Subtitle: The hereditary renal cancer syndromes in one place: VHL, hereditary papillary RCC, HLRCC, Birt–Hogg–Dubé, BAP1, SDH, Cowden, tuberous sclerosis and chromosome 3 translocations, with genes, tumour types, clues and 10 MCQs.
Author: PathologyMCQ Editorial Board
Category: Renal Pathology and Genetics
Last Updated: October 2026
Read Time: 7 minutes
At-a-Glance
- About 5–8% of RCCs are hereditary; suspect a syndrome if the tumours are bilateral, multifocal, early-onset or have a family history.
- Clear cell RCC: VHL, BAP1, chromosome 3 translocations, PTEN.
- Papillary RCC: hereditary papillary RCC (MET); FH-deficient RCC in HLRCC.
- Oncocytic tumours: Birt–Hogg–Dubé (FLCN), SDH-deficient RCC, tuberous sclerosis.
- The pathologist is often the first to suggest the syndrome from morphology and IHC (FH/2SC, SDHB, BAP1).
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Summary Table
Hereditary renal cancer syndromes
| Syndrome | Gene | Renal tumour | Other features |
|---|---|---|---|
| Von Hippel–Lindau | VHL (3p25) | Multifocal clear cell RCC, cysts | Haemangioblastomas, phaeochromocytoma, pancreatic NET/cysts |
| Hereditary papillary RCC | MET (7q31) | Multifocal low-grade papillary RCC | None |
| HLRCC (Reed) | FH (1q43) | FH-deficient RCC, aggressive | Cutaneous and uterine leiomyomas |
| Birt–Hogg–Dubé | FLCN (17p11.2) | Hybrid oncocytic tumour, chromophobe RCC, oncocytoma | Fibrofolliculomas, lung cysts, pneumothorax |
| SDH-deficient RCC | SDHB; less often SDHC/D | SDH-deficient RCC | Paraganglioma, phaeochromocytoma, GIST |
| Tuberous sclerosis | TSC1 (9q34), TSC2 (16p13) | AML, ESC RCC, RCC with fibromyomatous stroma | Angiofibromas, cortical tubers, LAM |
| BAP1 tumour predisposition | BAP1 (3p21) | Clear cell RCC | Uveal melanoma, mesothelioma |
| PTEN hamartoma (Cowden) | PTEN (10q23) | RCC (various) | Breast, thyroid, endometrial cancer |
| Chromosome 3 translocation | Constitutional t(3;…) | Clear cell RCC | None |
Von Hippel–Lindau (VHL) Disease
- Autosomal dominant; VHL on 3p25 regulates HIF, so loss drives pseudohypoxia.
- Multifocal, bilateral clear cell RCC and renal cysts; tumours are usually managed by the 3 cm rule.
- Type 1 (truncating): low phaeochromocytoma risk. Type 2 (missense): phaeochromocytoma; 2A low RCC risk, 2B high RCC risk, 2C phaeochromocytoma only.
- Also haemangioblastomas (retina, cerebellum, spine), pancreatic cysts and NETs, endolymphatic sac tumours.
Hereditary Papillary RCC and HLRCC
- Hereditary papillary RCC: germline activating MET mutation (7q31); bilateral multifocal low-grade papillary RCC. MET is mutated in under 10% of sporadic papillary RCC.
- HLRCC: germline FH mutation; cutaneous and uterine leiomyomas with FH-deficient RCC (formerly “type 2 papillary”).
- FH-deficient RCC: mixed papillary, tubulocystic, solid patterns; macronucleoli with perinucleolar halos; FH loss and 2SC positive; aggressive even when small.
Morphological clues to FH deficiency are shown in FH-deficient leiomyoma and HLRCC →
Birt–Hogg–Dubé, SDH Deficiency and Tuberous Sclerosis
- Birt–Hogg–Dubé (FLCN): hybrid oncocytic/chromophobe tumours, chromophobe RCC, oncocytoma; fibrofolliculomas and lung cysts.
- SDH-deficient RCC: eosinophilic cells with flocculent cytoplasmic vacuoles and inclusions; SDHB loss on IHC; usually germline; associated paraganglioma and GIST.
- Tuberous sclerosis (TSC1/TSC2): angiomyolipomas, cysts and mTOR-pathway tumours such as eosinophilic solid and cystic RCC.
The mTOR-pathway oncocytic tumours are covered in emerging renal tumours in WHO 2022 →
BAP1, PTEN and Chromosome 3 Translocations
- BAP1 tumour predisposition syndrome: clear cell RCC with uveal and cutaneous melanoma and mesothelioma.
- PTEN hamartoma tumour syndrome (Cowden): breast, thyroid and endometrial cancers, plus renal cell carcinoma.
- Constitutional chromosome 3 translocations: loss of the derivative chromosome 3 plus a second hit in VHL leads to multifocal clear cell RCC.
Clues for the Pathologist
When to suggest a hereditary syndrome
| Finding | Next step |
|---|---|
| Macronucleoli with perinucleolar halos | FH and 2SC IHC; suggest HLRCC testing |
| Eosinophilic cells with flocculent vacuoles | SDHB IHC |
| Hybrid oncocytic/chromophobe tumour, multiple | Consider Birt–Hogg–Dubé |
| Multifocal clear cell RCC or cysts, young patient | Consider VHL |
| Multiple papillary RCCs | Consider hereditary papillary RCC (MET) |
| ESC RCC or multiple AMLs | Consider tuberous sclerosis |
Test Yourself: 10 MCQs
Hereditary renal cancer syndromes: 10 MCQs
Genes, tumours and clinical clues, with instant explanations.
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More practice: the renal pathology MCQ bank →
Exam Pearls
- VHL: 3p25, clear cell RCC, haemangioblastoma; type 2C = phaeochromocytoma only.
- HPRCC: MET 7q31, multifocal papillary RCC.
- HLRCC: FH, leiomyomas, aggressive FH-deficient RCC.
- BHD: FLCN, fibrofolliculomas, lung cysts, hybrid oncocytic tumours.
- SDH-deficient RCC: SDHB loss, flocculent vacuoles.
- BAP1: ccRCC, uveal melanoma, mesothelioma.
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FRCPath Part 1FRCPath Part 1 HistopathologyNotes, MCQ/EMQ bank and full mocksView course →FRCPath Part 2Ultimate FRCPath Part 2 Study ProgramShort surgicals, long cases and macro practiceView course →NEET-SS · DMNEET-SS / DM OncopathologyRenal and GU pathology, WHO updates and mocksView course →
Related reads: FH-deficient leiomyoma and HLRCC → · Emerging renal tumours, WHO 2022 →
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References
- WHO Classification of Tumours Editorial Board. Urinary and Male Genital Tumours. 5th ed. IARC; 2022.
- Haas NB, Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014;21:81–90.
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