Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

Adolescent Adult Aged Female Humans Male Middle Aged Young Adult Biomarkers, Tumor / genetics Carcinoma, Renal Cell / pathology DNA Copy Number Variations High-Throughput Nucleotide Sequencing Kidney / pathology Kidney Neoplasms / pathology Mutation Neoplasm Recurrence, Local TOR Serine-Threonine Kinases / genetics

Journal

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

ISSN: 1530-0285

Titre abrégé: Mod Pathol

Pays: United States

ID NLM: 8806605

Informations de publication

Date de publication:
03 2022

Historique:

received: 05 05 2021

accepted: 01 09 2021

revised: 27 08 2021

pubmed: 16 9 2021

medline: 5 4 2022

entrez: 15 9 2021

Statut: ppublish

Résumé

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.

Identifiants

DOI: 10.1038/s41379-021-00923-6 PMID: 34521993

pubmed: 34521993

doi: 10.1038/s41379-021-00923-6

pii: S0893-3952(22)00311-8

doi:

Substances chimiques

Biomarkers, Tumor 0

MTOR protein, human EC 2.7.1.1

TOR Serine-Threonine Kinases EC 2.7.11.1

Types de publication

Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

344-351

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Références

He, H. et al. “High-grade oncocytic renal tumor”: morphologic, immunohistochemical, and molecular genetic study of 14 cases. Virchows Arch 473, 725–738 (2018).

doi: 10.1007/s00428-018-2456-4

Chen, Y. B. et al. Somatic mutations of TSC2 or MTOR characterize a morphologically distinct subset of sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm. Am. J. Surg. Pathol. 43, 121–131 (2019).

doi: 10.1097/PAS.0000000000001170

Trpkov, K. et al. High-grade oncocytic tumour (HOT) of kidney in a patient with tuberous sclerosis complex. Histopathology 75, 440–442 (2019).

doi: 10.1111/his.13876

Trpkov, K. et al. Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod. Pathol. 34, 1167–1184 (2021).

doi: 10.1038/s41379-021-00737-6

Gatalica, Z., Xiu, J., Swensen, J. & Vranic, S. Comprehensive analysis of cancers of unknown primary for the biomarkers of response to immune checkpoint blockade therapy. Eur. J. Cancer 94, 179–186 (2018).

doi: 10.1016/j.ejca.2018.02.021

Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet 51, 202–206 (2019).

doi: 10.1038/s41588-018-0312-8

Vanderwalde, A., Spetzler, D., Xiao, N., Gatalica, Z. & Marshall, J. Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients. Cancer Med. 7, 746–756 (2018).

doi: 10.1002/cam4.1372

Ruder, D. et al. Concomitant targeting of the mTOR/MAPK pathways: novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer. Oncotarget 9, 33995–34008 (2018).

doi: 10.18632/oncotarget.26129

Siadat, F. & Trpkov, K. ESC, ALK, HOT and LOT: Three letter acronyms of emerging renal entities knocking on the door of the WHO Classification. Cancers 12, 1 (2020).

doi: 10.3390/cancers12010168

Guo, J. et al. Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am. J. Surg. Pathol. 38, 1457–1467 (2014).

doi: 10.1097/PAS.0000000000000248

Tjota, M. et al. Eosinophilic renal cell tumors with a TSC and MTOR gene mutations are morphologically and immunohistochemically heterogenous: clinicopathologic and molecular study. Am. J. Surg. Pathol. 44, 943–954 (2020).

doi: 10.1097/PAS.0000000000001457

Palsgrove, D. N. et al. Eosinophilic solid and cystic (ESC) renal cell carcinomas harbor TSC mutations: Molecular analysis supports an expanding clinicopathologic spectrum. Am. J. Surg. Pathol. 42, 1166–1181 (2018).

doi: 10.1097/PAS.0000000000001111

Williamson, S. R. et al. Diagnostic criteria for oncocytic renal neoplasms: a survey of urologic pathologists. Hum. Pathol. 63, 149–156 (2017).

doi: 10.1016/j.humpath.2017.03.004

Petersson, F. et al. Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases. Virchows Arch 456, 355–365 (2010).

doi: 10.1007/s00428-010-0898-4

Delongchamps, N. B. et al. Hybrid tumour ‘oncocytoma-chromophobe renal cell carcinoma’ of the kidney: a report of seven sporadic cases. BJU Int. 103, 1381–1384 (2009).

doi: 10.1111/j.1464-410X.2008.08263.x

Mai, K. T., Dhamanaskar, P., Belanger, E. & Stinson, W. A. Hybrid chromophobe renal cell neoplasm. Pathol. Res. Pr. 201, 385–389 (2005).

doi: 10.1016/j.prp.2005.03.008

Hes, O., Petersson, F., Kuroda, N., Hora, M. & Michal, M. Renal hybrid oncocytic/chromophobe tumors - a review. Histol. Histopathol. 28, 1257–1264 (2013).

pubmed: 23740406

Trpkov, K. & Hes, O. New and emerging renal entities: a perspective post-WHO 2016 classification. Histopathology 74, 31–59 (2019).

doi: 10.1111/his.13727

Trpkov, K. et al. New developments in existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod. Pathol. 34, 1392–1424 (2021).

doi: 10.1038/s41379-021-00779-w

Alaghehbandan, R., Perez Montiel, D., Luis, A. S. & Hes, O. Molecular genetics of renal cell tumors: a practical diagnostic approach. Cancers 12, 1 (2019).

doi: 10.3390/cancers12010085

Tretiakova, M. S. Eosinophilic solid and cystic renal cell carcinoma mimicking epithelioid angiomyolipoma: series of 4 primary tumors and 2 metastases. Hum. Pathol. 80, 65–75 (2018).

doi: 10.1016/j.humpath.2018.05.023

Trpkov, K. et al. Eosinophilic, solid, and cystic renal cell carcinoma: Clinicopathologic study of 16 unique, sporadic neoplasms occurring in women. Am. J. Surg. Pathol. 40, 60–71 (2016).

doi: 10.1097/PAS.0000000000000508

Trpkov, K. et al. Eosinophilic solid and cystic renal cell carcinoma (ESC RCC): Further morphologic and molecular characterization of ESC RCC as a distinct entity. Am. J. Surg. Pathol. 41, 1299–1308 (2017).

doi: 10.1097/PAS.0000000000000838

Parilla, M. et al. Are sporadic eosinophilic solid and cystic renal cell carcinomas characterized by somatic tuberous sclerosis gene mutations? Am. J. Surg. Pathol. 42, 911–917 (2018).

doi: 10.1097/PAS.0000000000001067

Shah, R. B. et al. “Renal cell carcinoma with leiomyomatous stroma” harbor somatic mutations of TSC1, TSC2, MTOR, and/or ELOC (TCEB1): Clinicopathologic and molecular characterization of 18 sporadic tumors supports a distinct entity. Am. J. Surg. Pathol. 44, 571–581 (2020).

doi: 10.1097/PAS.0000000000001422

Schultz, L. et al. Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. Am. J. Surg. Pathol. 35, 1549–1556 (2011).

doi: 10.1097/PAS.0b013e31822895e5

Kwiatkowski, D. J. et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 22, 2445–2452 (2016).

doi: 10.1158/1078-0432.CCR-15-2631

Roldan-Romero, J. M. et al. Molecular characterization of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor outcome. Mod. Pathol. 33, 2580–2590 (2020).

doi: 10.1038/s41379-020-0607-z

Chaux, A. et al. Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas. Hum. Pathol. 44, 2323–2330 (2013).

doi: 10.1016/j.humpath.2013.05.014

Chen, Y. B. et al. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat. Commun. 7, 13131 (2016).

doi: 10.1038/ncomms13131