TY - JOUR
T1 - Lineage infidelity in FH-deficient RCC with secondary somatic alterations
T2 - a case report and implications for diagnosis and treatment
AU - Zhao, Jianping
AU - Allison, Derek B.
AU - Genovese, Giannicola
AU - Rock, Stephanie
AU - Spies, Noah
AU - Hensley, Michael
AU - Khegai, Gleb
AU - Makeeva, Anastasiya
AU - Melikhova, Daria
AU - Bedniagin, Lev
AU - Hensley, Patrick J.
AU - Myint, Zin W.
AU - Msaouel, Pavlos
N1 - Publisher Copyright:
© The Author(s), 2026. This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
PY - 2026/1/1
Y1 - 2026/1/1
N2 - Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) can exhibit striking histologic and immunophenotypic heterogeneity. A 36-year-old woman with uterine leiomyomas presented with a 5.1-cm left renal sinus mass and retroperitoneal adenopathy. Biopsy showed juxtaposed lower-grade oncocytic (PAX8 strong, GATA3 weak) and higher-grade pleomorphic (PAX8 negative, GATA3 and CK7 strong) components. DNA sequencing revealed germline pathogenic FH p.S419P, clonal TP53 p.H193D, and subclonal NF2 and KMT2A mutations, establishing FH-deficient RCC associated with hereditary leiomyomatosis and renal cell carcinoma syndrome. Nivolumab + cabozantinib reduced the lesion before nephrectomy, which showed predominantly pleomorphic tumor cells that were PAX8 negative and GATA3/p63 positive, mimicking upper tract urothelial carcinoma. Transcriptome sequencing mapped the tumor midway between renal and bladder cancer. Postoperatively, nivolumab + ipilimumab with radiotherapy achieved disease control. In this hypothesis-generating case report, TP53, NF2, and KMT2A secondary alterations on an FH-null background were associated with lineage infidelity, which can create diagnostic challenges that underscores the role for integrated pre- and post-treatment multi-omics in diagnostically ambiguous renal tumors.
AB - Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) can exhibit striking histologic and immunophenotypic heterogeneity. A 36-year-old woman with uterine leiomyomas presented with a 5.1-cm left renal sinus mass and retroperitoneal adenopathy. Biopsy showed juxtaposed lower-grade oncocytic (PAX8 strong, GATA3 weak) and higher-grade pleomorphic (PAX8 negative, GATA3 and CK7 strong) components. DNA sequencing revealed germline pathogenic FH p.S419P, clonal TP53 p.H193D, and subclonal NF2 and KMT2A mutations, establishing FH-deficient RCC associated with hereditary leiomyomatosis and renal cell carcinoma syndrome. Nivolumab + cabozantinib reduced the lesion before nephrectomy, which showed predominantly pleomorphic tumor cells that were PAX8 negative and GATA3/p63 positive, mimicking upper tract urothelial carcinoma. Transcriptome sequencing mapped the tumor midway between renal and bladder cancer. Postoperatively, nivolumab + ipilimumab with radiotherapy achieved disease control. In this hypothesis-generating case report, TP53, NF2, and KMT2A secondary alterations on an FH-null background were associated with lineage infidelity, which can create diagnostic challenges that underscores the role for integrated pre- and post-treatment multi-omics in diagnostically ambiguous renal tumors.
KW - case report
KW - fumarate hydratase-deficient renal cell carcinoma
KW - hereditary leiomyomatosis
KW - immunoradiotherapy
KW - lineage infidelity
KW - tumor evolution
UR - https://www.scopus.com/pages/publications/105042108119
UR - https://www.scopus.com/pages/publications/105042108119#tab=citedBy
U2 - 10.1177/17588359261456676
DO - 10.1177/17588359261456676
M3 - Article
C2 - 42317258
AN - SCOPUS:105042108119
SN - 1758-8340
VL - 18
JO - Therapeutic Advances in Medical Oncology
JF - Therapeutic Advances in Medical Oncology
ER -