Renal cell carcinoma associated with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) genetic alterations

Argani, Pedram; Mehra, Rohit

doi:10.1038/s41379-021-00971-y

Cited by 16 publications

(19 citation statements)

References 31 publications

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“…Loss of FH and 2 succinyl cysteine positivity by IHC and/or detection of FH mutation (either germline or somatic) can further confirm the diagnosis (20,40). Lastly, PRNRP with a prominent tubular pattern may be confused with recently characterized low-grade oncocytic tumor or eosinophilic vacuolated tumor; however, these tumors are frequently associated with mutations involving TSC/MTOR pathways and typically lack the inverted nuclei and GATA3 positivity in PRNRP (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity

et al. 2022

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Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described, rare renal tumor that differs clinically, morphologically, and molecularly from papillary renal cell carcinoma (RCC). To further characterize the pathological spectrum of this rare tumor, in this study, we retrospectively identified 16 cases of PRNRP from three institutions to comprehensively investigate the clinicopathological and molecular genetic features, using immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and targeted next-generation sequencing (NGS). The patients included nine men and seven women, with age ranging from 47 to 80 years (median = 67.5 years, mean = 65 years). The tumor size ranged from 0.4 to 9.5 cm in the greatest dimension (median = 1.8 cm, mean = 2.6 cm). Most tumors (12/16) were incidentally identified by imaging studies. By AJCC stage, 15 were categorized as pT1 and 1 was pT2. Follow-up showed no recurrences, metastases, or disease-related deaths in all the 16 patients. Grossly, 14 cases demonstrated at least a partially cystic appearance. Microscopically, all PRNRPs except 1 (case 13) were composed predominantly of thin, branching papillary architecture covered by a single layer of cuboidal cells with finely granular cytoplasm, and low-grade nuclei typically located toward the apical surface away from the basement. Case 13 consisted mostly of solid, densely packed tubules with only a minor papillary component (5%). Other commonly seen histological features included hyalinized or edematous papillae (n = 11), lymphocyte aggregation in fibrovascular cores (n = 10), mast cell infiltration (n = 8), and intralesional hemorrhage (n = 7). Uncommonly seen histological features included lymphoid cuff (n = 4), hemosiderin deposition (n = 5), foci of clear cell change (n = 4), intracytoplasmic vacuoles (n = 4), eosinophilic hobnail cells (n = 2), and infarct-type necrosis (n = 1). Two PRNRPs were concurrent with ipsilateral clear cell papillary RCC and clear cell RCC, respectively. By IHC, the tumors were consistently positive for GATA3, CK7, and PAX8. Fourteen out of 16 tumors showed a basolateral-membranous E-cadherin expression pattern, and 12/16 cases were positive for 34βE12.The expression of AMACR, CD10, and vimentin was either absent or only weak and focal. By targeted NGS, 13/14 evaluated PRNRPs harbored KRAS missense mutations involving c.35G>T resulting in p.G12V (7/13), c.35G>A resulting in p.G12D (4/13), and c.34G>T resulting in p.G12C (2/13). By FISH, 1/15 had gains of chromosomes 7 and 17, and 2/8 male cases had deletion of chromosomes Y. In conclusion, our study confirms that PRNRP is an indolent renal cell neoplasm with unique morphology, consistent immunohistochemical profile, and recurrent KRAS mutation. Our study expands the morphologic spectrum of PRNRP and provides further evidence supporting it as a novel entity.

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Section: Discussionmentioning

confidence: 99%

Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity

et al. 2022

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“…7 Moreover, it should be noted that the TSC/mTOR pathway gene is secondarily mutated in ~5% of conventional RCC subtypes such as bona-fide ccRCC and chRCC. 116 Several promising clinical trials using an mTOR inhibitor are ongoing for nonclear-cell RCCs, including pRCCs, chRCCs, unclassified RCCs, RCCs with TSC/MTOR pathway alterations, but currently available data are limited. [117][118][119][120] Further studies are needed to fully understand the characteristics and differences in histomorphology, biological behaviour, and frequency of TSC/mTOR pathway alterations between the oncocytic tumours, including chRCC, the emerging entities, and other unclassified oncocytic tumours, and utilize them in clinical management and treatment.…”

Section: Recent Advances In the Assessment Of Chromophobe Renal Cell ...mentioning

confidence: 99%

“…It is recommended to add a comment in the diagnosis of such tumours that these tumours cannot be clearly diagnosed as oncocytomas or chromophobe RCC 7 . Moreover, it should be noted that the TSC/mTOR pathway gene is secondarily mutated in ~5% of conventional RCC subtypes such as bona‐fide ccRCC and chRCC 116 . Several promising clinical trials using an mTOR inhibitor are ongoing for nonclear‐cell RCCs, including pRCCs, chRCCs, unclassified RCCs, RCCs with TSC/MTOR pathway alterations, but currently available data are limited 117–120 .…”

Section: Recent Advances In the Assessment Of Chromophobe Renal Cell ...mentioning

confidence: 99%

WHO 2022 landscape of papillary and chromophobe renal cell carcinoma

et al. 2022

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The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin‐like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of ‘other oncocytic tumours’ with oncocytoma/chRCC‐like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so‐called ‘low‐grade’ oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma.

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“…T he role of the mammalian target of rapamycin (MTOR) pathway in renal cell carcinoma is complex. 1 Tuberous sclerosis comples (TSC) genes regulate mTOR signaling which coordinates cell growth by altering mRNA translation, metabolism, and protein turnover. It has long been known that mutations in the tumor suppressor genes TSC1 and TSC2, as well as the gene including the downstream protein (MTOR), are secondary events in approximately 5% of the more common types of renal cell carcinoma (RCC), including clear cell and chromophobe RCC cases.…”

mentioning

confidence: 99%

“…The role of the mammalian target of rapamycin (MTOR) pathway in renal cell carcinoma is complex 1. Tuberous sclerosis comples ( TSC) genes regulate mTOR signaling which coordinates cell growth by altering mRNA translation, metabolism, and protein turnover.…”

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confidence: 99%

Xanthomatous Giant Cell Renal Cell Carcinoma

Argani¹,

Matoso

Pallavajjalla³

et al. 2022

American Journal of Surgical Pathology

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Over the past decade, several distinct novel renal epithelial neoplasms driven by underlying tuberous sclerosis comples (TSC)/mammalian target of rapamycin (MTOR) pathway mutations have been described. We report herein two distinctive TSC2-mutated renal cell carcinomas which do not fit any previously described entity. The two renal carcinomas occurred in young patients (ages 10 and 31 y), and were characterized by highly permeative growth within the kidney with metastases to perirenal lymph nodes. The neoplastic cells were predominantly large, multinucleated giant cells having variably eosinophilic to xanthomatous cytoplasm with basophilic stippling and frequent vacuolization. While the discohesive nature of the neoplastic cells, xanthomatous cytoplasm, immunoreactivity for histiocytic markers and minimal immunoreactivity for conventional epithelial markers raised the possibility of a histiocytic neoplasm, multifocal immunoreactivity for cytokeratin 20 helped establish their epithelial nature. Despite the aggressive growth pattern of these neoplasms and lymph node metastases, mitotic figures were rare and Ki-67 indices were low (<1%). One patient with follow-up shows no evidence of disease seven years after nephrectomy with no adjuvant therapy. Next-generation sequencing demonstrated TSC2 mutations in each case. By immunohistochemistry, downstream markers of mTOR pathway activation S6K1, 4EBP1, and glycoprotein nonmetastatic melanoma protein B were all highly expressed in these neoplasms, suggesting mTOR pathway activation as the neoplastic driver. While the cytokeratin 20 immunoreactivity and focal basophilic cytoplasmic stippling suggest a relationship to eosinophilic solid and cystic renal cell carcinoma, and cytoplasmic vacuolization suggests a relationship to eosinophilic vacuolated tumor, these neoplasms appear to be distinctive given their permeative growth patterns and predominant xanthomatous giant cell morphology. Addition of cytokeratin 20 to a panel of epithelial markers helps avoid misdiagnosis in such cases.

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Renal cell carcinoma associated with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) genetic alterations

Cited by 16 publications

References 31 publications

Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity

Papillary renal neoplasm with reverse polarity: A clinicopathological and molecular genetic characterization of 16 cases with expanding the morphologic spectrum and further support for a novel entity

WHO 2022 landscape of papillary and chromophobe renal cell carcinoma

Xanthomatous Giant Cell Renal Cell Carcinoma

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