SDH- and FH-deficient renal cell carcinomas (RCC) are prototypical “metabolic” kidney tumors and sit at the crossroads of urologic oncology, genetics, and surgical decision-making. Although they account for a small fraction of kidney cancers, their identification has outsized clinical consequences: these tumors frequently flag underlying hereditary syndromes (SDHx-related paraganglioma/phaeochromocytoma for SDH; HLRCC for FH), and their biology influences when to undergo surgery, how closely to surveil, and which systemic therapies to consider.
Why is the Diagnosis Challenging?
In day-to-day practice, the workup still begins with hematoxylin and eosin (H&E), and it is often nontrivial. FH-deficient RCC can show mixed and papillary architecture with striking macronucleoli in eosinophilic cells, sometimes with necrosis, but these findings substantially overlap with other eosinophilic tumors. SDH-deficient RCC typically has solid/nested oncocytic growth with uniform eosinophilic cytoplasm and occasional cytoplasmic inclusions, yet this pattern also mimics chromophobe RCC and oncocytoma. In short, neither entity is morphologically pathognomonic; without targeted metabolic immunohistochemistry (IHC), clinical context, and, when needed, molecular testing, misclassification is a real risk.
Why Should Surgeons and Urologists Care?
Because management paradigms diverge. In hereditary settings such as VHL syndrome, active surveillance with delayed intervention is widely adopted; by contrast, FH-deficient RCC behaves aggressively and is generally managed with early definitive surgery rather than watchful waiting. SDH-deficient RCC is often indolent and amenable to conservative, nephron-sparing approaches, with earlier intervention reserved for high-grade or dedifferentiated presentations. On the systemic treatment side, FH-deficient disease can be considered for regimens such as bevacizumab plus erlotinib or modern ICI/TKI combinations used in non–clear-cell RCC, whereas SDH-deficient disease should be triaged to trials when possible.
What Did We Do?
We ran a nationwide, web-based 25-item survey through the Italian Study Group of Uropathology (GIUP) to capture real-world diagnostic pathways for SDH- and FH-deficient RCC across Italian pathology services. Twenty-one practicing pathologists from 11 regions responded. We summarized the most strongly triggering factors, the prioritized hallmarks, and the availability/usage of confirmatory IHC and molecular testing.
What Did We Find?
- Recognition is morphology-led. Morphology was the top trigger for both SDH- and FH-deficient RCC, confirming that work-up still starts on H&E. However, the survey reveals a paradox typical of rare tumor entities: a high level of theoretical knowledge coexists with limited direct diagnostic exposure even among senior pathologists with longstanding experience in uropathology (more than 50% had never signed out a confirmed FH- or SDH-deficient RCC in the last 5 years).
- Key IHC biomarkers exist but are applied unevenly. FH (for FH-deficiency) and SDHB (for SDH-complex loss) were appropriately prioritized. However, 2-succinocysteine (2SC)—the most sensitive surrogate for fumarate accumulation—was virtually unavailable (reported by 1/21). As a result, many laboratories rely on FH loss alone, which can be falsely negative in missense FH variants that retain immunoreactive but inactive protein, thereby perpetuating under-recognition of FH-deficient RCC.
- Molecular testing isn’t universal. ~57% would request molecular testing in all suspected cases; the remainder reserve it for equivocal scenarios, highlighting infrastructural disparity and the lack of a coordinated referral pathway.
- Don’t stop at morphology. When FH-deficient RCC is suspected, pair FH IHC with 2SC, where available; if 2SC is unavailable, lower the threshold for referral/confirmatory testing. For SDH-deficient RCC, loss of SDHB remains the linchpin.
- Think about heritability systematically. These tumors are sentinel lesions. Build automatic triggers for genetic counseling and germline testing into local pathways (e.g., all confirmed FH-deficient RCC; for SDH-deficient RCC, strong consideration in younger patients, bilateral/multifocal disease, or personal/family history of paraganglioma/pheochromocytoma).
- Therapeutic implications are real. Precise subtyping informs surgical timing, guides systemic choices, and enables trial referral.
The challenge lies in implementation. Outside reference centers, access to specific IHC biomarkers and routine molecular confirmation is uneven. Our GIUP survey quantifies these gaps across Italy and advocates a hub-and-spoke network: spoke hospitals standardize pre-analytics and core IHC; regional/national hubs provide validated metabolic IHC, next-generation sequencing, germline workup, and multidisciplinary review within a molecular tumor board. Finally, curated digital slide repositories and shared SOP/EQA programs can raise morphological literacy and harmonize interpretation.
Take-Home Messages
- Metabolic RCC recognition is predominantly morphology-based, but constraints in uneven access to validated metabolic IHC and molecular testing can perpetuate under-recognition.
- Relying on FH-loss alone risks false-negative FH-deficient RCC; therefore, it is necessary to build reflex pathways to 2SC/molecular confirmation.
- Including germline genetics and multidisciplinary review in the diagnostic workflow is mandatory to ensure timely referral, uniform quality, and coordinated management within hub-and-spoke networks.
Written by:
- Giuseppe Nicolò Fanelli, MD, PhD, University of Pisa, Italy
- Anna Caliò, MD, PhD, University of Verona, Italy
- Guido Martignoni, MD, University of Verona, Italy
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