Fumarate hydratase-deficient renal cell carcinoma

• Molecularly defined renal carcinoma caused by functional biallelic FH inactivation.
• Includes hereditary tumours of HLRCC (FH tumour predisposition syndrome) and sporadic tumours; renamed from HLRCC-associated RCC in WHO 2022.
• Exceptionally broad morphology: papillary, tubular, tubulocystic, cribriform, solid, cystic, infiltrative and oncocytic.
• Most show high-grade nuclei with eosinophilic viral inclusion-like macronucleoli and perinucleolar halos; useful but neither specific nor constant.
• Hallmark: complete FH loss and/or aberrant 2SC; rare tumours retain FH protein.
• Classic tumours are aggressive and may metastasise when small; a deceptively bland low-grade oncocytic subset exists, including metastatic cases.
• Hereditary, family-screening and treatment implications.

Diagnostic pearl: not just a high-grade papillary carcinoma with big nucleoli: unusual architectural heterogeneity or an unexplained low-grade oncocytic phenotype can be FH deficiency.

Clinical

• Wide age range including children and young adults; hereditary cases present earlier, sporadic ones in older adults.
• Usually solitary and unilateral; haematuria, pain or metastatic disease; some found on surveillance of germline carriers.

Gross

• Highly variable: tan-white, grey, yellow or haemorrhagic; solid and cystic.
• Infiltrative borders, necrosis, renal sinus or perinephric extension; some deceptively well demarcated.
• Low-grade oncocytic tumours may look like oncocytoma.

Hereditary context

• Cutaneous piloleiomyomas and early, numerous uterine leiomyomas; renal tumours can occur without family history or extrarenal signs.

Diagnostic pearl: young age, a small but infiltrative mass, or leiomyomas in the patient or family raise suspicion, but none is required.

Architectural heterogeneity

• Several patterns coexist; papillary and tubular are most frequent.
• Solid, cribriform, tubulocystic or infiltrative areas next to papillae; abrupt transitions matter.

Cells and nuclei

• Cuboidal, polygonal, columnar or hobnail cells; eosinophilic or amphophilic, sometimes clear or oncocytic.
• Enlarged nuclei with cherry-red nucleoli and clear halos; moderate to marked pleomorphism; some lack macronucleoli.

Stroma and other

• Delicate, hyalinised, myxoid or desmoplastic; infiltrative tubules mimic collecting duct carcinoma.
• Necrosis, lymphovascular invasion, sarcomatoid change and inflammation may occur.

Diagnostic pearl: mixed patterns + macronucleoli + infiltration is very suggestive, but one or two features are enough to test.

• Papillary: delicate or broad, often hyalinised cores; eosinophilic lining, pseudostratification, high grade; foamy macrophages inconsistent.
• Branching papillary: complex networks merging with tubules or solid areas; resembles former “type 2” PRCC.
• Tubulopapillary: tubules and papillae merge; eosinophilic secretions.
• Papillary clear cell: mimics CCPRCT or PRCC with clear change.
• Low-grade papillary areas: may transition to high grade; low grade does not mean favourable.

Diagnostic pearl: a historical “type 2 PRCC” should always prompt FH/2SC.

• Tubular: irregular or branching tubules with hobnail cells; in desmoplastic stroma mimics CDC.
• Tubulocystic: may reproduce the bubble-wrap of tubulocystic RCC; small non-tubulocystic foci may need extensive sampling.
• Microcystic: small spaces merging with cribriform or sieve-like areas.
• Macrocystic: large cysts; infiltrative or high-grade foci support carcinoma.
• Low-grade clear cell tubular: rare; mimics CCPRCT.

Diagnostic pearl: a tubulocystic-predominant tumour with even a limited solid, papillary or infiltrative component must be evaluated for FH deficiency.

• Cribriform / sieve-like: sheets with crowded lumina; widens the differential to CDC and medullary carcinoma.
• Solid / nested: eosinophilic, amphophilic or clear cells, often high grade; some bland oncocytic areas.
• Infiltrative glandular: angulated glands with desmoplasia, extending into sinus or fat; closely mimics CDC.
• Reticular: cords overlapping SMARCB1-deficient medullary carcinoma; INI1 may be needed.
• Sarcomatoid: conventional areas may be focal.

Diagnostic pearl: desmoplasia, cribriform growth or solid high-grade carcinoma should not become CDC or unclassified RCC without excluding FH deficiency.

• Macronucleoli: large round dense eosinophilic (cherry-red) nucleoli, visible at low power; chromatin pushed peripherally.
• Perinucleolar halo: clear zone creating an inclusion-like look; often focal.
• Not unique: other high-grade RCCs can look similar; some FH-deficient tumours have only modest nucleoli; low-grade oncocytic ones may lack them.
• Marked pleomorphism, multinucleated cells and mitoses in aggressive lesions.

Diagnostic pearl: inclusion-like nucleoli are a reason to order FH/2SC, not proof; their absence does not exclude FH deficiency.

• Solid, nested, trabecular or compact acinar growth of uniform cells with abundant granular eosinophilic cytoplasm.
• Small round nuclei, inconspicuous nucleoli; vacuoles or pale flocculent inclusions like SDH-deficient RCC.
• May be pure or mixed with conventional high-grade areas.
• FH lost, 2SC positive, SDHB retained; CK7 often negative or limited.
• Same pathogenic FH mechanism, not a separate benign entity.
• Mostly favourable follow-up, but metastatic cases are documented; “low grade” describes morphology only.

Diagnostic pearl: an oncocytic tumour with SDH-deficient-like vacuoles but retained SDHB should prompt FH/2SC.

• FH: complete cytoplasmic loss in most; the principal screen.
• 2SC: aberrant strong nuclear and cytoplasmic staining from fumarate-driven succination; key when FH is retained or equivocal; limited availability.
• PAX8: usually positive. CK7: often negative or focal. AMACR: frequently positive (overlaps PRCC). CD10: variable.
• SDHB and INI1: usually retained; help exclude SDH-deficient RCC and medullary carcinoma.
• AKR1B10: promising surrogate, not a substitute for FH/2SC or molecular confirmation.

Diagnostic pearl: the most useful pair is FH + 2SC: FH loss is strong evidence, 2SC catches FH-retained functionally deficient tumours.

• Retained FH does not exclude deficiency: some missense variants make stable, inactive, immunoreactive protein; use 2SC or sequencing.
• Internal controls are mandatory: tubules, endothelium, inflammatory and stromal cells must stain; if not, the stain is uninterpretable.
• Heterogeneous or equivocal staining: consider necrosis, poor preservation or technical issues; repeat or add tests.
• FH and 2SC are not interchangeable: protein presence vs downstream biochemistry.
• A normal FH stain is not a hereditary screen: strong suspicion still merits counselling or testing.

Diagnostic pearl: an FH-retained, 2SC-positive renal tumour deserves serious consideration of FH-deficient RCC.

• FH (1q42.3–q43) encodes fumarase, converting fumarate to malate in the TCA cycle (mitochondrial and cytosolic).
• Biallelic inactivation: germline variant plus somatic second hit (often LOH), or two somatic events; missense, truncating or splice variants.
• Fumarate accumulates as an oncometabolite and succinates proteins (2SC).
• Inhibits α-ketoglutarate-dependent dioxygenases, altering DNA and histone methylation.
• Oxidative stress, NRF2 activation and pseudohypoxic signalling contribute to an aggressive phenotype.

Diagnostic pearl: an oncometabolite-driven malignancy: loss of a metabolic enzyme with epigenetic, redox and transcriptional consequences.

• Alteration: germline variant + somatic second hit vs biallelic somatic inactivation.
• Morphology, FH and 2SC: overlapping; cannot determine germline status.
• Tumour-only sequencing and variant allele fraction cannot reliably establish germline origin.
• Family history may be absent; a single renal tumour may be the first manifestation.
• HLRCC: autosomal dominant; painful multiple piloleiomyomas; early numerous uterine leiomyomas; incomplete but aggressive renal penetrance.
• Every FH-deficient RCC should trigger genetic counselling and consideration of germline testing.

Diagnostic pearl: report FH-deficient RCC, not presumed hereditary status, but always flag hereditary risk.

Papillary RCC

• FH-d: mixed architecture, macronucleoli, CK7 often negative, FH lost, 2SC+. PRCC: papillary dominant, CK7 frequent, FH retained, +7/+17, MET.
• AMACR is positive in both and settles nothing; CK7 negativity supports but is insufficient.

Collecting duct carcinoma

• Shared: medullary location, infiltrating tubules, desmoplasia, high grade, neutrophils, advanced stage.
• FH-d favours mixed papillary/tubulocystic/solid areas, macronucleoli with halos, FH loss/2SC.
• CDC is a diagnosis of exclusion with FH retained and 2SC negative after other molecular entities are excluded.

Diagnostic pearl: never label an eosinophilic high-grade papillary tumour PRCC because it is AMACR positive, or call CDC before FH/2SC.

Tubulocystic RCC (2024 multicentre: 6 TC-RCC vs 10 tubulocystic FH-d)

• TC-RCC: pure, <4 cm, Ki-67 <5%, FH retained, 2SC negative.
• FH-d: larger, more proliferative, FH lost and 2SC+ in 10/10, all with a non-tubulocystic component.

Others

• SDH-deficient RCC: vacuoles/inclusions; SDHB loss vs FH loss.
• TFE3-rearranged RCC: cathepsin K, melanocytic markers, fusion testing.
• SMARCB1-deficient medullary carcinoma: sickle hemoglobinopathy, INI1 loss.
• ESC RCC: coarse stippling, CK20, TSC1/2.
• ccRCC: capillary network, box-like CAIX, VHL/3p.

Diagnostic pearl: in the low-grade oncocytic setting, SDHB and FH/2SC are more consequential than CK7/CD117.

1. Suspect: heterogeneous papillary, tubular, tubulocystic, cribriform or infiltrative architecture; prominent nucleoli; or a low-grade oncocytic SDH-like phenotype.
2. FH IHC with retained internal controls.
3. 2SC when available, especially if FH is retained or equivocal.
4. Mimics: SDHB, INI1, CK7, AMACR, cathepsin K as the differential dictates.
5. Molecular testing for discordant results.
6. Hereditary: genetic counselling and germline testing.

On biopsy

• One pattern may be sampled: papillary (PRCC-like), tubulocystic (TC-RCC-like), infiltrative (CDC-like) or oncocytic (SDH/oncocytoma-like); nucleoli may be absent.
• Confirmed: FH-deficient RCC; loss of FH with retained internal controls [and aberrant 2SC]; genetic counselling and germline FH testing recommended.
• Suspicious with retained FH: RCC with features suspicious for FH deficiency; 2SC and/or molecular testing recommended.

• Conventional tumours are aggressive; early nodal and distant spread; advanced stage is common.
• Small size does not guarantee a good outcome.
• Grade 3–4-like nuclei are common, but WHO/ISUP grading has uncertain independent value; stage and molecular class matter more; record sarcomatoid/rhabdoid change and necrosis.
• Low-grade oncocytic tumours are often indolent but can metastasise.
• Bevacizumab + erlotinib (Srinivasan, NEJM 2025): 43 patients with advanced HLRCC-associated RCC, confirmed response 72%, median PFS 21.1 months, median OS 44.6 months; 35% response in a separate sporadic papillary RCC cohort.

Diagnostic pearl: the aggressive potential cannot be judged from nuclear morphology; accurate diagnosis now has direct therapeutic relevance.

• Low-grade oncocytic FH-deficient RCC: 5 cases overlapping SDH-deficient RCC (Xie, Virchows Arch 2025); some have metastatic potential.
• Retained FH protein: nontruncating variants keep immunoreactivity; a 2026 Italian survey highlighted this and limited 2SC access.
• Bevacizumab + erlotinib: prospective phase II activity in HLRCC-associated RCC; not automatically transferable to every sporadic tumour.
• Tubulocystic distinction: all tubulocystic FH-d tumours had extra patterns, FH loss and 2SC; diagnose pure TC-RCC cautiously, especially on biopsy.
• Broader morphology: low-grade clear cell tubular, papillary clear cell, cystic, solid/sieve-like and oncocytic phenotypes; screen by morphology broadly, not indiscriminately.

• Functional biallelic FH inactivation; hereditary (HLRCC) or sporadic.
• Heterogeneous: papillary, tubular, tubulocystic, solid, cribriform, cystic and infiltrative patterns coexist.
• Macronucleoli with halos are characteristic but nonspecific; their absence does not exclude.
• Low-grade oncocytic tumours mimic SDH-deficient RCC; they are not benign.
• FH loss with intact internal controls is highly informative; FH may be retained in functional deficiency.
• Aberrant nuclear and cytoplasmic 2SC supports deficiency; FH and 2SC are complementary.
• PAX8+, CK7 often negative or focal, AMACR not discriminatory.
• Exclude FH deficiency in high-grade papillary, tubulocystic and CDC-like carcinomas.
• A tumour-only FH variant does not prove hereditary disease, but every case merits genetic counselling.
• Bevacizumab + erlotinib is active in advanced HLRCC-associated RCC.
• Sequence: morphologic suspicion → FH/2SC → molecular clarification → hereditary assessment.