History

RO was first described by Zippel in 1942 as a neoplasm entirely composed of large eosinophilic cells called oncocytes.8 Later, in 1976, Klein and Valensi9 identified another 13 cases as a distinct clinical pathological entity with a typical benign histological presentation and clinical course. RO was originally thought to derive from renal proximal tubules, but most pathologists now suggest a distal origin,10 most likely arising from intercalated cells of collecting ducts. The first description of chRCCs, as distinct from ccRCCs, was made by Theones et al in 1985,11 and a year later, they added the chRCC subtype to the classification of renal tumours.12 The cell characteristic had been described prior to the 1985 publication but only in experimentally induced adenomas in animals. The chromophobe cells had slightly opaque or finely reticular cytoplasm that resisted staining with haematoxylin and eosin. They were able to be distinguished from ccRCCs by a strongly positive reaction within their cytoplasm to Hale’s colloidal iron, and a weaker positive reaction with Alcian Blue, a distinction that has since been found to be unreliable. The authors, however, made a step forward for classification of RCCs by suggesting that the descriptive term ‘light cell’ RCC should be discarded and replaced by either ‘clear cell’ or ‘chromophobe cell’ as appropriate. They pointed out that chromophobe cell tumours were likely to have a different derivation from ccRCCs and other RCCs, and that they may also have a different prognosis, a fact that has since been established. Since the description of chRCCs came a decade later than ROs, there were many instances in that era where renal tumours, which were likely to be chRCCs, were described as ROs. This may have contributed to the confusion surrounding the original recognition of the benign nature of ROs.

Epidemiology

Renal tumours are highly heterogeneous with at least 16 known subtypes, of which four subtypes predominate.13 ,14 CcRCCs, arising from the proximal tubular epithelial cells, is the most common subtype constituting 70–80% of RCCs, followed by papillary (10–15%), chRCCs (5%) and collecting duct RCCs (<1%).15 ,16 RO accounts for approximately 3–7% of all adult renal neoplasms. The peak age of incidence for detection of ROs tends to be in the seventh decade of life. For chRCCs, the peak incidence occurs in the sixth decade. For cases of RO, men seem to be affected twice as often as women. For chRCCs, the disease tends to affect men and women equally.17

ROs and chRCCs can develop as either sporadic or familial forms, and both can be associated with distinct genetic mutations. The majority of ROs and chRCCs occur as sporadic cases.18 ,19 There is also the occasional occurrence of familial renal cancers of oncocytoma with BHD syndrome. Familial oncocytoma is due to partial or complete loss of multiple chromosomes. BHD syndrome is an autosomal dominant inherited syndrome with the BHD gene locus located in the short arm of chromosome 17.20 ,21 This syndrome is characterised by fibrofolliculomas, lung cysts that can lead to spontaneous pneumothoraxes, and various subtypes of renal tumours including hybrid tumours, ROs, chRCCs and ccRCCs.

Sometimes in rare instances, patients can present with renal oncocytosis. Renal oncocytosis was first described in 198222: multiple and bilateral oncocytic nodules and a spectrum of oncocytic changes are found diffusely throughout the renal parenchyma. A large series investigating renal oncocytosis revealed that hybrid development of ROs and chRCCs was most common.23

Clinical presentation

Generally, patients with ROs tend to be asymptomatic and present incidentally following cross-sectional imaging for an unrelated complaint. Similarly, the majority of patients with chRCCs present incidentally with asymptomatic renal masses.24 Less commonly, chRCCs may present with local symptoms of haematuria, flank mass and loin pain, and constitutional symptoms of weight loss and loss of appetite.18 chRCCs Can also present with paraneoplastic syndrome and metastases with predilection to the liver.25 In the largest published series to date, chRCCs present with metastases at a rate of 1.3%.24 Generally, patients with chRCCs tend to present in less advanced stages (I and II), less frequently with metastases and are usually of better performance status25 compared with other subtypes of RCCs. It should be noted, however, that the local and constitutional symptoms for chRCCs are similar to those seen for other RCCs.

ROs will almost always follow a benign clinical course with no significant risk of metastases, whereas malignant chRCCs can subsequently progress to metastases. There have been a few isolated case reports of metastatic ROs on initial presentation or following resection of the ROs,13 ,26 however, these case reports have not been substantiated with proper histopathological confirmation of the metastatic deposits, except for one liver metastasis.6 Therefore, the distinction of almost exclusively benign ROs from malignant, potentially metastatic, chRCCs is needed to guide the management of these often difficult-to-separate entities.

Renal tumours can be detected by radiological imaging using ultrasonography, CT, MRI and positron emission tomography (PET). Usually, following the suspicion of a renal mass, either clinically or via ultrasound, a 4-phase CT scan will be performed to delineate its nature. Multiphase CT scans can clearly delineate the renal tumour, its local extension to surrounding tissues and detect any metastases to regional lymph nodes or other organs. Cases of small renal masses (lesions <4 cm) detected incidentally are increasing in incidence largely owing to the widespread use of ultrasound and CT scans. Generally, there is no accurate differentiation between benign and malignant renal lesions using CT scans (except angiomyolipoma), but retrospectively, about 20% of these small renal masses will be found to be benign lesions. Percutaneous biopsy of these small renal masses provides an enticing strategy to identify lesions of no or low malignant potential, however, widespread uptake of biopsy into clinical practice has been limited.

Predicting whether a small renal mass is malignant, based on its growth velocity, has been reported, but there is no good correlation of malignancy with growth rate.16 A recent meta-analysis of small renal masses which included benign and malignant lesions, showed a mean growth rate of 0.28 cm annually (range 0.09 to 0.86) for small renal masses followed with imaging.14 ROs increase in size with variable velocity, with one case series reporting an observed growth rate of 0.20 cm annually.15 The largest pool of 33 biopsy-proven benign ROs demonstrated a growth rate similar to reported growth rates for RCCs, thus highlighting again that observation of growth cannot distinguish between the benign or malignant nature of such lesions.16 The locality and size of tumours may also be variable. Uncommonly, there have been case reports of large ROs (25×15×12 cm),27 but the average size is normally around 4.9±2.7 cm.28 Published reports worldwide show that ROs can be multifocal in 6–11%,29 ,30 and bilaterality was reported in about 3–5%.29 ,31 By comparison, the median size of chRCCs is about 6.0 cm,18 which is larger compared with other subtypes of RCCs.32 Multifocality of chRCCs is usually around 10–12%.33

Diagnostic dilemma

The increasing use of CT scans for small renal masses has led to a diagnostic dilemma of accurately characterising the nature of these renal lesions and their subsequent management. Typically, on CT scans, RCCs are solid heterogeneous masses with contrast enhancement showing areas of patchy uptake of contrast. Locally advanced tumours may directly invade the adrenal gland, renal vein, inferior vena cava and regional lymph nodes. ChRCCs usually demonstrate homogeneous enhancement, whereas ccRCCs, papillary and collecting duct RCCs tended to show heterogeneous or predominantly peripheral enhancement. Calcification was seen more commonly in chRCCs than in papillary or conventional RCCs.34 On MRI, chRCCs typically have heterogeneous T2 signal intensity and enhancement.

By contrast, on CT scanning, ROs typically show a well-defined, smooth, relatively homogeneous solid mass with a central area of hypoattenuation due to the presence of a central stellate scar, and rarely show any extension to the renal vein, inferior vena cava or the adrenals. MRI scan will typically reveal low to moderate homogeneous intensity on T1-weighted images and relatively high signal intensity on T2-weighted images.35 Classically, if renal angiography on ROs were performed, it would show a typical spoke-wheel pattern, highlighting the marked peripheral vascularity in contrast with the relatively hypovascular central part of the tumour. However, classical hypoattenuation of the central stellate scar on CT scan is seen in less than one-third of ROs, and although characteristic of ROs, it is not diagnostic.14 ,20 Moreover, there are no consistently reliable pathognomic CT scan features that can safely differentiate ROs from RCCs.36 Therefore, most ROs are treated as suspicious of RCCs based on imaging, and thereafter, are subjected to surgical resection.

A recent study on the ability of MRI to discriminate ROs from chRCCs showed that these two entities exhibited similar findings, and no MRI features were reliable in distinguishing between the two.37 The ability of any renal lesion to uptake the 18-fluorodeoxyglucose (FDG) is the basis of 18-FDG PET/CT scans. However, in detection of renal tumours, the role of FDG PET is limited as there are high false negative rates38 Benign ROs are also often FDG-avid, and thus, this cannot be used in separating them from malignant renal tumours.39 Recently, multiphasic multidetector CT scans have helped to discriminate ccRCCs from ROs, papillary RCCs and chRCCs, by using the different enhancements at various phases of the scans.40 This will aid somewhat in the distinction of ccRCCs from ROs, but not the discrimination of ROs from chRCCs. Arterial phase enhancements >500% and washout values >50% in Hounsfield units obtained in multiphasic CT scans can be seen exclusively in ROs and can aid in distinguishing ROs from other subtypes of RCCs.41

Pathology

Despite the non-invasive discriminatory features of multiphasic CT scans, renal mass biopsy provides the best opportunity for preoperative diagnosis. However, there are numerous potential shortcomings for this procedure, leading to the inevitability of surgical excision. One of the main drawbacks of renal mass biopsy is the relative difficulty faced by pathologists to accurately and conclusively diagnose renal tumour subtype from the limited tissue biopsy samples, as usually an entire range of cytoarchitectural features is necessary for examination to arrive at a diagnosis.42 However, as a general rule, if the lesion looks like chRCCs on needle biopsy, it can be confidently reported as such. By comparison, a lesion that looks like an RO may be incompletely sampled, with other areas merging into the eosinophilic variant of chRCCs. This may be a hybrid tumour or simply oncocytoma-like areas in a chRCC. Therefore, most pathologists would not diagnose an RO outright on a needle biopsy, and make a comment as to the possibility of having chRCCs elsewhere in the tumour. In addition to the difficulties in differentiating ROs from chRCCs clinically, the pathological features following surgical resection of these tumours often overlap and pose a diagnostic challenge to pathologists.

ChRCCs are well-circumscribed encapsulated tumours which have a light-brown to tan cut surface. These are typically solid but cystic areas can be found. Central scarring may be seen. Histologically, there are two types. The classic type has large polygonal cells with finely granular cytoplasm. These have prominent plant-like thick cell membranes. The eosinophilic variant is composed of polygonal cells with abundant eosinophilic cytoplasm. Nuclei are irregular, crinkled and angulated, often with perinuclear clearing. Binucleation is common. A solid sheet-like pattern with poor cellular cohesion is commonly found. ROs are also well circumscribed, but unencapsulated tumours which are typically mahogany brown but sometimes tan coloured. A central stellate scar is present in about one-third of cases. Rarely, cystic change or haemorrhage can be found. Histologically, there are large round polygonal cells with abundant eosinophilic cytoplasm and round nuclei. Nucleoli are inconspicuous. Cells form nests, tubules, acini and microcysts. Focal degenerative nuclear atypia may be seen. Figure 1 demonstrates histopathology of chRCCs and ROs.

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Figure 1

(A) H&E-stained section of an example of eosinophilic variant of chromophobe renal cell carcinoma, showing typical large, pale, polygonal cells with prominent cell membranes. Nuclei tend to be irregular and wrinkled, and cells are sometimes binucleated (asterisks). Perinuclear clearing can be prominent. (B) H&E stained section of an example of renal oncocytoma, showing large oncocytes with densely granular eosinophilic cytoplasm. Cells are round to polygonal and nuclei are round and monotonous. Nucleoli are small and inconspicuous.

Hybrid tumours have zones classic for ROs and chRCCs as described above. Some cases of chRCCs have features overlapping with ccRCCs in which the component cells have granular cytoplasm. In ccRCCs, at least some areas have cells with completely clear cytoplasm with high vascularity and typical, delicate, thin-walled, vascular structure throughout the tumour, contrasting with thick-walled blood vessels present in chRCCs. Also, a ccRCC lacks the plant-like architecture seen in chRCCs.

Table 1 describes the macroscopic and microscopic features of ROs and chRCCs. Despite having some subtle distinguishing macroscopic, microscopic and ultrastructural differences, there is often need to use ancillary histochemical and immunohistochemical (IHC) stains to differentiate these two entities. Recently, a new oncocytic variant of a chRCC was described, that morphologically resembles RO, but has the biological characteristics of a chRCC.43 This further adds to the difficulties for pathologists to discern ROs from all these variants of chRCCs.

To date, none of the histochemical, IHC or cytogenetic features has been proven to be reliable and specific.44 However, IHC markers may be a cost-effective and valuable form of information for monitoring disease for both prognosis and treatment-planning regimens. Tables 2⇓–4 list some of the histochemical and IHC markers that have been published. Hale's colloidal iron staining is still used. Currently, the most useful IHC markers for the differentiation of renal tumours are vimentin, cytokeratin (CK)7, CD10 and marker for RCC (RCCma). Vimentin has been shown to be positive in ccRCCs and negative in chRCCs and ROs, and CK7 is positive in chRCCs and negative in ROs and ccRCCs. RCCma and CD10 are positive in ccRCCs and negative in both chRCCs and ROs. Hale’s colloidal iron staining with diffuse reticular pattern and perinuclear halo is present in chRCCs but non-existent in ROs and ccRCCs.45 Colloidal iron and widespread CK7 positivity have been suggested to be useful in distinguishing chRCCs from ROs. In ROs, colloidal iron staining is usually negative and CK7 shows only focal positivity. However, there is overlap in the staining patterns, preventing these stains to be of much practical value. Negative staining for vimentin and widespread staining for CK7 versus negative staining for CK7 and positive staining for vimentin can be useful in distinguishing chRCCs from ccRCCs.

However, as seen in table 2, these IHC markers still have their pitfalls in distinguishing between chRCCs and ROs. For example, the problems with Hale's colloidal iron in certain instances is its failure to stain adequately, or the staining pattern (diffuse cytoplasmic vs luminal) could not be adequately assessed.46 However, vimentin may be useful in discriminating chRCCs from other RCCs, and a panel of vimentin with GST-α and EpCAM may achieve 100% sensitivity and specificity for the differential diagnosis of chRCCs, ROs and ccRCCs.47

ROs and chRCCs share histologic and cytologic features, and also share IHC markers for S100A1 and CD117 (KIT).48 Several other studies with IHC markers, including kidney-specific cadherin, CK7, EMA, CD10, RCC, c-KIT, and RON proto-oncogene have been used to distinguish chRCCs from ROs, but the results of these studies are inconsistent and unsatisfactory.49 Table 3 illustrates current biomarkers used to differentiate chRCCs from ROs, directly or indirectly. BCA2, a RING H2 finger protein RING E3 ligase, holds potential as a tool to distinguish ROs from its mimickers, like chRCCs.50 Additionally, RO has significantly higher expression of the cancer-testis antigens (CTAs), such as MAGE-A3/4 and NY-ESO-1.51 Further investigation is needed to evaluate the potential diagnostic implications for these markers.

The cadherins comprise of a family of transmembrane glycoproteins that function as calcium-dependent homotypic adhesion molecules and are expressed by the majority of epithelium. Currently, over 20 different tissue-specific cadherins have been identified.52 The promise of cadherin proteins in distinguishing chRCCs from ROs is shown in table 4. CKs are a family of intermediate filaments that are characteristic markers of epithelial differentiation. Currently, 20 distinct CKs have been identified. They can be useful in the differential diagnosis of neoplasms of epithelial origin, and consequently, several CKs been investigated in renal neoplasms.53 The CKs that have been trialled to discriminate chRCCs from other RCCs and also ROs, are listed in table 5, but none holds major promise, including CK7. Caveolin-1 is a scaffolding protein encoded by the Cav-1 protein. This has demonstrated better promise in differentiating chRCCs from ROs than CK7.47