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Morphologic Characteristics and Mutational Analysis of Fumarate Hydratase Deficient Kidney and Smooth Muscle Tumors
Valarie McMurtry1,2, Jonathan Mahlow1,2, Joshua F Coleman1,2
1The Institute for Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.
Objectives:
Fumarate hydratase (FH)-deficient tumors can occur due to germline or somatic mutations and have distinctive morphologic features. The aims of this study are to refine morphologic criteria and identify mutations in FH-deficient smooth muscle tumors (SMTs).
Methods:
The morphology of SMTs and kidney tumors submitted to a national reference laboratory for FH immunohistochemistry (IHC) was reviewed by two gynecologic and two genitourinary pathologists, respectively. Fisher exact test was used for analysis. Fourteen SMTs were sequenced using the Illumina TruSight Oncology 500 Assay.
Results:
Twenty-two kidney tumors (5 FH deficient) and 51 SMTs (27 FH deficient) were reviewed. FH-deficient kidney tumors exclusively showed cord-like growth, rhabdoid change, and absence of coagulative tumor necrosis and psammoma bodies. FH-deficient SMTs were significantly more likely to have staghorn vessels, eosinophilic cytoplasmic inclusions, schwannoma-like areas, or hereditary leiomyomatosis and renal cell cancer-like nuclei (P < .05 for each). Seven of 14 sequenced SMTs showed mutations of the FH gene and no other driver mutations.
Conclusions:
FH-deficient SMTs submitted for FH immunohistochemistry (IHC) showed distinct morphology. Although FH IHC is used for screening of FH-deficient tumors, FH mutations were identified in only 50% of FH-deficient SMTs. This highlights the need for additional exploration of mechanisms of FH protein loss in tumors lacking FH mutations.
Insights
Fumarate hydratase (FH)-deficient tumors exhibit distinct morphology. While FH immunohistochemistry (IHC) aids screening, FH mutations are found in only 50% of deficient smooth muscle tumors (SMTs), necessitating further research.
Area of Science:
- Oncology
- Pathology
- Genetics
Background:
- Fumarate hydratase (FH)-deficient tumors arise from germline or somatic mutations and possess unique morphologic characteristics.
- Identifying these distinct features is crucial for accurate diagnosis and understanding tumor biology.
Purpose of the Study:
- To refine morphologic criteria for FH-deficient smooth muscle tumors (SMTs).
- To identify specific gene mutations associated with FH deficiency in SMTs.
Main Methods:
- Morphologic review of FH-deficient kidney tumors and SMTs by specialized pathologists.
- Genetic sequencing of 14 SMTs using the Illumina TruSight Oncology 500 Assay.
- Statistical analysis using Fisher exact test to compare tumor features.
Main Results:
- FH-deficient kidney tumors showed characteristic cord-like growth and rhabdoid changes.
- FH-deficient SMTs frequently displayed staghorn vessels, eosinophilic inclusions, and schwannoma-like areas.
- FH gene mutations were identified in 7 out of 14 sequenced SMTs, with no other driver mutations detected.
Conclusions:
- FH-deficient SMTs possess distinct morphological features identifiable through pathological review.
- FH immunohistochemistry (IHC) is valuable for screening, but FH mutations are not universally present in FH-deficient SMTs.
- Further investigation is required to understand the mechanisms of FH protein loss in tumors without identified FH mutations.
