Rhabdoid and undifferentiated phenotype in renal cell carcinoma: Analysis of 32 cases indicating a distinctive common pathway of dedifferentiation frequently associated with SWI/SNF complex deficiency

Abbas Agaimy, Liang Cheng, Lars Egevad, Bernd Feyerabend, Ondřej Hes, Bastian Keck, Stefano Pizzolitto, Stefano Sioletic, Bernd Wullich, Arndt Hartmann

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/ SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalAmerican Journal of Surgical Pathology
Volume41
Issue number2
StatePublished - 2017

Fingerprint

Renal Cell Carcinoma
Sucrose
Phenotype
Carcinoma
Chromatin Assembly and Disassembly
Age Distribution
Cellular Structures
Neoplasms
Clone Cells
Survival

Keywords

  • ARID1A
  • Dedifferentiated
  • Renal cell carcinoma
  • Rhabdoid
  • SMARCA2
  • SMARCA4
  • SMARCB1
  • SMARCC1
  • SMARCC2
  • SWI/SNF complex

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Rhabdoid and undifferentiated phenotype in renal cell carcinoma : Analysis of 32 cases indicating a distinctive common pathway of dedifferentiation frequently associated with SWI/SNF complex deficiency. / Agaimy, Abbas; Cheng, Liang; Egevad, Lars; Feyerabend, Bernd; Hes, Ondřej; Keck, Bastian; Pizzolitto, Stefano; Sioletic, Stefano; Wullich, Bernd; Hartmann, Arndt.

In: American Journal of Surgical Pathology, Vol. 41, No. 2, 2017, p. 253-262.

Research output: Contribution to journalArticle

Agaimy, Abbas ; Cheng, Liang ; Egevad, Lars ; Feyerabend, Bernd ; Hes, Ondřej ; Keck, Bastian ; Pizzolitto, Stefano ; Sioletic, Stefano ; Wullich, Bernd ; Hartmann, Arndt. / Rhabdoid and undifferentiated phenotype in renal cell carcinoma : Analysis of 32 cases indicating a distinctive common pathway of dedifferentiation frequently associated with SWI/SNF complex deficiency. In: American Journal of Surgical Pathology. 2017 ; Vol. 41, No. 2. pp. 253-262.
@article{2d7c76c6fc6549d299e5ee2a9bbe20bd,
title = "Rhabdoid and undifferentiated phenotype in renal cell carcinoma: Analysis of 32 cases indicating a distinctive common pathway of dedifferentiation frequently associated with SWI/SNF complex deficiency",
abstract = "Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65{\%}) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88{\%}) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/ SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.",
keywords = "ARID1A, Dedifferentiated, Renal cell carcinoma, Rhabdoid, SMARCA2, SMARCA4, SMARCB1, SMARCC1, SMARCC2, SWI/SNF complex",
author = "Abbas Agaimy and Liang Cheng and Lars Egevad and Bernd Feyerabend and Ondřej Hes and Bastian Keck and Stefano Pizzolitto and Stefano Sioletic and Bernd Wullich and Arndt Hartmann",
year = "2017",
language = "English (US)",
volume = "41",
pages = "253--262",
journal = "American Journal of Surgical Pathology",
issn = "0147-5185",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Rhabdoid and undifferentiated phenotype in renal cell carcinoma

T2 - Analysis of 32 cases indicating a distinctive common pathway of dedifferentiation frequently associated with SWI/SNF complex deficiency

AU - Agaimy, Abbas

AU - Cheng, Liang

AU - Egevad, Lars

AU - Feyerabend, Bernd

AU - Hes, Ondřej

AU - Keck, Bastian

AU - Pizzolitto, Stefano

AU - Sioletic, Stefano

AU - Wullich, Bernd

AU - Hartmann, Arndt

PY - 2017

Y1 - 2017

N2 - Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/ SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.

AB - Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/ SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent with studies on similar neoplasms in other organs. Thorough sampling of such tumors that are usually huge and locally advanced is necessary for recognizing the clone of origin and hence for proper subtyping and also for differentiating them from undifferentiated urothelial carcinoma.

KW - ARID1A

KW - Dedifferentiated

KW - Renal cell carcinoma

KW - Rhabdoid

KW - SMARCA2

KW - SMARCA4

KW - SMARCB1

KW - SMARCC1

KW - SMARCC2

KW - SWI/SNF complex

UR - http://www.scopus.com/inward/record.url?scp=85010822267&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010822267&partnerID=8YFLogxK

M3 - Article

C2 - 27984237

AN - SCOPUS:85010822267

VL - 41

SP - 253

EP - 262

JO - American Journal of Surgical Pathology

JF - American Journal of Surgical Pathology

SN - 0147-5185

IS - 2

ER -