Quantitative evaluation with SUV measurements performed in HERMES Hybrid Viewer PDR v2.5 did not improve the performance on a 99mTc-Sestamibi SPECT/CT examination in differentiating RO, a benign renal tumour from RCC. 99mTc-Sestamibi uptake was visually evident in 5 out of 5 HOCTs (100%), 9 out of 11 RO (82%) (Fig. 3), and 6 out of 11 chRCCs (55%) in decreasing order of frequency. All HOCTs and approximately half of the chRCC cases were classified as Sestamibi-positive, raising the question of the clinical importance of misclassifying tumour entities with an indolent clinical course [29]. This finding could be eventually incorporated into modern active surveillance programs [30] resulting in a multimodality imaging approach concerning the non-invasive characterisation of renal neoplasia.
A noteworthy observation is that 3 of 11 chRCCs were re-classified as LOTs upon expert review, and these 3 tumours were all classified as Sestamibi-positive. Our findings suggest that Sestamibi-positive renal tumours are of low malignant potential and thus could be considered in active surveillance programs utilising renal biopsy and longer-term imaging follow up. The emerging question, however, concerns the diagnostic accuracy of the biopsy obtained from those renal tumours that are Sestamibi-positive.
The limitations of imaging methods for accurate differentiation of renal tumours Sestamibi-positive on 99mTc-Sestamibi SPECT/CT (RO, HOCT, chRCC) are valid not only on hybrid molecular and conventional imaging but also considering the complexities on histopathologic evaluation. In the current study, 4 diagnoses of RO were amended, either into HOCT or chRCC following a combined morphological and immunohistochemical assessment of three biopsies and one resection. These reclassifications are consistent with the findings from systematic review and meta-analysis [31], suggesting that core biopsy can often be unreliable for the diagnosis of RO. The diagnosis on renal biopsy can be problematic also due to the regional tumour heterogeneity and for these reasons many pathologists do not even issue a definitive diagnosis of RO on biopsy. In particular, Patel et al. [31] demonstrated that 1 in 4 RO cases was misdiagnosed with 12.5% and 6.3% of tumours re-classified as chRCCs or HOCTs following excision, respectively. It is also important to note that one of the most challenging areas in the routine renal pathology practice is the diagnosis of tumours with overlapping or equivocal features between RO and chRCC, as well as differentiating RO and chRCC from other oncocytic renal tumours that do not completely fill the diagnostic criteria. However, current consensus is that these difficult to classify “hybrid” oncocytic tumours have exceedingly low risk for developing metastatic disease.
Immunohistochemistry plays a major role in renal tumour diagnostics due to its widespread availability; a panel comprising cytokeratin 7 (CK7)/carbonic anhydrase IX (CAIX)/alpha-methyl acyl-CoA racemase (AMACR)/KIT (CD117) may be used for screening [32]. Other emerging markers such as FOXI1, RHCG, and LINC01187 that appear to be lineage-specific for renal epithelial neoplasms arising from intercalated cells in the distal nephron segment, may also play a role in the future [33]. Nevertheless, limitations are well known in routine practice, and slight differences in immunohistochemical profiles have also been identified among HOCT subtypes (i.e. Birt-Hogg-Dubé syndrome, renal oncocytosis/oncocytomatosis and sporadic form) [13, 34].
Other approaches to potentially identify unique oncocytic tumour-specific features include (i) whole scale approach of computer-assisted morphometry [35], (ii) molecular genetic approaches, including gene expression, microRNA, single-nucleotide polymorphism (SNP) as well as array comparative genomic hybridisation (array-CGH) profiling analyses [36, 37] and (iii) metabolomic approach [38, 39]. Currently, however, these diagnostic tools are generally restricted to the research setting and are not part of the routine clinical practice.
In this study, a semi-quantitative immunohistochemical analysis of the mitochondrial content did not demonstrate any significant differences between Sestamibi-positive and Sestamibi-negative renal tumour subsets, possibly attributed either to the functional status of the mitochondria or to the intratumoral heterogeneity, given the limited tumour sampling. Despite increased mitochondrial density documented in various oncocytic tumours, electron microscopy assessment has shown morphological differences in the degree of mitochondrial pleomorphism and/or structure of cristae, in parallel with distinct genomic and metabolomic alterations [40]. Of interest is that Rowe et al. demonstrated a marginal association of mitochondrial staining with 99mTc-sestamibi uptake ratio, which was improved by incorporation of multi-drug resistance pump expression via subtractive normalisation [41].
A continuous number of publications indicate that the vast majority of ROs are Sestamibi positive [6–9, 20, 21]. Patients with Sestamibi positive renal tumours could avoid or postpone surgical treatment. Instead, a renal biopsy could be preferred as well as a longer follow up period to track the dynamics of the examined renal neoplasia. The knowledge mentioned above that 99mTc-Sestamibi SPECT/CT brings in the characterisation of renal neoplasia followed by a confirmatory renal biopsy can reduce not only the overtreatment of benign renal tumours but also reduce the percentage of untreated malignant renal tumours. The use of 99mTc-Sestamibi SPECT/CT should be considered in clinical praxis since it is a diagnostic tool identifying renal tumours of indolent clinical course namely RO, HOCT, chRCC and LOT [28, 29].