Aims Low-grade oncocytic tumour (LOT) has recently been introduced as a potential distinct entity.
Methods At the Indiana University department of pathology, primary renal epithelial neoplasms between 2005 and 2020 were searched after appropriate institutional review board permissions.
Results Twenty-three cases (male/female ratio 14/9) with a median age of 66 (23–84 years) were identified. The majority of patients underwent partial nephrectomy (15/23, 65%), with a median tumour size of 4.0 cm (2.2–10.5 cm). Only one case had infiltration beyond the kidney (perinephric fat). Solid/diffuse proliferation of tightly packed oncocytic tumour cells and occasional tubule formations, with an abrupt edematous change in the stroma with loosely connected small clusters of tumour cells. Along with diffuse CK7 expression with lack of CD117 in all cases, vimentin was positive in 8/23 cases (35%, 5 focal). CD10 was expressed in 6/13 (46%, 4 focal). Alpha-Methylacyl-CoA Racemase (AMACR) was positive in 5/8 (63%) cases. Focal but intense cytoplasmic colloidal iron stain was present in 3/20 (15%) cases. Luminal or cytoplasmic/perinuclear precipitation was observed in 8/20 (40%) cases. Succinate Dehydrogenase B (SDHB) was performed in 6 cases, with all retained expression.
Conclusions LOT is a clinically indolent and potentially benign entity with distinguishable morphology and immunohistochemical profile that can be performed and be easily interpreted in most of surgical pathology settings. Additional studies with larger cohorts, comprehensive molecular evaluation and longer follow-up are needed to definitively recognise these tumours as a separate entity and to further address the possibility of active surveillance options in eligible patients.
- kidney neoplasms
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Renal neoplasms with eosinophilic cytomorphology are a potential diagnostic challenge, particularly in the setting of non-papillary low-grade tumour cytomorphology. The main differential diagnosis is oncocytoma, a well-established benign renal tumour1–3 with the ability to present extrarenal involvement such as perinephric adipose tissue4 or renal vein5 with no metastatic potential. Moreover, significant morphological overlap exists with malignant tumours, including eosinophilic chromophobe renal cell carcinoma (RCC),6 eosinophilic clear cell RCC, succinate dehydrogenase (SDH) deficient RCC,7 hybrid oncocytic tumours,8 and rarely fumarate hydratase (FH) deficient RCC with low-grade features.9
Several emerging eosinophilic renal neoplasms10 have been identified in the last decade. Trpkov et al have recently identified “low-grade oncocytic tumour (LOT)” based on distinct morphological and immunohistochemical (IHC) features.11 They described 28 tumours with characteristic features, including unencapsulated well-circumscribed renal tumours having monomorphic tumour cells with abundant eosinophilic cytoplasm, round-to-oval nuclei with minimal cytological atypia and occasional perinuclear halos. These tumours displayed tightly packed small clusters of oncocytic cells and tubules with occasional ‘archipelago-like’ connected nests in the background of an edematous stroma.11 Consistent IHC pattern of diffuse CK7 expression with negative CD117 separated these tumours from oncocytoma and eosinophilic chromophobe RCC. Strikingly, in 27 patients with available clinical follow-up with a median of 21 months, none recurred, progressed or developed metastatic disease. This entity is currently categorised as provisional at the latest Genitourinary Pathology Society consensus update and likely to be introduced in the upcoming the World Health Organization (WHO) renal tumours classification with some variation in terminology.12 Herein, we present a single institutional clinicopathological series of 23 LOT.
Materials and Methods
All primary renal epithelial neoplasms between 2005 and 2020 were searched from electronic records after appropriate institutional review board permissions. Tumours diagnosed as ‘RCC unclassified’ (RCCU), or ‘low-grade eosinophilic renal neoplasms,’ were identified and reviewed. Patients with a known history of hereditary kidney cancer syndromes were excluded. Tumours with CK7+/CD117− immunoprofile and morphologically consistent with LOTs11 were selected and included. Patient’s age, gender, surgical procedure, tumour size, International Society of Urologic Pathology (ISUP)/WHO nuclear grade, tumour stage per eighth edition of American Joint Committee on Cancer guideline, IHC profile and available clinical follow-up were recorded. The extent and intensity of IHC assay expression were semiquantifed as diffuse (expression in ≥50% of tumour cells) and focal (expression in <50% of tumour cells); mild (1+), moderate (2+) or strong (3+).
Clinical information and follow-up
Reports of 7429 primary renal neoplasms in the years between 2005 and 2020 were reviewed. Among these, 343 were diagnosed as RCCU or low-grade renal eosinophilic neoplasm. Twenty-seven cases were identified, displaying CK7+/CD117− immunoprofile. Of these, 23 cases had low-grade eosinophilic cellular features with minimal anisocytosis. Of 23 cases, 21 (91%) were diagnosed as RCCU, whereas 2 (9%) cases were finalised with the microscopic description of ‘low-grade oncocytic/eosinophilic renal neoplasm). Fourteen cases (14/23, 61%) were sent from outside institutions for a second opinion; all H&E and IHC-stained slides, with blocks of the representative sections, were included.
The male-to-female ratio was 14/9, with a median age of 66 years (range 22–84 years). The majority of the surgical procedures were partial nephrectomy (15/23, 65%), followed by radical nephrectomy (7/23, 31%) and one biopsy (1/23, 4%). The median tumour size was 4 cm (range 1.6–10.5 cm). The most common tumour stage was pT1a (n=10/22, 45%), followed by pT1b (n=9/22, 40%). The remaining three cases were staged pT2a, pT2b and pT3a, each (13%). Clinical information was available for 14 patients, and the median follow-up was 30 months (range 2–93 months). No patient demonstrated recurrence or developed metastasis. One patient (case 22) died of a cerebrovascular accident, irrelevant of her renal tumour, after 23 months of her nephrectomy. Please refer to online supplemental data for the detailed clinicopathological information of each individual cases
Morphological and IHC characteristics
Grossly, all patients had solitary tumours with well-delineated and non-infiltrative borders. The tumours were solid, soft pink or light brown, with a homogeneous glistening cut surface (figure 1A) on sectioning. Cystic change, central scarring and haemorrhage were uncommon and were only seen in larger tumours (4/23, 17%). Necrosis was not identified in any of the tumours.
Microscopically, the most common growth pattern was solid/diffuse proliferation of tightly packed oncocytic tumour cells and occasional tubule formations (figure 1A,B), with an abrupt edematous change in the stroma with loosely connected small clusters of tumour cells (figure 1A,B). Haemorrhage can be seen (figure 1D). Tubuloreticular and trabeculated areas were also seen in several cases. The tumour cells were monotonous and had abundant eosinophilic cytoplasm and round-to-oval nuclei with smooth nuclear contours (figure 1E). In 16 (70%) cases, ISUP/WHO equivalent nuclear grade was 2, with either small or slightly prominent nucleoli. The remainder had conspicuous, usually solitary nucleoli (7, 30%). Many of the cells showed perinuclear clearing similar to perinuclear halos of chromophobe RCC, but none of the cases showed this finding in the majority of the cells. Spindled eosinophilic cells were also seen, especially in hypocellular areas with myxoid stroma. Focal degenerative changes or multinucleation were occasionally seen. Prominent nuclear pleomorphism, sarcomatoid or rhabdoid features were not present. No necrosis or mitotic figures were identified.
IHC stain for keratin 7 was diffusely positive in all cases, along with a uniformly negative expression of CD117 (figure 1F,G, respectively). Vimentin was positive in 8/23 cases (35%); five were focal. CD10 was expressed in 6/13 (46%) cases; four displayed only focal expression. Alpha-Methylacyl-CoA Racemase (AMACR) was positive in 5/8 (63%) cases. Colloidal iron was negative in nine of the 20 tested cases (45%). The focal but intense cytoplasmic colloidal iron stain was present in 3/20 (15%) cases. Luminal or cytoplasmic/perinuclear precipitation was observed in 8/20 (40%) cases. Succinate dehydrogenase B (SDHB) was performed in 6 cases due to clinical suspicion, and all had retained expression (figure 1H) . IHC and histochemical studies are summarised in table 1.
The focus of diagnostic recommendations on non-papillary low-grade eosinophilic renal tumours has long been centred around the dichotomy between oncocytoma and eosinophilic chromophobe RCC13–15 due to the significant morphological overlap and the potential impact of misdiagnosis on clinical management. Recently, a survey conducted by urological pathologists16 concluded that most experts consider increased mitotic activity (more than one in one entire section) as incompatible with oncocytoma. Moreover, the majority (94%) approved the use of IHC and special stains in select cases, with very limited CK7 expression deemed acceptable for oncocytoma. On the malignant end, eosinophilic chromophobe RCC has innate nuclear atypia and perinuclear halos with a much more prominent solid and diffuse growth pattern. Consistent and diffuse IHC expressions of CK7 and CD117 are the key to this diagnosis.14 16
Other than oncocytoma and eosinophilic chromophobe RCC, another entity with predominantly low-grade nuclear tumour cells and distinct morphology is SDH deficient RCC.7 It demonstrates solid sheets of monomorphous eosinophilic tumour cells, occasionally entrapping benign renal parenchymal elements, and the hallmark cytological feature is the presence of intracytoplasmic vacuoles or inclusions.7 Although loss of SDHB protein by IHC is the most important finding and a requisite for the diagnosis, most SDH deficient RCC lack CK7 expression, another helpful feature to distinguish from LOT. Hybrid oncocytic tumours, low-grade eosinophilic tumours having morphological and IHC features of both oncocytoma and chromophobe RCC is in the differential diagnosis, particularly in the setting of multifocal tumours.8 Lastly, rare m anifestation of FH deficient RCC with low-grade features may present with morphological features resembling SDH deficient RCC; these tumours also tend to be CK7 negative, and more importantly, loss of FH by IHC is evident.9
This study presents our experience on LOT, an eosinophilic/oncocytic renal neoplasm with low-grade non-papillary morphology and characteristic CK7+/CD117- IHC profile.17 All cases in our cohort had similar histomorphological features as described by Trpkov et al11 (table 2), including well-circumscribed borders, despite the presence of occasionally larger tumour size, low-grade eosinophilic tumour cell cytology, absent mitotic activity, oncocytoma-like areas of interconnected cell clusters in the edematous stroma, and tubular formation. Along with CK7+/CD117− expression, we also identified focal vimentin and CD10 expression in a subset of cases. Although vimentin expression is seen in a subset of cases (8/23), most cases exhibited diffuse (n=5) or strong (n=6) expression. This is an unexpected observation that appears to contradict with the previous LOT reports.11 18 Focal vimentin expression is reported in oncocytoma and SDH deficient RCC, and thankfully, vimentin is not usually employed as one of the critical biomarkers in the differential diagnosis of renal eosinophilic neoplasms with low-grade cytology. Moreover, we observed consistent focal AMACR expression in 5/8 cases. Colloidal iron staining was present in 45% of the tested cases (9/20), and mostly atypically (luminal only) localised staining pattern was in agreement with Trpkov et al.11 study. Most importantly, unanimous lack of recurrence or metastasis was the unique characteristic of these tumours, despite occasionally larger tumour size. Along with Trpkov et al’s cohort,11 a couple of other small-sized cohorts18 19 presented LOT with similar histomorphological and immunophenotypical features.
Losses of loci 19p33.3 and 1p36.33 with comparative genomic hybridisation were found in LOT, suggesting distinct molecular pathogenesis.11 In another study, Tjota et al19 grouped eosinophilic tumours with unusual features into three groups, of which, group 2 tumours had histomorphological features almost identical to LOT, with diffuse CK7 and consistent AMACR expression.19 Moreover, these tumours were found to have pathogenic variants in TSC1, TSC2 and mTOR genes. These findings indicate a homogeneous molecular landscape in these tumours, in line with the shared morphological and IHC expression profile.
Non-papillary low-grade eosinophilic tumours, once the oncocytoma and eosinophilic chromophobe RCC are excluded, are most likely put in RCCU category, 75% of which exhibit eosinophilic morphology and 32% of those having low-grade features.20 The increasing efforts in recognising ‘non-oncocytoma’ low-grade eosinophilic neoplasms pursue the goal of identifying tumours with indolent, potentially benign nature.
There are several limitations of our study. Although all of the IHC assays of the cases from outside institutions were reviewed at our institution, we do not have detailed information on the specific clones and the methodology used. Another limitation of our study is the lack of molecular interrogation of the tumours to characterise the genetic landscape of LOT. We are now performing the next-generation sequencing on the available cases, and the findings will be reported separately.
In our study and similar available literature, LOT is a clinically indolent and potentially benign entity with distinguishable morphology and IHC profile that can be performed and be easily interpreted in most surgical pathology settings. Additional studies with larger cohorts, comprehensive molecular evaluation and longer follow-up are needed to definitively recognise these tumours as a separate entity and to further address the possibility of active surveillance options in eligible patients.
Take home messages
CK7+/CD117− low-grade renal eosinophilic neoplasms encompass a distinct entity with a favourable outcome.
Distinct morphology and immunoprofile with highly used immunohistochemical facilitate their recognition.
These tumours should be ruled out before diagnosing renal cell carcinoma, unclassified.
This study is conducted under the approval of Institutional Review Board of Indiana University Health (approval ID/Project title Protocol# 1609400417 'Genitourinary neoplastic and non-neoplastic morphological pathology and clinical correlation with immunohistochemical marker analysis').
Handling editor Tahir S Pillay.
Contributors Each author listed in the manuscript played significant role in designing the project, writing the manuscript, creating the figures and tables, and other necessary actions.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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