Pavlos Msaouel, Assistant Professor of Genitourinary Medical Oncology at MD Anderson Cancer Center, shared a post on LinkedIn:
“New open access case report out in Therapeutic Advances in Medical Oncology that I think is a useful teaching case on tumor plasticity and the value of integrated, longitudinal molecular pathology.
A young patient with HLRCC syndrome (germline FH p.S419P) presented with a renal sinus mass. The tumor showed two intermixed components – a lower-grade oncocytic component (PAX8+, GATA3 weak) and a higher-grade pleomorphic component (PAX8–, GATA3+, CK7+). After nivolumab + cabozantinib and nephrectomy, the resection specimen was dominated by the PAX8-negative, GATA3/p63-positive pleomorphic component with only variably positive 2SC – closely mimicking upper tract urothelial carcinoma.
That resemblance is a genuine diagnostic pitfall, and getting it wrong would have pointed toward urothelial-directed therapy. What resolved it was integrating DNA and RNA profiling across both pre- and post-treatment tissue: Transcriptomics showed lineage infidelity already present at diagnosis, and the post-treatment tumor mapped midway between RCC and bladder cancer – a transcriptional ‘hybrid’ identity.
Critically, the infidelity was partial, not a complete lineage switch: the tumor gained upstream urothelial transcription factors (GATA3/p63) but never engaged the downstream urothelial differentiation program – uroplakins, TROP2, and HER2 were near-absent (HER2 IHC 0). A markedly elevated EMT signature pointed to EMT-driven dedifferentiation as the mechanism.
Biallelic FH loss plus a low tumor mutational burden (3 mut/Mb) confirmed FH-deficient RCC rather than urothelial carcinoma (which typically carries a much higher TMB).
This is a single-patient, hypothesis-generating report and cannot establish causality between the secondary TP53/NF2/KMT2A alterations and the lineage infidelity, nor frequency. The aim is to illustrate how diagnosis-informed, integrated management operates in a genuinely ambiguous setting. Clonal dynamics were informative too: therapy appeared to debulk the PAX8-positive oncocytic clone while a PAX8-negative TP53/KMT2A-mutant clone came to dominate, and a subclonal NF2 variant was lost post-treatment – consistent with treatment-associated clonal selection.
This biology directly shaped management. The molecular profile eliminated the rationale for urothelial agents (no TROP2 – no sacituzumab govitecan; HER2-negative), and cabozantinib resistance made continued VEGFR/MET inhibition unattractive. The patient was treated with nivolumab + ipilimumab integrated with radiotherapy, with marked regression of treated and untreated lesions and no evidence of active disease at the most recent follow-up, 16 months after surgery.”
Title: Lineage infidelity in FH-deficient RCC with secondary somatic alterations: a case report and implications for diagnosis and treatment
Authors: Jianping Zhao, Derek B. Allison, Giannicola Genovese, Stephanie Rock, Noah Spies, Michael Hensley, Gleb Khegai, Anastasiya Makeeva, Daria Melikhova, Lev Bedniagin, Patrick J. Hensley, Zin W. Myint, Pavlos Msaouel
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