Eosinophilic Renal Cell Tumors With a TSC and MTOR Gene Mutations Are Morphologically and Immunohistochemically Heterogenous

Tjota, Melissa Y.; Chen, Heather; Parilla, Megan; Wanjari, Pankhuri; Segal, Jeremy P.; Antic, Tatjana

doi:10.1097/pas.0000000000001457

Cited by 63 publications

(84 citation statements)

References 39 publications

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“…18 Furthermore, both eosinophilic TSC/MTOR -mutated tumors and ChRCC are consistently immunoreactive with broad-spectrum cytokeratins and EMA. 41,42 Due to these overall discrepancies, the diagnostic considerations were broadened to include a translocation-associated RCC, especially considering the focal finding of a distinct second population of cells encircling aggregates of basement membrane-type material. Indeed, the tumor did demonstrate positivity for melan-A and HMB45, which along with underexpression of cytokeratins aligned with this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…These can have morphologic overlap with the recently described eosinophilic tumors with TSC/ MTOR gene mutation, which have a solid, cystic, and papillary growth pattern, and cells with low-or high-grade nuclei and abundant granular eosinophilic cytoplasm. [40][41][42]46 Less likely were other tumors on the differential with eosinophilic CRCCs-oncocytoma, and the eosinophilic variant of ChRCC.…”

Section: Discussionmentioning

confidence: 99%

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A Tale of 2 Morphologies: Diagnostic Pitfalls inTFEB-Associated Renal Cell Carcinomas, Including a NovelNEAT1-TFEBFusion

et al. 2020

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Aims Translocation-associated renal cell carcinomas (RCCs) have been extensively subcharacterized in recent years, such that each is largely recognized by the 2016 World Health Organization as categorical neoplastic entities in the genitourinary tract. Those belonging to the t(6;11) family of tumors classically have a fusion between TFEB and MALAT1/α, and display a particular histomorphology. Specifically, they show a biphasic population of both small and large epithelioid cells, the smaller component of which surrounds basement membrane-type material. Despite this apt description, the tumors have variable morphology and mimic other RCCs including those with TFE3 translocations. Therefore, a high degree of suspicion is required to make the correct diagnosis. Methods The 2 cases described in this article were of strikingly different appearance, and initially considered consistent with other non-translocation–associated renal tumors. These included clear cell RCC (CCRCC), perivascular epithelioid cell tumor (PEComa), and other eosinophilic RCCs (mainly papillary RCC type 2). Results Using RNA sequencing techniques, they were found to harbor distinct pathogenic rearrangements involving the TFEB gene, namely, fusions with CLTC and NEAT1 (the latter partnering heretofore never reported). Conclusions These alterations manifested in 2 notably dissimilar lesions, underscoring the importance of including this family of carcinomas in the differential of any renal neoplasm that does not display immunophenotypic characteristics consistent with its morphology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Tale of 2 Morphologies: Diagnostic Pitfalls inTFEB-Associated Renal Cell Carcinomas, Including a NovelNEAT1-TFEBFusion

et al. 2020

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“…Although the morphology of these cases was very close to renal oncocytoma or the eosinophilic variant of chromophobe RCC, these tumours ended up in the 'unclassified' RCC category because of an unusual histology or immunophenotype with a dense and more abundant eosinophilic cytoplasm, diffuse staining of CK7, absent to weak staining of CK20 or positivity for P504S. 78,79 Chen et al studied five cases and Tjota et al 18 cases. Both groups identified somatic inactivating mutations of TSC2 or activating mutations of MTOR as the primary molecular alterations, consistent with hyperactive mTOR complex 1 (mTORC1) signalling in most chromophobe-like or renal oncocytoma-like cases.…”

Section: Tumours With Tsc Alterationsmentioning

confidence: 99%

“…97 A few case reports have demonstrated clinical benefit in using mTOR inhibitors to treat TSC associated RCCs, including complete response in a case of sporadic, metastatic ESC RCC. 78,98 Interestingly, one of the cases described as responding to mTOR inhibitor therapy was originally diagnosed as chromophobe RCC. The patient was found to have a germline TSC1 mutation without other characteristics of a TSC tumour.…”

Section: Treatment Of Metastatic Chromophobe Rccmentioning

confidence: 99%

Chromophobe renal cell carcinoma: current and controversial issues

Moch

Ohashi

2021

Pathology

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It has been 35 years since Professor Thoenes and his colleagues discovered chromophobe renal cell carcinoma (RCC). Since then, our knowledge about this tumour entity has changed and novel tumour entities have been discovered. The aim of this review is to discuss recent molecular findings and open questions in diagnosing chromophobe-like/oncocytic neoplasms. The broader differential diagnosis of chromophobe-like and oncocytomalike neoplasms includes SDH-deficient renal cell carcinoma, fumarate hydratase (FH) deficient RCC, epitheloid angiomyolipoma ('oncocytoma like'), MiT family translocation RCC and the emerging entity of eosinophilic solid and cystic renal cell carcinoma. After separation of these tumours from chromophobe RCC, it becomes evident that chromophobe RCC are low malignant tumours with a 5-6% risk of metastasis. Recent next generation sequencing (NGS) and DNA methylation profiling studies have confirmed Thoenes' theory of a distal tubule derived origin of chromophobe RCC and renal oncocytomas. Comprehensive genomic analyses of chromophobe RCC have demonstrated a low somatic mutation rate and identified TP53 and PTEN as the most frequently mutated genes, whereas 'unclassified' RCC with oncocytic or chromophobe-like features can show somatic inactivating mutations of TSC2 or activating mutations of MTOR as the primary molecular alterations. For the future, it would be desirable to create a category of 'oncocytic/chromophobe RCC, NOS' with the potential of further molecular studies for identification of TSC1/2 mutations in these rare tumours.

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“…Since then, there have been new entries introduced into the WHO classification system, such as a clear cell papillary RCC and ones that can only be confirmed by molecular and germline testing such as MiT family translocation RCC, succinate dehydrogenase-deficient RCC, and fumarate hydratase-deficient RCC [5]. The cytopathology literature includes articles describing the features of these new entities, but IHC or molecular analysis is still required for the definitive diagnosis [6][7][8][9]. Thus, as RCCs have become increasingly grouped by molecular signatures, the number of entities in a differential increases, making it difficult for cytopathologists to diagnose FNAs on cytomorphology without ancillary studies such as immunohistochemical (IHC) studies and molecular testing.…”

Section: Introductionmentioning

confidence: 99%

Accuracy of Subclassification and Grading of Renal Tumors on Fine Needle Aspiration Cytology Alone

Chen¹,

Lapadat²,

Lastra³

et al. 2021

Acta Cytologica

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Background: Fine needle aspiration (FNA) of renal masses can distinguish between benign and malignant neoplasms in 73–94% of cases. Previous studies suggested the correct subclassification of renal cell carcinomas (RCCs) by cytomorphology can be achieved in up to 80% of cases. However, as RCCs become increasingly subclassified by molecular signatures, correct subclassification based on cytology alone is increasingly difficult. Design: Two FNA passes (2 stained with Diff-Quik® and 2 with the Papanicolaou method) were performed on all fresh nephrectomy specimens for a 1-year period. There were 30 cases in this study, with 29 primary renal tumors and 1 case of metastatic lung adenocarcinoma. Each case was assigned a random number and came with 2 slides (1 from each staining method). Eight cytopathologists were asked to provide a diagnosis and the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading if applicable. Fleiss’ Kappa and Cohen’s Kappa equations were used to look at inter-rater variability. Results: When compared to the surgical pathology diagnosis, the average percent correct diagnosis for all cytopathologist was 35%. Chromophobe RCCs had the best average percent accuracy at 72% followed by clearcell RCC at 48%. Average accuracy for grading RCCs was 40%. Inter-rater variability among the cytopathologists for all RCC diagnoses was fair with a Fleiss’ Kappa coefficient of 0.28. For the WHO/ISUP grade, the weighted coefficient for each pathologist ranged from 0.11 to 0.45, ranging from fair to moderate, respectively. Conclusions: Renal tumors are difficult to classify on cytopathology alone. Core needle biopsy and ancillary studies are necessary if diagnosis will change management.

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Eosinophilic Renal Cell Tumors With a TSC and MTOR Gene Mutations Are Morphologically and Immunohistochemically Heterogenous

Cited by 63 publications

References 39 publications

A Tale of 2 Morphologies: Diagnostic Pitfalls inTFEB-Associated Renal Cell Carcinomas, Including a NovelNEAT1-TFEBFusion

A Tale of 2 Morphologies: Diagnostic Pitfalls inTFEB-Associated Renal Cell Carcinomas, Including a NovelNEAT1-TFEBFusion

Chromophobe renal cell carcinoma: current and controversial issues

Accuracy of Subclassification and Grading of Renal Tumors on Fine Needle Aspiration Cytology Alone

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