FLCN-mutated renal neoplasms

• Heterogeneous renal epithelial tumours with pathogenic alterations of FLCN (17p11.2), a tumour suppressor.
• Germline FLCN variants cause Birt-Hogg-Dubé syndrome (BHD), autosomal dominant; tumours usually multiple and bilateral, but a solitary tumour may come first.
• Characteristic types: hybrid oncocytic/chromophobe tumour (HOCT), oncocytoma-like and chromophobe RCC-like tumours.
• Sporadic tumours with somatic FLCN alterations exist without BHD.
• Not restricted to oncocytic morphology: unclassified tumours mimic ESC RCC, EVT, SDH-deficient RCC, PRCC, TFE3/TFEB RCC.
• GPNMB often strong and diffuse (FLCN-mTOR-TFEB/TFE3 axis).
• Classic HOCT shows a mosaic / checkerboard of oncocytic and clearer cells; unusual tumours may lack it.
• Conventional lesions are indolent; atypical high-grade FLCN-mutated carcinomas can recur or metastasise.
• A tumour FLCN mutation does not prove germline status or that FLCN is the driver.

Diagnostic pearl: FLCN-mutated renal neoplasia is a much broader spectrum than BHD-associated HOCT.

• “FLCN-mutated renal neoplasm” is a useful molecular umbrella, not a single WHO 2022 entity with a validated grading system.
• “HOCT” fits the classic phenotype; do not apply it to every FLCN-mutated tumour.

• Autosomal dominant constitutional FLCN variant; variable penetrance and expression.
• Extrarenal: multiple fibrofolliculomas, basal lung cysts, spontaneous (recurrent) pneumothorax, family history of renal tumours, lung cysts or pneumothorax.
• Renal: bilateral or multifocal tumours, oncocytic nodules and oncocytosis, HOCT, ChRCC, less often clear cell or papillary morphology, cysts.
• Pitfalls: skin signs subtle or absent; no pneumothorax does not exclude BHD; a solitary tumour may come first; older age does not exclude a germline variant.

Diagnostic pearl: a tumour with FLCN-type morphology may be the first sign of BHD, even without family history or skin and lung findings.

• Conventional: circumscribed solid, tan-brown, mahogany or grey-tan, oncocytoma- or ChRCC-like; multiple tumours of different size and type in one kidney; small background oncocytic nodules.
• Atypical: solid or solid-cystic, grey-white to variegated, haemorrhage or necrosis, irregular infiltrative border in aggressive tumours.
• Background kidney: microscopic oncocytic proliferations, oncocytosis, small cysts with oncocytic lining, separate tumours of differing phenotype.

Diagnostic pearl: multiple bilateral oncocytic tumours suggest hereditary FLCN disease, but unusual solitary tumours can also be FLCN-driven.

• Solid nests, sheets and packed tubules; oncocytoma-like and chromophobe-like areas; uniform solid oncocytic look at low power; delicate or hyalinised septa.
• Oncocytic cells: granular eosinophilic cytoplasm, round central nuclei, smooth contours, small to moderate nucleoli.
• Chromophobe-like cells: sharp membranes, pale eosinophilic or amphophilic cytoplasm, some perinuclear clearing, less raisinoid than ChRCC.
• Hybrid: the two populations intermixed as clusters, zones or an irregular mosaic; one may dominate.

Diagnostic pearl: HOCT is not a collision of oncocytoma and ChRCC but a distinctive hybrid phenotype in one tumour.

• Oncocytic cells interspersed with clear or paler, sometimes vacuolated cells, singly or in small clusters, with conspicuous borders.
• Not necessarily separate clones; diffuse or regional; not degenerative clearing; proportions vary.

Diagnostic pearl: a checkerboard of oncocytic and clear/vacuolated cells strongly suggests conventional FLCN-mutated HOCT, but its absence does not exclude FLCN.

• Oncocytoma-like: nests and sheets of granular eosinophilic cells, round nuclei, oedematous stroma; small clearer or vacuolated foci reveal the FLCN phenotype.
• ChRCC-like: defined borders, perinuclear clearing, pallor, nuclear irregularity, solid or alveolar; can be nearly identical to eosinophilic ChRCC.
• A conventional oncocytoma or ChRCC in a BHD patient need not look hybrid.
• Conventional ChRCC has multiple chromosome losses; FLCN-mutated HOCT often lacks that profile.

Diagnostic pearl: test FLCN when an oncocytoma- or ChRCC-like tumour has odd cytology, discordant IHC or multifocality.

• Solid eosinophilic: sheets with variable nuclei and nucleoli; mimic EVT, ESC RCC or oncocytic PRCC.
• Solid and cystic: aggregates with cysts, hobnail or eosinophilic lining; mimic ESC RCC or TSC/mTOR tumours.
• Tubular and papillary: tubules, papillae and solid areas with eosinophilic or clear cells; overlap with PRCC and MiT RCC.
• SDH-deficient RCC-like: vacuoles or inclusions, solid or nested; SDHB retained.
• Histiocyte-rich: many histiocytes among tumour cells; an increasingly recognised clue.

Diagnostic pearl: nonconventional tumours usually lack the checkerboard; recognising them needs unusual morphology, a directed panel and molecular testing.

• Solid or nested epithelium partly obscured by many interspersed histiocytes; fibrosis or cysts.
• Bland to atypical eosinophilic or amphophilic cells; some with oncocytic and vacuolated cells, others without HOCT features.
• Foamy or eosinophilic macrophages diffusely, not only in cysts or papillary cores; CD68/CD163 if needed.

Argani et al., AJSP 2026: 11 histiocyte-rich renal epithelial neoplasms; 5 FLCN-altered, at least 3 with evidence of occult BHD; all 5 diffusely GPNMB+, as were 3 of 6 without FLCN mutation; GPNMB+ epithelial cysts in the background kidney of 2 syndromic cases.

Diagnostic pearl: a histiocyte-rich eosinophilic renal tumour with diffuse GPNMB warrants FLCN testing, even without hybrid morphology.

• Complex papillary, tubulopapillary, solid infiltrative, glandular, cribriform or nested; heterogeneous.
• Eosinophilic and clear cells, nuclear enlargement, prominent nucleoli, pleomorphism, mitoses.
• Adverse: necrosis, infiltration, desmoplasia, regional or distant metastasis.

Wang et al., Virchows Arch 2026: 6 high-grade papillary-patterned RCCs with FLCN frameshift mutations; 5/6 germline or likely germline; 3/6 distant metastases; 2 deaths. A selected series, not the risk of typical FLCN tumours.

Diagnostic pearl: FLCN alteration is not equivalent to an indolent oncocytic neoplasm; a high-grade papillary or solid RCC with diffuse GPNMB and no other defining alteration may warrant FLCN sequencing.

• Folliculin with FNIP1/FNIP2; links to AMPK and lysosomal nutrient sensing.
• Two-hit: germline variant plus somatic loss in BHD; two acquired hits in sporadic tumours; second hit by mutation, deletion or LOH.

A single tumour FLCN variant may be

• A somatic driver, one of two hits, constitutional, a passenger, or a VUS.

Diagnostic pearl: biallelic inactivation and no better alternative driver strengthen the case that a tumour is truly FLCN-driven.

• FLCN is a GAP for RagC/D; its loss impairs lysosomal recruitment and phosphorylation of TFEB/TFE3, which stay nuclear and active.
• GPNMB is a downstream target of this programme.
• Canonical mTORC1 substrates may still be activated through compensation and feedback, so nuclear TFEB/TFE3 and mTORC1 activity coexist.

Diagnostic pearl: FLCN-mutated tumours can show a MiT-family transcriptional phenotype without any TFE3 or TFEB rearrangement.

No marker is universally specific for FLCN-driven renal neoplasia.

• Strong cytoplasmic, sometimes membranous or granular, often diffuse; stains conventional and nonconventional tumours and background oncocytic proliferations.

Xia et al., AJSP 2025: 18 FLCN-mutated tumours (10 HOCT, 8 unclassified), all strongly diffuse. Argani et al., AJSP 2025: all 8 clinically sporadic tumours positive. A 2026 seven-patient series: diffuse in all 5 evaluable.

Pitfall

• Also positive in TFE3- and TFEB-altered RCC, ESC RCC, TSC/mTOR tumours and other MiT-activated tumours.

Diagnostic pearl: GPNMB opens a differential, it does not prove FLCN; it is most useful once TFE3/TFEB and TSC/mTOR explanations are excluded.

• FOXI1: intercalated cell differentiation; marks one HOCT component; frequent in ChRCC.
• L1CAM: in LOT and other oncocytic tumours; can mark a different population from FOXI1.

Wan et al., Hum Pathol 2026: 5 conventional FLCN-mutated tumours with mutually exclusive FOXI1 and L1CAM, biallelic FLCN loss in 4/5, without the ChRCC chromosome-loss profile.

Diagnostic pearl: complementary FOXI1/L1CAM is the immunophenotypic counterpart of the checkerboard; promising but not a validated criterion.

• Argani et al.: 8 clinically sporadic FLCN-mutated tumours, all in women aged 25–77, all confined to the kidney.
• 5 likely true somatic, 3 occult BHD; morphology overlapped with TSC/mTOR eosinophilic tumours and TFE3/TFEB RCC; all GPNMB+.
• Occult BHD cases had multiple chromosomal gains and losses absent from the somatic cases.

Diagnostic pearl: a clinically sporadic presentation does not prove a somatic-only FLCN mutation.

• Confirmed germline: variant in constitutional DNA; BHD; tumour may show loss of the other allele; family evaluation and surveillance.
• Confirmed somatic: not in constitutional DNA; supports a sporadic FLCN-driven tumour if concordant.
• Tumour-only variant: origin uncertain; VAF is a clue, not proof (copy number, LOH, purity); genetic counselling or paired normal testing.
• FLCN in an otherwise established RCC: another driver defines the tumour; consider incidental germline or secondary somatic variants.

Diagnostic pearl: tumour-only NGS finds FLCN alterations but cannot reliably separate somatic from constitutional origin.

Supports a driver

• Pathogenic loss-of-function, biallelic inactivation, compatible morphology, diffuse GPNMB, no alternative defining driver, oncocytosis or BHD findings.

Caution

• Single variant without a second hit, VUS, an established molecular diagnosis (VHL ccRCC, TFEB-amplified RCC), morphology fully typical of another tumour, no functional evidence.

In a 2026 seven-patient Human Pathology series, a clear cell RCC carried a probable germline FLCN alteration together with TFEB locus amplification.

Diagnostic pearl: classify by the driver responsible for tumour identity, not by any alteration in a hereditary gene.

Diagnostic pearl: an oncocytoma-like tumour with widespread pale or vacuolated cells, diffuse GPNMB and mosaic CK7/CD117 deserves HOCT consideration.

Favours ChRCC

• Widespread raisinoid nuclei, classic diffuse CK7, broad multi-chromosome losses, FOXI1 intercalated phenotype.

Favours FLCN-mutated HOCT

• Mosaic of oncocytic and clear/vacuolated cells, complementary populations, diffuse GPNMB, no ChRCC copy-number pattern, proven FLCN inactivation.

Diagnostic pearl: some FLCN tumours look like eosinophilic ChRCC but lack its chromosome-loss signature.

Diagnostic pearl: all four touch lysosomal/mTOR signalling, so GPNMB and cathepsin K overlap; test molecularly when the phenotype is incomplete.

• Shared: eosinophilic or clear cells; solid, papillary, nested or cystic; GPNMB; cathepsin K; nuclear TFE3 staining.
• FLCN-mutated: functional TFEB/TFE3 activation without rearrangement; FLCN inactivation shown molecularly.
• TFE3-rearranged RCC: an expressed fusion; IHC alone is insufficient.
• TFEB-rearranged / amplified RCC: demonstrable fusion or focal amplification (interpret against polysomy).

Diagnostic pearl: strong TFE3 and diffuse GPNMB in an FLCN-deficient tumour mimic MiT RCC; transcriptional activation is not a fusion.

• SDH-deficient: bland oncocytic cells, flocculent inclusions, vacuoles, SDHB loss; hereditary SDHx implications.
• FH-deficient: oncocytic, papillary, tubular, tubulocystic, cribriform or solid; large nucleoli; FH loss / 2SC; HLRCC implications.
• FLCN-mutated: can mimic either; SDHB and FH retained; GPNMB may be strong; molecular testing may be needed.

Diagnostic pearl: do not assign BHD on GPNMB alone; FH and SDH deficiency carry different clinical implications.

1. Morphology: classic hybrid, unusual eosinophilic/cystic, histiocyte-rich, or unclassified high-grade papillary.
2. Context: multifocality, bilaterality, oncocytosis, cysts, family history, lung cysts, pneumothorax, skin findings.
3. Directed IHC: CK7, CD117, GPNMB, cathepsin K; FOXI1, L1CAM or SOX9 when useful.
4. Exclude mimics: SDHB, FH/2SC, TFE3/TFEB and other molecular entities.
5. Investigate FLCN: suitable panel with copy number and biallelic assessment.
6. Somatic vs germline: genetics referral or paired constitutional testing.
7. Report: keep the morphological phenotype, state the molecular result, do not assert BHD from tumour-only sequencing.

• Conventional: “Hybrid oncocytic/chromophobe tumour, FLCN-mutated. Assessment for Birt-Hogg-Dubé syndrome may be appropriate.”
• Atypical: “FLCN-mutated renal epithelial neoplasm with nonconventional oncocytic morphology. A tumour-associated mutation does not establish germline status.”
• High grade: “FLCN-mutated renal cell carcinoma, high grade, with papillary and solid architecture. Aggressive behaviour is documented in a subset of atypical FLCN-mutated RCCs.”
• Uncertain: “Renal epithelial neoplasm with [morphology]; FLCN variant of uncertain significance. Data do not establish pathogenicity or driver status.”

Diagnostic pearl: keep morphological phenotype, FLCN driver evidence and hereditary status as three separate statements.

• Conventional HOCT: usually indolent; disease-free after local treatment; in BHD, new tumours over time, so the problem is multifocal burden rather than metastasis.
• Nonconventional: heterogeneous; some indolent, recurrence and metastasis documented.
• High-grade FLCN RCC: aggressive in a small selected subset; necrosis, high-grade atypia, infiltration and metastasis are concerning; no validated FLCN-specific grading.

Diagnostic pearl: the favourable course of BHD-associated HOCT should not be extrapolated to every FLCN-mutated RCC.

Consider hereditary evaluation for

• Bilateral or multifocal tumours, HOCT morphology, oncocytosis, young age, family history of renal tumours or pneumothorax, lung cysts or skin lesions, tumour findings of FLCN loss even when sporadic.

ERN GENTURIS 2024 (confirmed BHD)

• Lifelong renal surveillance from about age 20; MRI preferred, every 1–2 years.
• Nephron-sparing treatment; intervention commonly considered around 3 cm, individualised.
• Genetic counselling and cascade testing for at-risk relatives.

These recommendations apply to BHD, not automatically to a confirmed purely somatic FLCN tumour.

• Sporadic FLCN-driven tumours exist; occult BHD is real; the morphological spectrum is expanding; GPNMB is sensitive, not specific; aggressive tumours are documented; TFEB/TFE3 and mTORC1 dysregulation is central and differs from canonical TSC neoplasia.

• FLCN-mutated tumours include germline BHD-associated and sporadic somatic neoplasms; sporadic presentation does not exclude occult BHD.
• Typical BHD tumours are HOCT with a checkerboard of oncocytic and clear/vacuolated cells; oncocytosis and bilateral tumours support hereditary disease.
• CK7 and CD117 can be mosaic; FOXI1 and L1CAM mark complementary cells; GPNMB is frequently diffuse but not specific.
• FLCN loss deregulates TFEB/TFE3 via RagC/D; TFEB/TFE3 activation is not a rearrangement.
• Mimics: ESC RCC, EVT, SDH-deficient RCC, PRCC and MiT RCC; histiocyte-rich morphology is a new clue.
• High-grade papillary and solid FLCN carcinomas can be aggressive; typical HOCT is indolent.
• Biallelic inactivation strengthens driver attribution; tumour-only results cannot establish germline status; an incidental FLCN variant does not override another molecular diagnosis.
• Morphology, driver assessment and hereditary risk are three distinct tasks.