Tubulocystic carcinoma of the kidney with poorly differentiated foci

Steven C. Smith, Kiril Trpkov, Ying Bei Chen, Rohit Mehra, Deepika Sirohi, Chisato Ohe, Andi K. Cani, Daniel H. Hovelson, Kei Omata, Jonathan B. Mchugh, Wolfram Jochum, Maurizio Colecchia, Mitual Amin, Mukul K. Divatia, Ondřej Hes, Santosh Menon, Isabela Werneck Da Cunha, Sergio Tripodi, Fadi Brimo, Anthony J. Gill & 14 others Adeboye O. Osunkoya, Cristina Magi-Galluzzi, Mathilde Sibony, Sean R. Williamson, Gabriella Nesi, Maria M. Picken, Fiona Maclean, Abbas Agaimy, Liang Cheng, Jonathan I. Epstein, Victor E. Reuter, Satish K. Tickoo, Scott A. Tomlins, Mahul B. Amin

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes - including FH - performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.

Original languageEnglish (US)
Pages (from-to)1457-1472
Number of pages16
JournalAmerican Journal of Surgical Pathology
Volume40
Issue number11
DOIs
StatePublished - Oct 1 2016

Fingerprint

Fumarate Hydratase
Renal Cell Carcinoma
Carcinoma
Kidney
Leiomyomatosis
Immunohistochemistry
Genetic Counseling
Neoplasms
Christianity
Mutation
Triage
Genetic Testing
Terminology
Genes
Adenocarcinoma

Keywords

  • 2SC
  • fumarate hydratase
  • fumarate hydratase-deficient RCC
  • HLRCC
  • renal cell carcinoma
  • tubulocystic carcinoma of the kidney

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Smith, S. C., Trpkov, K., Chen, Y. B., Mehra, R., Sirohi, D., Ohe, C., ... Amin, M. B. (2016). Tubulocystic carcinoma of the kidney with poorly differentiated foci. American Journal of Surgical Pathology, 40(11), 1457-1472. https://doi.org/10.1097/PAS.0000000000000719

Tubulocystic carcinoma of the kidney with poorly differentiated foci. / Smith, Steven C.; Trpkov, Kiril; Chen, Ying Bei; Mehra, Rohit; Sirohi, Deepika; Ohe, Chisato; Cani, Andi K.; Hovelson, Daniel H.; Omata, Kei; Mchugh, Jonathan B.; Jochum, Wolfram; Colecchia, Maurizio; Amin, Mitual; Divatia, Mukul K.; Hes, Ondřej; Menon, Santosh; Werneck Da Cunha, Isabela; Tripodi, Sergio; Brimo, Fadi; Gill, Anthony J.; Osunkoya, Adeboye O.; Magi-Galluzzi, Cristina; Sibony, Mathilde; Williamson, Sean R.; Nesi, Gabriella; Picken, Maria M.; Maclean, Fiona; Agaimy, Abbas; Cheng, Liang; Epstein, Jonathan I.; Reuter, Victor E.; Tickoo, Satish K.; Tomlins, Scott A.; Amin, Mahul B.

In: American Journal of Surgical Pathology, Vol. 40, No. 11, 01.10.2016, p. 1457-1472.

Research output: Contribution to journalArticle

Smith, SC, Trpkov, K, Chen, YB, Mehra, R, Sirohi, D, Ohe, C, Cani, AK, Hovelson, DH, Omata, K, Mchugh, JB, Jochum, W, Colecchia, M, Amin, M, Divatia, MK, Hes, O, Menon, S, Werneck Da Cunha, I, Tripodi, S, Brimo, F, Gill, AJ, Osunkoya, AO, Magi-Galluzzi, C, Sibony, M, Williamson, SR, Nesi, G, Picken, MM, Maclean, F, Agaimy, A, Cheng, L, Epstein, JI, Reuter, VE, Tickoo, SK, Tomlins, SA & Amin, MB 2016, 'Tubulocystic carcinoma of the kidney with poorly differentiated foci', American Journal of Surgical Pathology, vol. 40, no. 11, pp. 1457-1472. https://doi.org/10.1097/PAS.0000000000000719
Smith, Steven C. ; Trpkov, Kiril ; Chen, Ying Bei ; Mehra, Rohit ; Sirohi, Deepika ; Ohe, Chisato ; Cani, Andi K. ; Hovelson, Daniel H. ; Omata, Kei ; Mchugh, Jonathan B. ; Jochum, Wolfram ; Colecchia, Maurizio ; Amin, Mitual ; Divatia, Mukul K. ; Hes, Ondřej ; Menon, Santosh ; Werneck Da Cunha, Isabela ; Tripodi, Sergio ; Brimo, Fadi ; Gill, Anthony J. ; Osunkoya, Adeboye O. ; Magi-Galluzzi, Cristina ; Sibony, Mathilde ; Williamson, Sean R. ; Nesi, Gabriella ; Picken, Maria M. ; Maclean, Fiona ; Agaimy, Abbas ; Cheng, Liang ; Epstein, Jonathan I. ; Reuter, Victor E. ; Tickoo, Satish K. ; Tomlins, Scott A. ; Amin, Mahul B. / Tubulocystic carcinoma of the kidney with poorly differentiated foci. In: American Journal of Surgical Pathology. 2016 ; Vol. 40, No. 11. pp. 1457-1472.
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abstract = "An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes - including FH - performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12{\%}). These tumors were aggressive, with 79{\%} showing perinephric extension, nodal involvement in 41{\%}, and metastasis in 86{\%}. Of these, 16 (55{\%}) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17{\%}) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28{\%}) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31{\%}). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term {"}FH-deficient RCC{"} as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.",
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T1 - Tubulocystic carcinoma of the kidney with poorly differentiated foci

AU - Smith, Steven C.

AU - Trpkov, Kiril

AU - Chen, Ying Bei

AU - Mehra, Rohit

AU - Sirohi, Deepika

AU - Ohe, Chisato

AU - Cani, Andi K.

AU - Hovelson, Daniel H.

AU - Omata, Kei

AU - Mchugh, Jonathan B.

AU - Jochum, Wolfram

AU - Colecchia, Maurizio

AU - Amin, Mitual

AU - Divatia, Mukul K.

AU - Hes, Ondřej

AU - Menon, Santosh

AU - Werneck Da Cunha, Isabela

AU - Tripodi, Sergio

AU - Brimo, Fadi

AU - Gill, Anthony J.

AU - Osunkoya, Adeboye O.

AU - Magi-Galluzzi, Cristina

AU - Sibony, Mathilde

AU - Williamson, Sean R.

AU - Nesi, Gabriella

AU - Picken, Maria M.

AU - Maclean, Fiona

AU - Agaimy, Abbas

AU - Cheng, Liang

AU - Epstein, Jonathan I.

AU - Reuter, Victor E.

AU - Tickoo, Satish K.

AU - Tomlins, Scott A.

AU - Amin, Mahul B.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes - including FH - performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.

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