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney. Mod. Pathol. 35, 333–343 (2022). PubMed DOI

Ishikawa, N. et al. A case of low-grade oncocytic tumor/chromophobe renal cell carcinoma (oncocytic variant) of the kidney. Case Rep. Pathol. 2021, 6684777 (2021). PubMed PMC

Sharma, D., Pai, T., Prakash, G., Desai, S. & Menon, S. Low-grade oncocytic tumor: Report of two cases of an emerging entity in the spectrum of oncocytic renal neoplasms. Turk. Pathol. Derg. (2021). Online ahead of print.

Mansoor, M., Siadat, F. & Trpkov, K. Low-grade oncocytic tumor (LOT) – a new renal entity ready for a prime time: An updated review. Histol. Histopathol. https://doi.org/10.14670/HH-18-435 . (2022). Online ahead of print.

Morini, A. et al. Low-grade oncocytic renal tumor (LOT): Mutations in mTOR pathway genes and low expression of FOXI1. Mod. Pathol. 35, 352–360 (2022). PubMed DOI

Farcas, M. et al. Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: Next-generation sequencing multi-institutional study of 19 cases. Mod Pathol. 35, 344–351 (2022). (2021). PubMed DOI

Siadat, F. & Trpkov, K. ESC, ALK, HOT and LOT: Three letter acronyms of emerging renal entities knocking on the door of the who classification. Cancers 12, 168 (2021). DOI

Miettinen, M. et al. GATA3: A multispecific but potentially useful marker in surgical pathology: A systematic analysis of 2500 epithelial and nonepithelial tumors. Am. J. Surg. Pathol. 38, 13–22 (2014). PubMed DOI PMC

Tong, K. & Hu, Z. FOXI1 expression in chromophobe renal cell carcinoma and renal oncocytoma: A study of The Cancer Genome Atlas transcriptome-based outlier mining and immunohistochemistry. Virchows Arch. 478, 647–658 (2021). PubMed DOI

Guo, J. et al. Tuberous sclerosis-associated renal cell carcinoma: A clinicopathologic study of 57 separate carcinomas in 18 patients. Am. J. Surg. Pathol. 38, 1457–1467 (2014). PubMed DOI

Schultz, L. et al. Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. Am. J. Surg. Pathol. 35, 1549–1556 (2011). PubMed DOI PMC

Roldan-Romero, J. M. et al. Molecular characterization of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor outcome. Mod. Pathol. 33, 2580–2590 (2020). PubMed DOI

Shah, A. et al. Acquired Cystic Kidney Disease-associated Renal Cell Carcinoma (ACKD-RCC) harbor recurrent mutations in KMT2C and TSC2 Genes. Am. J. Surg. Pathol. 44, 1479–1486 (2020). PubMed DOI

Chaux, A. et al. Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas. Hum. Pathol. 44, 2323–2330 (2013). PubMed DOI

Kwiatkowski, D. J. et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 22, 2445–2452 (2016). PubMed DOI PMC

Acceptance of emerging renal oncocytic neoplasms: a survey of urologic pathologists