ELOC (formerly TCEB1)-mutated renal cell carcinoma

• Molecularly defined renal carcinoma in WHO 2022; formerly TCEB1-mutated RCC.
• Pathogenic alterations of ELOC (8q21.11), encoding elongin C of the VHL-associated ubiquitin ligase complex.
• Typical: voluminous clear cells, acinar/tubular architecture and conspicuous fibromuscular stromal bands.
• Branching tubules, small papillae, cysts and solid nests may coexist.
• PAX8+, CK7+, diffuse membranous CAIX, usually complete (box-like) rather than cup-like.
• Overlaps with ccRCC, CCPRCT and TSC/mTOR-altered RCC with fibromyomatous stroma.
• A pathogenic ELOC mutation is essential for definitive classification.
• Mostly low stage, low grade and indolent; higher-stage and aggressive tumours exist.

Diagnostic pearl: clear cells + branching tubules + fibromuscular bands + CK7 + diffuse CAIX should raise suspicion; morphology and IHC alone cannot confirm it.

Clinical

• Extremely rare; middle-aged adults; marked male predominance in recent cohorts.
• Usually incidental, solitary and organ-confined.

Gross

• Well circumscribed, often pseudoencapsulated; tan-yellow to golden.
• Solid or mixed solid-cystic; fibromuscular bands may divide it into visible nodules.
• Haemorrhage, necrosis and infiltration are unusual in low-grade tumours.

Hou et al., Modern Pathology 2026 (35 cases)

• 34/35 male; median 2.5 cm (1.0–5.0); 20 grossly solid, 15 solid-cystic.

Diagnostic pearl: a small circumscribed clear cell tumour with fibromuscular stroma is typical, but neither stroma nor cysts are obligatory.

Fibromuscular stroma

• Thick smooth muscle-rich bands separate nodules, producing a multinodular, compartmentalised look.
• Muscle may also wrap smaller epithelial structures; amount varies and may be absent.

Architecture

• Acini, tubules and branching tubules; small papillae into dilated tubules or cysts; nests and solid areas; striking variation within one tumour.

Cells

• Cuboidal to columnar with abundant, optically clear, often voluminous cytoplasm (more than CCPRCT); distinct borders; focal eosinophilia.

Nuclei

• Low grade, round to oval, smooth membranes; usually without the widespread apical alignment of CCPRCT.

Diagnostic pearl: voluminous clear cells in acini and branching tubules within fibromuscular stroma, but the diagnosis should not depend on all three.

• Acinar: packed rounded gland-like structures; may resemble low-grade ccRCC.
• Branching tubular: curving, interconnected tubules; distinctive with thick bands.
• Papillary / tubulopapillary: delicate branching papillae with slender cores; widens the differential to CCPRCT, TSC/mTOR RCC and PRCC.
• Tubulocystic: dilated tubules and cysts with papillary tufts.
• Solid / nested: may lack tubules or stroma; extensive solid growth with atypia or necrosis needs evaluation.
• Multinodular: nodules divided by broad septa.
• Thyroid follicle-like: rare round spaces with eosinophilic secretion (2026 series); not thyroid differentiation.

Diagnostic pearl: cysts and papillae are common, not exceptions: cystic growth in 15/17 molecularly confirmed tumours in a 2025 study.

• Clear cytoplasm: voluminous, focal eosinophilia; major overlap with ccRCC and CCPRCT.
• Nuclear polarisation: usually absent; focal apical alignment in 5/35 (14%) in the 2026 series, so not an exclusion criterion.
• Myxoid stroma and lymphocyte-rich stroma may obscure the pattern.
• Nuclear pseudoinclusions: rare (1/17 in a 2025 comparison), much less than in TSC/mTOR RCC.
• High-grade features: high-grade nuclei, necrosis, solid alveolar growth in a minority; sample extensively, but they do not exclude the diagnosis.

Diagnostic pearl: absent fibromuscular stroma, focal apical nuclei or high-grade cytology do not invariably exclude ELOC-RCC.

IHC raises suspicion and selects cases for molecular testing.

• PAX8: positive.
• CK7: frequently moderate to strong, often extensive, especially in tubules and papillae; rare CK7-negative cases.
• CAIX: strong diffuse complete (box-like) membranous; differs from cup-like CCPRCT but overlaps with ccRCC and TSC/mTOR RCC.
• CD10: frequently positive, sometimes apical/luminal; helps against CCPRCT, not ccRCC.
• AMACR: variable, often weak or focal.
• GPNMB: usually negative; strong diffuse staining favours TSC/mTOR-altered RCC.
• GATA3, 34βE12: usually negative or focal; diffuse staining suggests CCPRCT or TSC/mTOR RCC.

Diagnostic pearl: working phenotype: diffuse CK7 + box-like CAIX + CD10 + no strong diffuse GPNMB. Molecular confirmation remains necessary.

Elongin C and the VHL complex

• Elongin C is part of the VHL–elongin B/C–CUL2 ligase that degrades hydroxylated HIF-α.
• Loss of function stabilises HIF-α and activates hypoxia programs, explaining clear cells and CAIX.
• ccRCC: VHL inactivation and 3p loss. ELOC-RCC: ELOC alteration, often with chromosome 8 loss. Convergent HIF biology, different entities.

Recurrent variants (Hou 2026, 35 cases)

• p.Y79C 30/35, p.Y79S 2/35, others (p.I95N, p.E92K, p.C112fs) 1 each.
• MAP2K4, HRAS and other co-alterations reported; significance uncertain.
• A variant of uncertain significance does not establish ELOC-RCC.

Diagnostic pearl: a panel limited to p.Y79C will miss tumours with other pathogenic variants.

• Loss of chromosome 8 or 8q is characteristic; with an ELOC mutation it produces biallelic inactivation.
• 2026 series: 8q deletion in 26/26 tumours profiled (12 also 8p loss); no 3p loss by FISH.
• Wang et al. 2025 (13 tumours): chromosome 8 loss in 11/13; fewer large-scale alterations than matched ccRCC; no PBRM1, SETD2 or BAP1 drivers.
• Chromosome 8 loss without a pathogenic ELOC mutation is insufficient; absent 8 loss on a low-resolution assay does not exclude.

Diagnostic pearl: ELOC mutation + 8q loss without VHL/3p findings is especially persuasive.

• Cytoplasm: voluminous clear (ELOC) vs clear to eosinophilic (ccRCC).
• Architecture: acini, branching tubules, papillae, cysts vs nests and alveoli with a delicate capillary network.
• Fibromuscular stroma: frequently prominent vs occasional.
• CK7: frequently positive vs usually negative or focal.
• CAIX: box-like in both. CD10: positive in both.
• Driver: ELOC vs VHL/3p.

Pitfall: ccRCC can have fibromuscular stroma and ELOC-RCC can lack it; CK7 + stroma is not a diagnosis without molecular confirmation.

• Nuclear polarity: usually absent or focal (ELOC) vs conspicuous apical alignment (CCPRCT).
• CAIX: complete box-like vs cup-like.
• CD10: frequently positive vs absent or limited.
• AMACR: variable vs usually absent.
• GATA3, 34βE12: usually negative vs frequently positive.
• CK7: diffuse in both; both can be low grade with fibromuscular stroma, papillae and cysts.

Diagnostic pearl: CAIX distribution, nuclear polarity and CD10/GATA3 are the best preliminary clues; difficult cases need molecular testing.

Arguably the hardest modern differential: often indistinguishable on morphology and routine IHC.

Shared

• Voluminous clear cells, branching tubules and papillae, thick fibromuscular bands, diffuse CK7 and CAIX, low grade.

Favours ELOC-RCC

• Frequent cysts with papillary tufts, few nuclear pseudoinclusions, no strong diffuse GPNMB, ELOC mutation with chromosome 8 loss.

Favours TSC/mTOR RCC

• Conspicuous pseudoinclusions, strong diffuse GPNMB, TSC1/TSC2/MTOR alteration, haemangioblastoma-like areas.

Human Pathology 2025 (17 ELOC vs 12 TSC/mTOR)

• Cysts 15/17 vs 2/12; pseudoinclusions 1/17 vs more frequent; strong diffuse GPNMB only in TSC/mTOR. Cohort-specific, not universal criteria.

Diagnostic pearl: GPNMB is the most useful adjunct here, but the distinction rests on ELOC vs TSC/mTOR alterations.

• Papillary RCC: CK7, CD10, AMACR overlap; usually lacks diffuse CAIX; +7/+17 and MET.
• MCRNLMP: cysts lined by low-grade clear cells without expansile branching tubules or papillae; cystic ELOC-RCC may mimic it.
• TFE3-rearranged RCC: nested, papillary or clear; CK7 limited; cathepsin K/melanocytic markers; molecular confirmation.
• RCC with fibromyomatous stroma, not molecularly classified: a descriptive term when testing is unavailable; it is not itself a molecular entity.

Diagnostic pearl: fibromyomatous stroma is a morphologic finding, not a molecular diagnosis.

1. Morphology: voluminous clear cells, branching acini/tubules, papillary tufts, cysts, thick fibromuscular bands.
2. CK7 and CAIX: extensive CK7 with complete CAIX raises suspicion (overlaps with ccRCC and TSC/mTOR RCC).
3. Refine: CD10, GPNMB, and GATA3 or 34βE12 if CCPRCT is considered.
4. Nuclei: extensive apical polarity favours CCPRCT; pseudoinclusions with GPNMB favour TSC/mTOR.
5. Molecular: pathogenic ELOC variants, ideally with VHL, TSC1, TSC2, MTOR and copy number.
6. Report ELOC-mutated RCC only when established; otherwise describe.

On biopsy

• Fibromuscular bands may be missing; cystic, papillary or solid areas may dominate.
• CK7/CAIX cannot establish the subtype; negative GPNMB does not prove ELOC-RCC; high-grade areas may be missed.
• Wording: RCC with clear cell and fibromyomatous features, suspicious for ELOC-mutated RCC.

Diagnostic pearl: a characteristic biopsy establishes suspicion, not certainty.

• Most tumours are small, organ-confined, low grade with favourable follow-up, but data are limited and follow-up short.
• Wang 2025 (13 tumours): 11 organ-confined; 2 higher stage with solid/alveolar growth, necrosis, extra copy-number changes and monoallelic VHL loss, one with nodal metastasis; better PFS and OS than matched ccRCC.
• Hou 2026: all patients with follow-up alive without progression.
• No validated predictor of progression; stage and follow-up as usual.

Diagnostic pearl: predominantly indolent, not universally benign.

• Broader morphology: dilated cysts, follicle-like spaces, myxoid and lymphocyte-rich stroma, focal polarity (2026 series).
• Y79 predominance: p.Y79C in 30/35; use comprehensive testing rather than a single hotspot.
• GPNMB: negative in all 28 evaluated ELOC tumours (2026) and strong diffuse only in TSC/mTOR RCC (2025).
• Apical CD10/EMA with basal nuclei and a CD10+/AMACR+/GPNMB− phenotype proposed in a 15-case AJSP 2025 series; needs validation, not a molecular surrogate.
• Simple genomes: few large-scale alterations; more complex tumours showed solid/alveolar growth and necrosis; no validated threshold.

• WHO 2022 molecular entity, formerly TCEB1-mutated RCC.
• Voluminous clear cells, branching tubules and acini, focal papillae; thick fibromuscular bands and multinodularity.
• Cystic, solid and follicle-like patterns occur; stroma is helpful but neither obligatory nor specific.
• Usually low grade; high-grade tumours exist.
• CK7 frequently positive; CAIX diffuse box-like; CD10 often positive; GPNMB usually negative.
• Focal apical nuclei do not exclude it; GATA3/34βE12 cannot separate it from CCPRCT alone.
• ELOC p.Y79C predominates; 8/8q loss common; ccRCC has VHL/3p.
• TSC/mTOR RCC with fibromyomatous stroma is the key molecular mimic.
• Molecular confirmation required; mostly indolent, but nodal metastasis is documented.