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Abstract

Renal tumors (i.e., abnormal growths within the kidney) encompass both benign and malignant entities. The pathologist plays a key role in determining the nature of the growth (i.e., benign or malignant) by evaluating the tumor with a microscope. It is essential to distinguish between these two categories, as malignant tumors possess the potential to spread or metastasize throughout the body, while benign tumors typically follow a less aggressive course and stay limited to the organ. Benign growths may be followed clinically or surgically removed. Excision is often considered if the benign mass, by virtue of its location, is pressing on the bowel or a blood vessel. The removal of a benign growth via surgical excision is typically curative. Therefore, the need for accurate differentiation between benign and malignant renal tumors cannot be emphasized enough as it is imperative for appropriate patient care and management. All this information is recorded and reported in the pathology report. The report is shared with the surgeon, or the primary care physician, who will review and discuss the findings with the patient. In this review we will discuss the histomorphology and challenges in diagnosis of some of the more frequently occurring benign renal neoplasms.

Keywords

Benign kidney tumor renal mass renal cystic mass oncocytoma

INTRODUCTION

Renal masses are frequently, although not exclusively, detected incidentally with imaging studies. The radiologists’ reports often summarize their suspicions about the renal mass being benign or malignant. Occasionally the radiologic findings are equivocal and in those cases the mass is reported as suspicious with a need for tissue biopsy or excision for definitive diagnosis. Alternatively, if the mass is small without a concern for malignancy, the recommendation may be “watchful waiting” where the patient remains in surveillance and imaging is performed at regular intervals (i.e., every 6 to 12 months) to watch the progress/growth rate of the mass. If the mass is growing at a slow rate, then they suspect it to be a “low-grade” lesion that could potentially be benign. If the growth is rapid, then the surgeon may recommend excision suspecting it to be a malignant lesion. Ultimately, with all this information, the patient will need to make the choice on how to proceed.

When a partial or total nephrectomy is performed, where a part of the kidney or the entire kidney is excised, respectively, the pathologist assesses the physical appearance and unique characteristics of the mass, as well as the extent of its involvement. The differentiation between benign and malignant renal neoplasms can be challenging in a subset of cases due to morphologic overlap but is critical as it can have a profound impact not only on the patient’s psyche, but also on the clinical management and prognosis. The World Health Organization (WHO) classification of renal neoplasms includes well established benign and malignant entities; it also mentions “emerging entities” which have been recognized by pathologists but require additional investigation regarding pathologic features, molecular alterations and clinical outcomes. Table 1 lists accepted and emerging benign renal tumors in the WHO, many of which (mostly the epithelial tumors) will be discussed in this review. Accordingly, we will delve into entities that share histological and immunohistochemical features but exhibit distinct variations that set them apart from malignant tumors.

Table 1.

Commonly Diagnosed Benign Renal Neoplasms.

RENAL CELL TUMORS

• Oncocytoma

• Renal papillary adenoma

OTHERS

• Low grade oncocytic tumor

• Eosinophilic vacuolated tumor

METANEPHRIC TUMORS

• Metanephric adenoma

• Metanephric adenofibroma

• Metanephric stromal tumors

MIXED EPITHELIAL AND STROMAL RENAL TUMORS

• Cystic nephroma

• Mixed epithelial and stromal tumor

MESENCHYMAL TUMORS IN ADULTS

• Angiomyolipoma

• Leiomyoma

• Hemangioma

• Lymphangioma

• Juxtaglomerular cell tumor

• Renomedullary interstitial cell tumor

• Schwannoma

RENAL ONCOCYTOMA

Renal oncocytoma (RO) is a benign neoplasm and accounts for approximately 6–10% of renal tumors, affecting a broad age range with a mean age of 62 years and a male-to-female ratio of 2 : 1 [1–6]. Although they frequently occur sporadically, rare hereditary cases and associations with Birt–Hogg–Dubé (BHD) syndrome have been reported. Multiple oncocytomas can also occur simultaneously, a condition referred to as “renal oncocytosis” [7]. Oncocytomas typically arise from the outer portion of the kidney (i.e., the renal cortex), and can occasionally extend into adjacent tissues (i.e., adipose tissue) with no change in overall behavior.

Oncocytoma, on gross inspection, is typically a well-circumscribed unencapsulated tumor that is mahogany-brown or yellow-tan in color with or without a central stellate or peripheral scar [3–6]. While oncocytomas have a favorable prognosis, they can sometimes be challenging to distinguish from other renal tumors. When reviewed under the microscope, it has a solid, nested, or microcystic architecture composed of pink or eosinophilic cells rich in mitochondria (Fig. 1) [5, 6]. Oncocytomas exhibit relatively distinctive features, including dense eosinophilic cytoplasm, round nuclei, and small prominent nucleoli. However, these microscopic features are not entirely specific and may be seen in other benign and malignant renal tumors, such as low-grade oncocytic renal tumors (LOT) and chromophobe renal cell carcinoma (ChRCC), respectively [8–12]. The distinction of these tumor entities can be confounding in a smaller subset of cases, especially on renal core biopsy specimens, which are typically small and may not be representative of the entire lesion. A special staining technique (i.e., immunohistochemistry) can be used for challenging cases with oncocytomas staining diffusely positive for KIT/CD117 and scattered rare cells positive for cytokeratin (KRT7); this is distinct from LOTs and ChRCCs, which are KIT negative and KRT7 diffusely positive and KIT and KRT7 diffusely positive, respectively [13–15].

Figure 1.

Renal oncocytoma. A. A gross image of a mahogany brown, well-circumscribed, tan-yellow mass with a uniform surface; notice it is the similar color as the adjacent non-neoplastic renal parenchyma. B. A high-power image reveals characteristic islands of oncocytic cells with abundant granular eosinophilic cytoplasm, round nuclei and prominent nucleoli in a background of edematous stroma.

Emerging Benign Renal Epithelial Neoplasms: Low grade oncocytic tumor (LOT) and Eosinophilic vacuolated tumor (EVT)

As briefly discussed above, many renal tumors can show overlapping histologic features with oncocytoma and ChRCC. Such ambiguous tumors were previously given several names like “oncocytic RCC, not otherwise specified (NOS)”, “oncocytic, low-grade RCC”, “renal oncocytic tumor, NOS”, “unclassified oncocytic tumor”, “oncocytic tumor with uncertain/low malignant potential”, and “borderline tumor” (or with “borderline features”) [8–10]. Despite the presence of low grade cytology, it was not always clear if these cases were benign or malignant. However, with recent technological advancements, these ‘ambiguous’ tumors have been analyzed further with molecular techniques, and ultimately resulted in the discovery of two distinct benign tumor entities: LOT [13, 14] and eosinophilic vacuolated tumor (EVT) [13, 18]. It is likely that LOTs and EVTs were previously (mis)diagnosed as RO, ChRCC or other eosinophilic/oncocytic RCCs. Surveillance and/or surgical excision is often the preferred treatment approach for oncocytoma, LOT and EVT, with a favorable prognosis, as these tumors tend to be low-grade and have a low risk of recurrence or metastasis. Long-term follow-up monitoring would only be needed to ensure early detection of any potential recurrence or complications.

LOW GRADE ONCOCYTIC TUMOR (LOT)

LOT is a relatively uncommon, eosinophilic renal tumor that may be more often seen in young individuals. They mostly occur sporadically or very rarely in a hereditary setting associated with tuberous sclerosis (TSC). The histopathologic features of LOT have been described as an entity with overlapping features of renal oncocytoma and ChRCC. LOT is typically a small, solid tumor with mahogany-brown to tan cut surface. It exhibits solid and compact nested growth; focal tubular and/or trabecular growth may be present [13–15]. The eosinophilic tumor cells have round to ovoid nuclei and although the nuclear membranes lack significant irregularities, they may show perinuclear clearing/halos like those seen in ChRCC (Fig. 2). The histomorphology reveals sharply delineated, edematous areas with scattered, irregularly arranged cells referred to as “boats in a bay” [13, 14]. These tumors lack prominent nucleoli and other high-grade features, such as necrosis and increased mitotic activity.

Figure 2.

A. Gross image of low grade oncocytic tumor (LOT) reveals a roughly well-circumscribed, tan or yellow-brown, solid tumor mass. B. A low-power image demonstrates eosinophilic tumor cells with a nested architecture; perinuclear clearing (halos) are present around small round nuclei which lack significant nucleoli. C. KRT7 is diffuse positive in LOTs. D. KIT/CD117 is negative in LOTs; the positive staining cells are mast cells (internal control). [Gross image courtesy of Dr. Sean Williamson]

As mentioned, LOT is diffusely positive for KRT7 and is typically negative for KIT/CD117; some studies have demonstrated positive GATA3 expression in LOTs [16]. On electron microscopy, a high-resolution microscope that allows pathologists to identify the contents of the tumor cell cytoplasm but not often used as a contemporary diagnostic tool, LOTs exhibits abundant, closely packed cytoplasmic mitochondria, like oncocytoma [3, 4, 11]. Molecular studies reveal TSC/MTOR pathway gene mutations in LOT; this is distinct from oncocytoma. Distinguishing LOT from oncocytomas is clinically insignificant as both are benign neoplasm; however, the association of MTOR pathway mutations in the former may be important in a small subset of patients [16–18]. The distinction of LOT from ChRCC/other RCCs is important to avoid mislabeling a malignant diagnosis for a benign neoplasm specifically because on imaging it shows up as an avid and typically heterogeneously enhancing solid renal mass which may suggest an RCC [20].

EOSINOPHILIC VACUOLATED TUMOR (EVT)

EVT is a relatively rare renal neoplasm that tends to occur more frequently in adults, with a median age typically ranging from 40 to 60 years. Although typically solitary and sporadic, they can rarely be seen in patients with TSC syndrome [21]. EVTs are solid tumors that typically lack a cystic component and are without a well-formed capsule. Histologically, tumor cells are characterized by abundant eosinophilic cytoplasm and distinctive intracytoplasmic vacuoles. The tumor cells typically have round nuclei with large prominent nucleoli (Fig. 3); some cells may demonstrate multinucleation. Immunohistochemical staining can help differentiate EVT from other renal tumors especially LOT, oncocytoma, and ChRCC. The immunoprofile of EVT includes KIT/CD117 diffuse positivity and KRT7 expression in scattered tumor cells; the distinction from oncocytoma (which demonstrated a similar KIT/KRT7 expression pattern) includes immunoreactivity for Cathepsin K and CD10 in EVT but not typically in oncocytoma. EVTs, unlike oncocytoma, but similar to LOTs, have been shown to harbor MTOR pathway mutations [21].

Figure 3.

A. A gross image of eosinophilic vacuolated tumor (EVT) demonstrates a well-circumscribed, tan-yellow and solid tumor without a distinct capsule. B. A high-power image demonstrates eosinophilic tumor cells with voluminous cytoplasm some with large intracytoplasmic vacuoles, round to oval nuclei that frequently have prominent nucleoli; some tumor cells demonstrate multinucleation. C. Cathepsin K and D. CD10 are expressed in EVTs. [Images courtesy of Dr. Farshid Siadat (gross) and Dr. Michelle Hirsch (microscopic)]

Occasionally, it is still difficult to completely distinguish non-descript low grade renal oncocytic tumors in the kidney due to overlapping morphologic and immunophenotypic findings. In these situations, the recommendation by the genitourinary pathology society (GUPS) is to use “oncocytic renal neoplasm of low malignant potential, NOS.” GUPS also recommends that the term “hybrid oncocytic tumor” be reserved only for renal tumors associated with familial mutations; such tumors are typically bilateral and multifocal as seen in syndromic (i.e., hereditary) settings [15].

RENAL PAPILLARY ADENOMA

Renal papillary adenomas (PAs) are primarily observed in elderly patients, particularly those aged 70–90 years, and are also found in 10% of individuals aged 21–40 years [1, 2, 24]. They are more common in people with certain kidney conditions like renal vascular disease, glomerulosclerosis, acquired cystic disease and those undergoing kidney transplantation for end stage kidney disease [25–27]. PAs typically arise in the renal cortex (i.e., the outer rim of the kidney, beneath the renal capsule). They can be solitary, or multiple. PAs are ill-defined lesions that lack a capsule and blend into the adjacent kidney tissue. By definition, PAs are typically≤15 mm in diameter [1, 2]. As they are small, they are not always distinctly visible on imaging studies or on gross inspection and are frequently found in kidney resections performed for other causes (tumors, end stage kidney disease or at autopsy). When viewed under the microscope, PAs are of a low histological grade and are characterized by pale cytoplasm, round to oval nuclei, monotonous nuclei with minimal variation in size, and lack mitoses. In keeping with their name, PAs demonstrate papillary, tubular, or tubulo-papillary growth patterns (Fig. 4).

Figure 4.

A-B. Renal papillary adenoma. A low-power images reveal small (<15 mm) unencapsulated lesions (cystic in A) with papillary proliferations and low nuclear grade. C-D. Metanephric adenoma. Low (C) and high (D) power images demonstrate small round blue cells forming tightly packed tubules, long branching and angulated ducts. Stroma can be scant with focal edema and scattered psammomatous calcifications.

The most important entity this subset of tumors can be mistaken for is papillary renal cell carcinoma, which are usually > 15 mm and are encapsulated. It has been suggested that PAs could be the precursor lesions to PRCC and may possibly represent a continuum of the same biological process, especially the PAs arising in the background of papillary RCC. Nevertheless, their definitive relationship is not completely understood, and more research is being performed to consolidate this theory of evolution [28, 29].

Papillary RCC, which will be further discussed in the accompanying review on renal tumors with papillary architecture in this special edition, but in brief can have an overlapping histologic appearance with PA, especially in low-grade areas. In contrast to PA, papillary RCC may present as a distinct large mass with extensive hemorrhage, variable areas of necrosis and cystic degeneration. Histologically, tumor cells can vary in size and tumor cell may appear more basophilic (i.e., blue) or eosinophilic (i.e, pink).

Immunohistochemical stains for KRT7, CD10, and AMACR will not help distinguish PA from papillary RCC, as these three biomarkers are typically diffusely positive in both neoplasms [30]. Given the indolent nature of PA with virtually no risk of spreading, monitoring and surveillance are typically advised to evaluate for any changes or concerns [31]. Accordingly, PAs often do not require surgical intervention, and the presence of one or more in a donor kidney does not exclude renal transplantation [27].

METANEPHRIC ADENOMA

Metanephric adenoma is another benign renal tumor that is commonly encountered in the fifth or sixth decade of life with a significant predominance in females [32]. Clinical presentations may include incidental discovery, abdominal pain, or hematuria. Interestingly, a small subset of patients can display erythropoietin-induced polycythemia which essentially means there is an overproduction of red blood cells due to the influence of erythropoietin, which can create vascular complications because of the increased density of blood [32, 33]. On gross inspection tumors are typically solid, well-circumscribed but unencapsulated. They can attain considerable size and therefore mimic an RCC. Histologically, metanephric adenomas contain small round blue cells with round nuclei, surrounded by minimal cytoplasm that are reminiscent of embryonic type cells called primitive metanephric tubular epithelium. Architecturally, they form closely packed acini/tubules or angulated ducts, and some demonstrate long branching and abortive glomeruli-like structures. Frequently, calcified bodies, called dystrophic or psammomatous calcifications form when calcium gets deposited on damaged or injured tissues (Fig. 4).

Immunohistochemistry assists in diagnosis, with positive staining for WT1 and CD57, and frequently a lack of KRT7 [33]. Metanephric adenomas often harbor BRAF mutations; accordingly, expression of BRAF by immunohistochemistry supports the diagnosis [34, 35]. Distinguishing metanephric adenoma from a histologically similar appearing tumor called ‘solid low-grade papillary RCC’ is mainly by immunohistochemistry as the latter stains KRT7 positive and typically BRAF negative [36, 37]. The other entity in the differential diagnosis is the epithelial-predominant nephroblastoma (i.e., Wilms tumor) which can be distinguished by younger age presentation, presence of pseudocapsule, high-grade nuclear features and lack of the BRAF mutation in most cases [38]. Although metanephric adenomas are generally benign, rare coexistence with nephroblastoma or papillary RCC has been reported [39].

MIXED EPITHELIAL AND STROMAL RENAL TUMORS

This family of tumors consists of two main entities. One is the mixed epithelial and stromal tumors (MEST), and the other is adult cystic nephroma (CN). Some believe they are on the same spectrum as both are benign and share some similar histologic findings [1, 2, 40–44]. These unilateral renal tumor masses may arise in the medulla, and are typically asymptomatic, but when symptoms occur, they often manifest as hematuria and abdominal pain. In some cases of large MEST or CN, the lesions may grow at the cost of normal renal function.

MESTs (Fig. 5) are frequently seen in middle aged to perimenopausal women at a median age of about 50 years [45–47]; history of chronic hormonal treatment has been suggested as a potential trigger, despite rare cases reported in male patients [46, 50, 51]. They are typically solitary, well circumscribed tumors, with variable solid and cystic components. The tumors are biphasic in nature and include epithelial cells that line cystic spaces that may resemble thyroid follicle-like spaces and stromal cells that comprise the fibrous tissue intervening between the cystic spaces. The stroma can resemble ovarian stroma which is immunoreactive for estrogen and progesterone receptors [40–42]. Radiologically, because of the complex cystic nature of these lesions, MESTs (70% have solid enhancing components) more than cystic nephromas are frequently classified as Bosnaik III cysts which indicates they are indeterminate cystic masses that may suggest malignancy [48]. Although a majority of these tumors are benign, rare reports of malignant transformation have been reported, including sarcomatous differentiation, MEST with rhabdoid features, undifferentiated components, and carcinosarcoma [49–54].

Figure 5.

Mixed epithelial and stromal tumor. A. A low-power image shows solid and cystic components of varying sizes. B. Scattered or clustered glands in dense stroma. C. High-power image shows cysts with hobnail and columnar lining cells. D. The stroma is hyalinized with large blood vessels and a collagenous nodule.

DICER1 tumors and synovial sarcoma are considered in the differential diagnosis of mixed mesenchymal epithelial stromal tumors due to their overlapping histopathological characteristics, including a spindle cell stroma/neoplasm which can create diagnostic challenges. Mutations in the DICER1 gene are implicated in a range of pediatric and adult tumors [55–61], including certain ovarian and renal neoplasms. When a renal mass exhibits a biphasic pattern with spindle cell stroma and glandular epithelial elements, a DICER1 tumor should always be considered as there are genetic implications. In contrast, synovial sarcoma is a mesenchymal malignancy composed of spindle cells and occasionally epithelial components that can rarely occur in the kidney [62–64]. Moreover, synovial sarcoma often expresses epithelial markers such as cytokeratins, further complicating the differentiation from MEST. However, the presence of the SYT-SSX fusion gene in synovial sarcoma, which results from the characteristic t(X;18) translocation, provides a critical diagnostic clue and can be identified through immunohistochemistry and/or molecular testing, distinguishing it from MEST and DICER1-associated tumors.

Cystic nephroma (Fig. 6) are comprised of non-communicating epithelium-lined cysts without a major solid/stromal component which as previously mentioned show estrogen and/or progesterone receptor positivity in the majority of cases [65–67]. In cystic nephromas, the cells lining the fluid-filled cysts are often flat, cuboidal or hobnailed (i.e., protrude in the cystic spaces). As mentioned, both tumors are exceedingly rare and generally benign, but malignant transformation, usually of the spindle cell stromal component may occur and has been reported in rare cases of MEST, leading to an aggressive clinical course. Therefore, resection may be necessary to confirm that it is indeed benign which is critical for clinical management of the patient [40–42, 66].

Figure 6.

Cystic nephroma. A. Gross image of a cystic nephroma reveals a well circumscribed, multilocular cystic mass with non-communicating cysts of varying sizes filled with serous to serosanguinous fluid. B. A low-power image reveals multiple septated cysts with minimal intervening stroma.

CONCLUSION

In conclusion, the range of benign renal epithelial tumors represents a diverse and complex spectrum of renal neoplasms that requires careful evaluation. The morphologic overlap between benign and malignant renal masses can be challenging; however, careful examination plus ancillary studies such as immunohistochemical can significantly aid the pathologist in making an accurate diagnosis. Understanding the growth patterns, cytologic similarities and differences, and molecular alterations of these tumors is critical for optimal patient management, as the distinction between a benign and malignant mass can significantly impact treatment decisions and prognosis. Therefore, recognizing the unique characteristics of benign renal epithelium plays a key role in guiding clinical strategies, providing reassurance to patients, and ensuring appropriate therapeutic interventions.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments.

FUNDING

The authors report no funding.

AUTHOR CONTRIBUTIONS

Drs. Kandukuri and Karne have equally contributed to this manuscript.

CONFLICTS OF INTEREST

Drs. Kandukuri and Karne have no conflicts of interest to report.

References

Moch

Amin

Berney

Compérat

Gill

Hartmann

Menon

Raspollini

Rubin

Srigley

Hoon Tan

Tickoo

Tsuzuki

Turajlic

Cree

Netto

. The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol. 2022;82(5):458–68. doi:10.1016/j.eururo.2022.06.016. Epub 2022 Jul 16. PMID: 35853783.

Moch

Cubilla

Humphrey

Reuter

Ulbright

. The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol. 2016;70(1):93–105. doi:10.1016/j.eururo.2016.02.029. Epub 2016 Feb 28. PMID: 26935559.

Amin

Crotty

Tickoo

Farrow

. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol. 1997;21(1):1–12. doi:10.1097/00000478-199701000-00001. Erratum in: Am J Surg Pathol. 1997;21(6):742. PMID: 8990136.

Gudbjartsson

Hardarson

Petursdottir

Thoroddsen

Magnusson

Einarsson

. Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases. BJU Int. 2005;96(9):1275–9. doi:10.1111/j.1464-410X.2005.05827. PMID: 16287444.

Perez-Ordonez

Hamed

Campbell

Erlandson

Russo

Gaudin

Reuter

. Renal oncocytoma: a clinicopathologic study of 70 cases. Am J Surg Pathol. 1997;21(8):871–83. doi:10.1097/00000478-199708000-00001. PMID: 9255250.

Trpkov

Yilmaz

Uzer

Dishongh

Quick

Bismar

Gokden

. Renal oncocytoma revisited: a clinicopathological study of 109 cases with emphasis on problematic diagnostic features. Histopathology. 2010;57(6):893–906. doi:10.1111/j.1365-2559.2010.03726. PMID: 21166703.

Kuroda

Tanaka

Ohe

Mikami

Nagashima

Sasaki

Inoue

Hes

Michal

Brunelli

Martignoni

. Review of renal oncocytosis (multiple oncocytic lesions) with focus on clinical and pathobiological aspects. Histol Histopathol. 2012;27(11):1407–12. doi:10.14670/HH-27.1407. PMID: 23018240.

Williamson

Gadde

Trpkov

Hirsch

Srigley

Reuter

Cheng

Kunju

Barod

Rogers

Delahunt

Hes

Eble

Zhou

McKenney

Martignoni

Fleming

Grignon

Moch

Gupta

. Diagnostic criteria for oncocytic renal neoplasms: a survey of urologic pathologists. Hum Pathol. 2017;63:149–56. doi:10.1016/j.humpath.2017.03.004. Epub 2017 Mar 14. PMID: 28315424.

Moch

Ohashi

. Chromophobe renal cell carcinoma: current and controversial issues. Pathology. 2021;53(1):101–8. doi:10.1016/j.pathol.2020.09.015. Epub 2020 Nov 9. PMID: 33183792.

10.

Amin

Paner

Alvarado-Cabrero

, et al. Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am J Surg Pathol. 2008;32(12):1822–34. doi:10.1097/PAS.0b013e3181831e68

11.

Petersson

Gatalica

Grossmann

Perez Montiel

Alvarado Cabrero

Bulimbasic

Swatek

Straka

Tichy

Hora

Kuroda

Legendre

Michal

Hes

. Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases. Virchows Arch. 2010;456(4):355–65. doi:10.1007/s00428-010-0898-4. Epub 2010 Mar 19. PMID: 20300772.

12.

Trpkov

Martinek

Isikci

Maggi-Galuzzi

Alaghehbandan

Gill

Tretiakova

Lopez

Williamson

Montiel

Sperga

Comperat

Brimo

Yilmaz

Pivovarcikova

Michalova

Slouka

Prochazkova

Hora

Bonert

Michal

Hes

. “High-grade oncocytic renal tumor”: morphologic, immunohistochemical, and molecular genetic study of 14 cases. Virchows Arch. 2018;473(6):725–38. doi:10.1007/s00428-018-2456-4. Epub 2018 Sep 19. PMID: 30232607.

13.

Trpkov

Hes

. New and emerging renal entities: a perspective post-WHO 2016 classification. Histopathology. 2019;74(1):31–59. doi:10.1111/his.13727. PMID: 30565301.

14.

Trpkov

Williamson

Gao

Martinek

Cheng

Sangoi

Yilmaz

Wang

San Miguel Fraile

Perez Montiel

Bulimbasić

Rogala

Hes

. Low-grade oncocytic tumour of kidney (CD117-negative, cytokeratin 7-positive): a distinct entity? Histopathology. 2019;75(2):174–84. doi:10.1111/his.13865. Epub 2019 Mar 21. PMID: 30895640.

15.

Trpkov

Hes

Williamson

Adeniran

Agaimy

Alaghehbandan

Amin

Argani

Chen

Cheng

Epstein

Cheville

Comperat

da Cunha

Gordetsky

Gupta

Hirsch

Humphrey

Kapur

Kojima

Lopez

Maclean

Magi-Galluzzi

McKenney

Mehra

Menon

Netto

Przybycin

Rao

Reuter

Saleeb

Shah

Smith

Tickoo

Tretiakova

True

Verkarre

Wobker

Zhou

Gill

. New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol. 2021;34(7):1392–424. doi:10.1038/s41379-021-00779-w. Epub 2021 Mar 4. PMID: 33664427.

16.

Williamson

Hes

Trpkov

Aggarwal

Satapathy

Mishra

Sharma

Sangoi

Cheng

Akgul

Idrees

Levin

Sadasivan

San Miguel Fraile

Rogala

Comperat

Berney

Bulimbasic

McKenney

Jha

Sampat

Mohanty

. Low-grade oncocytic tumour of the kidney is characterised by genetic alterations of TSC1, TSC2, MTOR or PIK3CA and consistent GATA3 positivity. Histopathology. 2023;82(2):296–304. doi:10.1111/his.14816. Epub 2022 Oct 18. PMID: 36208048.

17.

Mohanty

Satapathy

Aggarwal

Mishra

Sampat

Sharma

Williamson

. Oncocytic renal neoplasms with diffuse keratin 7 immunohistochemistry harbor frequent alterations in the mammalian target of rapamycin pathway. Mod Pathol. 2022;35(3):361–75. doi:10.1038/s41379-021-00969-6. Epub 2021 Nov 20. PMID: 34802045.

18.

Chen

Mirsadraei

Jayakumaran

Al-Ahmadie

Fine

Gopalan

Sirintrapun

Tickoo

Reuter

. 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. 2019;43(1):121–31. doi:10.1097/PAS.0000000000001170. PMID: 30303819; PMCID: PMC6686675.

19.

Siadat

Trpkov

. ESC, ALK, HOT and LOT: Three letter acronyms of emerging renal entities knocking on the door of the WHO classification. Cancers (Basel). 2020;12(1):168. doi:10.3390/cancers12010168. PMID: 31936678; PMCID: PMC7017067.

20.

Chai

Siegmund

Hirsch

Silverman

. Low-grade oncocytic tumor: a review of radiologic and clinical features. Abdom Radiol (NY). 2024;49(6):1940–8. doi:10.1007/s00261-023-04167-7. Epub 2024 Feb 19. PMID: 38372764.

21.

Farcaş

Gatalica

Trpkov

, et al. Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases. Mod Pathol. 2022;35(3):344–51. doi:10.1038/s41379-021-00923-6. Epub 2021 Sep 14. Erratum in: Mod Pathol. 2021;34(12):2243. doi: 10.1038/s41379-021-00941-4. Erratum in: Mod Pathol. 2022;35(2):289. doi: 10.1038/s41379-021-00967-8. PMID: 34521993.

22.

Lerma

Schade

Tretiakova

. 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. 2021;116:1–11. doi:10.1016/j.humpath.2021.06.002. Epub 2021 Jun 19. PMID: 34153307.21.

23.

Alaghehbandan

Siadat

Trpkov

. What’s new in the WHO classification of kidney tumours? Pathologica. 2022;115(1):8–22. doi:10.32074/1591-951X-818. Epub 2023 Jan 16. PMID: 36645398; PMCID: PMC10342217.

24.

Grignon

Eble

. Papillary and metanephric adenomas of the kidney. Semin Diagn Pathol. 1998;15(1):41–53. PMID: 9503505.

25.

Caliò

Warfel

Eble

. Papillary adenomas and other small epithelial tumors in the kidney: An autopsy study. Am J Surg Pathol. 2019;43(2):277–87. doi:10.1097/PAS.0000000000001189. PMID: 30418186.

26.

Denton

Magee

Ovuworie

Mauiyyedi

Pascual

Colvin

Cosimi

Tolkoff-Rubin

. Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: a pathologic analysis. Kidney Int. 2002;61(6):2201–9. doi:10.1046/j.1523-1755.2002.00374.x. PMID: 12028461.

27.

Eccher

Boschiero

Fior

Casartelli Liviero

Zampicini

Ghimenton

D’Errico-Grigioni

Caliò

Martignoni

Delahunt

Brunelli

. Donor kidneys with miliary papillary renal cell neoplasia: the role of the pathologist in determining suitability for transplantation. Ann Transplant. 2014;19:362–6. doi:10.12659/AOT.890620. PMID: 25055966.

28.

Saleeb

Farag

Ding

, et al. Integrated molecular analysis of papillary renal cell carcinoma and precursor lesions unfolds evolutionary process from kidney progenitor-like cells. Am J Pathol. 2019;189(10):2046–60. doi:10.1016/j.ajpath.2019.07.002. PMID: 31381885.

29.

Wang

Weinrach

Luan

, et al. Renal papillary adenoma–a putative precursor of papillary renal cell carcinoma. Hum Pathol. 2007;38(2):239–46. doi:10.1016/j.humpath.2006.07.016 PMID: 17056094.

30.

Hiasa

Kitamura

Nakaoka

Ohshima

Konishi

Kitahori

Hirao

Fukushima

Tho

Hayashi

, et al. Antigen immunohistochemistry of renal cell adenomas in autopsy cases: relevance to histogenesis. Oncology. 1995;52(2):97–105. doi:10.1159/000227438. PMID: 7531836.

31.

Umbreit

Thompson

. Metastatic potential of the small renal mass: why can’t we agree? Eur Urol. 2011;60(5):983–5; discussion 985-6. doi:10.1016/j.eururo.2011.07.004. Epub 2011 Jul 12. PMID: 21783319.

32.

Jones

Pins

Dickersin

Young

. Metanephric adenoma of the kidney. A clinicopathological, immunohistochemical, flow cytometric, cytogenetic, and electron microscopic study of seven cases. Am J Surg Pathol. 1995;19(6):615–26. doi:10.1097/00000478-199506000-00001. PMID: 7755148.

33.

Davis

Jr Barton

Sesterhenn

Mostofi

. Metanephric adenoma. Clinicopathological study of fifty patients. Am J Surg Pathol. 1995;19(10):1101–14. doi:10.1097/00000478-199510000-00001. PMID: 7573669.

34.

Pinto

Signoretti

Hirsch

Barletta

. Immunohistochemical staining for BRAF V600E supports the diagnosis of metanephric adenoma. Histopathology. 2015;66(6):901–4. doi:10.1111/his.12509. Epub 2015 Jan 23. PMID: 25130952.

35.

Caliò

Eble

Hes

Martignoni

Harari

Williamson

Brunelli

Osunkoya

Wang

Comperat

Lopez-Beltran

Wang

Zhang

Curless

Post

Chang

Luchini

Baldrige

MacLennan

Montironi

Grignon

Cheng

. Distinct clinicopathological features in metanephric adenoma harboring BRAF mutation. Oncotarget. 2016;8(33):54096–105. doi:10.18632/oncotarget.11117. PMID: 28903326; PMCID: PMC5589565.

36.

Kinney

Eble

Hes

Williamson

Grignon

Wang

Zhang

Baldrige

Martignoni

Brunelli

Wang

Comperat

Fan

Montironi

MacLennan

Cheng

. Metanephric adenoma: the utility of immunohistochemical and cytogenetic analyses in differential diagnosis, including solid variant papillary renal cell carcinoma and epithelial-predominant nephroblastoma. Mod Pathol. 2015;28(9):1236–48. doi:10.1038/modpathol.2015.81. Epub 2015 Aug 7. PMID: 26248896.

37.

Mantoan Padilha

Billis

Allende

Zhou

Magi-Galluzzi

. Metanephric adenoma and solid variant of papillary renal cell carcinoma: common and distinctive features. Histopathology. 2013;62(6):941–53. doi:10.1111/his.12106. Epub 2013 Apr 3. PMID: 23551615.

38.

Argani

. Metanephric neoplasms: the hyperdifferentiated, benign end of the Wilms tumor spectrum? Clin Lab Med. 2005;25(2):379–92. doi:10.1016/j.cll.2005.01.002. PMID: 15848742.

39.

Wobker

Matoso

Pratilas

Mangray

Zheng

Lin

Debeljak

Epstein

Argani

. Metanephric Adenoma-Epithelial Wilms Tumor Overlap Lesions: An Analysis of BRAF Status. Am J Surg Pathol. 2019;43(9):1157–69. doi:10.1097/PAS.0000000000001240. PMID: 31192863.

40.

Jevremovic

Lager

Lewin

. Cystic nephroma (multilocular cyst) and mixed epithelial and stromal tumor of the kidney: a spectrum of the same entity? Ann Diagn Pathol. 2006;10(2):77–82. doi:10.1016/j.anndiagpath.2005.07.011. PMID: 16546041.

41.

Antic

Perry

Harrison

Zaytsev

Pins

Campbell

Picken

. Mixed epithelial and stromal tumor of the kidney and cystic nephroma share overlapping features: reappraisal of 15 lesions. Arch Pathol Lab Med. 2006;130(1):80–5. doi:10.5858/2006-130-80-MEASTO. PMID: 16390243.

42.

Lane

Campbell

Remer

Fergany

Williams

Novick

Weight

Magi-Galluzzi

Zhou

. Adult cystic nephroma and mixed epithelial and stromal tumor of the kidney: clinical, radiographic, and pathologic characteristics. Urology. 2008;71(6):1142–8. doi:10.1016/j.urology.2007.11.106. Epub 2008 Mar 3. PMID: 18313107.

43.

Turbiner

Amin

Humphrey

Srigley

De Leval

Radhakrishnan

Oliva

. Cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (REST) as a unifying term. Am J Surg Pathol. 2007;31(4):489–500. doi:10.1097/PAS.0b013e31802bdd56. PMID: 17414095.

44.

Zhou

Kort

Hoekstra

Westphal

Magi-Galluzzi

Sercia

Lane

Rini

Bukowski

Teh

. Adult cystic nephroma and mixed epithelial and stromal tumor of the kidney are the same disease entity: molecular and histologic evidence. Am J Surg Pathol. 2009;33(1):72–80. doi:10.1097/PAS.0b013e3181852105. PMID: 18971776.

45.

Caliò

Eble

Grignon

Delahunt

. Mixed epithelial and stromal tumor of the kidney: A clinicopathologic study of 53 cases. Am J Surg Pathol. 2016;40(11):1538–49. doi:10.1097/PAS.0000000000000733. PMID: 27635943.

46.

Adsay

Eble

Srigley

Jones

Grignon

. Mixed epithelial and stromal tumor of the kidney. Am J Surg Pathol. 2000;24(7):958–70. doi:10.1097/00000478-200007000-00007. PMID: 10895818.

47.

Michal

Hes

Bisceglia

Simpson

Spagnolo

Parma

Boudova

Hora

Zachoval

Suster

. Mixed epithelial and stromal tumors of the kidney. A report of 22 cases. Virchows Arch. 2004;445(4):359–67. doi:10.1007/s00428-004-1060-y. Epub 2004 Aug 20. PMID: 15322873.

48.

Bata

Tarnoki

Szasz

Poloskei

Fejer

Gyebnar

Nyirady

Berczi

Karlinger

Szendroi

. Bosniak category III cysts are more likely to be malignant than we expected in the era of multidetector computed tomography technology. J Res Med Sci. 2014;19(7):634–8. PMID: 25364363; PMCID: PMC4214022.

49.

Svec

Hes

Michal

Zachoval

. Malignant mixed epithelial and stromal tumor of the kidney. Virchows Arch. 2001;439(5):700–2. doi:10.1007/s004280100518. PMID: 11764393.

50.

Suzuki

Hiragata

Hosaka

Oyama

Kuroda

Hes

Michal

. Malignant mixed epithelial and stromal tumor of the kidney: report of the first male case. Int J Urol. 2013;20(4):448–50. doi:10.1111/j.1442-2042.2012.03155.x. Epub 2012 Sep 19. PMID: 22989206.

51.

Zou

Zhang

Xiang

. Malignant mixed epithelial and stromal tumor of the kidney: the second male case and review of literature. Int J Clin Exp Pathol. 2014;7(5):2658–63. PMID: 24966982; PMCID: PMC4069895.

52.

Jung

Shen

Tran

Jun

Truong

Ayala

. Mixed epithelial and stromal tumor of kidney with malignant transformation: report of two cases and review of literature. Hum Pathol. 2008;39(3):463–8. doi:10.1016/j.humpath.2007.08.008. PMID: 18261632.

53.

Nakagawa

Kanai

Fujimoto

Kitamura

Furukawa

Maeda

Oyama

Takesaki

Hasegawa

. Malignant mixed epithelial and stromal tumours of the kidney: a report of the first two cases with a fatal clinical outcome. Histopathology. 2004;44(3):302–4. doi:10.1111/j.1365-2559.2004.01782.x. PMID: 14987239.

54.

Sukov

Cheville

Lager

Lewin

Sebo

Lewin

. Malignant mixed epithelial and stromal tumor of the kidney with rhabdoid features: report of a case including immunohistochemical, molecular genetic studies and comparison to morphologically similar renal tumors. Hum Pathol. 2007;38(9):1432–7. doi:10.1016/j.humpath.2007.03.022. PMID: 17707262.

55.

Foulkes

Priest

Duchaine

. DICER mutations, microRNAs and mechanisms. Nat Rev Cancer. 2014;14(10):662–72. doi:10.1038/nrc3802. Epub 2014 Sep 1. PMID: 25176334.

56.

Schultz

KAP

Williams

Kamihara

Stewart

Harris

Bauer

Turner

Shah

Schneider

Carr

Harney

Baldinger

Frazier

Orbach

Schneider

Malkin

Dehner

Messinger

Hill

. DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies. Clin Cancer Res. 2018;24(10):2251–61. doi:10.1158/1078-0432.CCR-17-3089. Epub 2018 Jan 17. PMID: 29343557; PMCID: PMC6260592.

57.

Hill

Ivanovich

Priest

Gurnett

Dehner

Desruisseau

Jarzembowski

Wikenheiser-Brokamp

Suarez

Whelan

Williams

Bracamontes

Messinger

Goodfellow

. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009;325(5943)::965. doi:10.1126/science.1174334. Epub 2009 Jun 25. PMID: 19556464; PMCID: PMC3098036.

58.

Bahubeshi

Bal

Rio Frio

Hamel

Pouchet

Yilmaz

Bouron-Dal Soglio

Williams

Tischkowitz

Priest

Foulkes

. Germline DICER1 mutations and familial cystic nephroma. J Med Genet. 2010;47(12):863–6. doi:10.1136/jmg.2010.081216. Epub 2010 Oct 29. PMID: 21036787.

59.

Schultz

Pacheco

Yang

Williams

Messinger

Hill

Dehner

Priest

. Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol. 2011;122(2):246–50. doi:10.1016/j.ygyno.2011.03.024. Epub 2011 Apr 17. PMID: 21501861; PMCID: PMC3138876.

60.

de Kock

Sabbaghian

Druker

Weber

Hamel

Miller

Choong

Gottardo

Kees

Rednam

van Hest

Jongmans

Jhangiani

Lupski

Zacharin

Bouron-Dal Soglio

Huang

Priest

Perry

Mueller

Albrecht

Malkin

Grundy

Foulkes

. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol. 2014;128(4):583–95. doi:10.1007/s00401-014-1318-7. Epub 2014 Jul 15. PMID: 25022261; PMCID: PMC4381868.

61.

Sabbaghian

Addidou-Kalucki

Bernard

Zou

Reeve

Eccles

Cole

Choong

Charles

Tan

Iglesias

Goodyer

Foulkes

. Biallelic DICER1 mutations occur in Wilms tumours. J Pathol. 2013;230(2):154–64. doi:10.1002/path.4196. PMID: 23620094.

62.

Long

J-A

Dinia

Saada-Sebag

Cyprien

Pasquier

Thuillier

Terrier

Boillot

Descotes

J-L

Rambeaud

J-J

. Primitive renal synovial sarcoma: a cystic tumor in young patients. Prog Urol. 2009;19(7):474–8. French. doi:10.1016/j.purol.2009.01.018. Epub 2009 May 21. PMID: 19559377.

63.

Bakhshi

Khan

Shaikh

Khan

Jamadar

. Primary renal synovial sarcoma. Clin Pract. 2012;2(2):e44. doi:10.4081/c2012.e44. PMID: 24765443; PMCID: PMC3981284.

64.

Schoolmeester

Cheville

Folpe

. Synovial sarcoma of the kidney: a clinicopathologic, immunohistochemical, and molecular genetic study of 16 cases. Am J Surg Pathol. 2014;38(1):60–5. doi:10.1097/PAS.0b013e31829b2d0d. PMID: 24061517.

65.

Mukhopadhyay

Valente

de la Roza

. Cystic nephroma: a histologic and immunohistochemical study of 10 cases. Arch Pathol Lab Med. 2004;128(12):1404–11. doi:10.5858/2004-128-1404-CNAHAI.

66.

Caliò

Eble

Grignon

Delahunt

. Cystic nephroma in adults: A clinicopathologic study of 46 cases. Am J Surg Pathol. 2016;40(12):1591–600. doi:10.1097/PAS.0000000000000732. PMID: 27831959.

67.

Wilkinson

Palit

Bardapure

Thomas

Browning

Gill

Biyani

. Adult multilocular cystic nephroma: Report of six cases with clinical, radio-pathologic correlation and review of literature. Urol Ann. 2013;5(1):13–7. doi:10.4103/0974-7796.106958. PMID: 23662002; PMCID: PMC3643315.

Unveiling the Spectrum: Insights into Benign Renal Neoplasms

Abstract

Keywords

INTRODUCTION

RENAL ONCOCYTOMA

Emerging Benign Renal Epithelial Neoplasms: Low grade oncocytic tumor (LOT) and Eosinophilic vacuolated tumor (EVT)

LOW GRADE ONCOCYTIC TUMOR (LOT)

EOSINOPHILIC VACUOLATED TUMOR (EVT)

RENAL PAPILLARY ADENOMA

METANEPHRIC ADENOMA

MIXED EPITHELIAL AND STROMAL RENAL TUMORS

CONCLUSION

Footnotes

ACKNOWLEDGMENTS

FUNDING

AUTHOR CONTRIBUTIONS

CONFLICTS OF INTEREST

References