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.
When a rare inherited kidney cancer looks like bladder cancer: how integrated pathology and genetic testing helped guide diagnosis and treatment in one patient Some rare kidney cancers can be very difficult to identify correctly. In this report, we describe a 36-year-old woman with an inherited form of kidney cancer linked to changes in the FH gene. This condition is associated with hereditary leiomyomatosis and renal cell carcinoma syndrome, which can also cause skin and uterine smooth muscle tumors. In her case, the kidney tumor did not look typical. Parts of it had features expected for kidney cancer, but other parts looked more like cancer of the urinary tract, also called urothelial or bladder-type cancer. This created a major diagnostic challenge. To clarify the diagnosis, the care team combined standard pathology with detailed DNA and RNA testing of tumor samples taken before and after treatment. These tests confirmed that the tumor was an FH-deficient renal cell carcinoma, even though the later surgical specimen had changed and closely resembled urothelial cancer. The molecular findings were especially helpful because treatment effects and inflammation made the post-treatment tissue harder to interpret. This distinction mattered clinically. Treatments commonly used for urothelial cancer were considered less appropriate after the molecular results showed that the tumor fit better with FH-deficient kidney cancer. Based on the full picture, the patient was treated with immunotherapy, targeted therapy against kidney cancer, surgery, and radiation. Her disease was controlled, and she remained clinically well at the latest follow-up described in the manuscript. This is a report of a single patient, so it cannot prove how often this happens or whether the additional mutations found in the tumor caused these unusual features. Even so, this case highlights an important practical lesson: when a kidney tumor has mixed or confusing features, especially in a younger patient, integrated pathology and molecular testing can be critical for making the correct diagnosis and choosing treatment.
Therapeutic advances in medical oncology. 2026 Jun 16*** epublish ***
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
Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Allison Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Caris Life Sciences, Phoenix, AZ, USA., BostonGene Corporation, Waltham, MA, USA., Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA., Markey Cancer Center, Lexington, KY, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center Unit 1374, 1155 Pressler St., Houston, TX 77030-3721, USA.