Tubulocystic renal cell carcinoma

• Rare renal epithelial neoplasm of tightly packed tubules and cysts of variable size separated by delicate fibrous septa.
• Low power: a bubble-wrap, Swiss-cheese or sponge-like appearance.
• Lining: flattened, cuboidal or hobnail cells with eosinophilic cytoplasm and conspicuous nucleoli.
• Despite the nucleoli, little pleomorphism and very low mitotic activity.
• WHO recognises it as a distinct entity and emphasises pure tubulocystic morphology.
• A significant solid, papillary, cribriform or poorly differentiated component should prompt a search for another RCC, especially FH-deficient RCC.
• PAX8+, AMACR+, CD10 variable, CK7 absent or limited; FH retained, 2SC negative.
• Strictly classified cohorts are overwhelmingly indolent.
• No single diagnostic alteration; chromosome 9 loss and 17 gain recur.

Diagnostic pearl: pure tubulocystic architecture is essential. A carcinoma with tubulocystic areas is not necessarily tubulocystic RCC.

Clinical

• Adults, often 6th to 7th decade; marked male predominance.
• Usually incidental, small and localised.
• Can be multifocal, particularly in chronic or end-stage kidney disease; may coexist with papillary adenomas or other renal tumours.

Gross

• Well circumscribed, spongy, multicystic cut surface of many tiny cysts (bubble wrap); grey-white to tan.
• A solid expansile nodule, extensive necrosis or solid tumour is not characteristic and needs further work-up.

Location

• Corticomedullary or medullary in some cohorts; superficial tumours may protrude toward the capsule or perinephric fat.

Diagnostic pearl: a small, circumscribed spongy tumour fits TC-RCC, but several other cystic renal tumours look the same grossly.

Tubules and cysts

• Round, oval, elongated or irregular spaces with marked variation in size, even in one field.
• Densely packed, separated only by narrow fibrous septa; the pattern extends throughout the lesion.

Lining

• Single layer of flattened, cuboidal or low columnar cells; hobnail nuclei bulge into lumina.
• Eosinophilic or amphophilic, sometimes granular cytoplasm; clear cells are not typical.

Nuclei

• Round to oval with nucleoli comparable to WHO/ISUP grade 3, but no significant pleomorphism or mitoses.

Stroma

• Delicate fibrovascular septa, variably hyalinised; no desmoplastic or expansile cellular stroma.

Diagnostic pearl: prominent nucleoli with very low mitotic activity is the cytologic paradox of TC-RCC; nucleolar grade does not predict behaviour here.

• Small tubular: packed tubules with identifiable lumina and visible septa; may resemble compact tubular PRCC.
• Microcystic: many small cysts with thin septa, sieve-like at medium power.
• Macrocystic: larger dilated spaces with flattened lining; correlate with classic areas.
• Hobnail-predominant: eosinophilic hobnail cells; may resemble FH-deficient RCC.
• Focal luminal tufting: acceptable; well-developed expansile papillae are not.
• Fibrotic / hyalinised: thick septa may separate and obscure the tubules.

Crucial distinction: variation within the tubulocystic pattern is acceptable; a separate solid, infiltrative, cribriform or substantial papillary component is not an ordinary variant.

• Prominent nucleoli: can be conspicuous in otherwise bland cells; alone they do not mean an aggressive tumour.
• Hobnail cells: supportive, not unique to TC-RCC.
• Perinucleolar halos around viral inclusion-like nucleoli should raise concern for FH-deficient RCC.
• Mitoses: very few; numerous or atypical mitoses do not fit pure TC-RCC.
• Necrosis: uncommon; extensive necrosis suggests FH-deficient RCC, high-grade PRCC or another carcinoma.

Diagnostic pearl: the worrying findings are marked pleomorphism, brisk proliferation and morphologic heterogeneity, not large nucleoli alone.

IHC mainly confirms renal lineage and excludes mimics, above all FH-deficient RCC.

• PAX8: positive; confirms lineage, not subtype.
• AMACR: usually strong and diffuse; also strong in PRCC and FH-deficient RCC.
• CD10: variable luminal/membranous, often positive; not subtype-specific.
• CK7: negative or focal in many strictly defined cohorts; more extensive in some older series. Not obligatory.
• CAIX: usually negative or focal.
• FH retained / 2SC negative: central to an FH-proficient tumour. Complete FH loss with intact internal control, or aberrant 2SC, supports FH-deficient RCC. Retained FH alone does not exclude every FH-deficient tumour.

Diagnostic pearl: FH and 2SC are the most consequential stains, more than an extended routine RCC panel.

Copy-number profile (2019, 9 pure TC-RCCs)

• Chromosome 9 loss in 9/9 and chromosome 17 gain in 9/9; Y loss in 5/5 evaluable male tumours.
• Chromosome 7 gain, typical of PRCC, was not a feature.
• Small cohort: not universally defining.

Chromatin-modifying genes

• KMT2C and KDM5C each mutated in 2/9 (22%); biologically interesting, not specific.

Absent alternative drivers

• No FH, ccRCC-type or other molecularly defined RCC signatures; no pathogenic FH mutations in that series.

Diagnostic pearl: 9 loss with 17 gain is a useful association, but its sensitivity and specificity are not fully established.

The single most important differential: FH-deficient RCC can be predominantly tubulocystic.

• Architecture: pure tubules and cysts (TC-RCC) vs tubulocystic with focal papillary, solid, cribriform or infiltrative areas (FH-d).
• Nuclei: prominent nucleoli, limited pleomorphism vs inclusion-like nucleoli with perinucleolar halos.
• FH / 2SC: retained / negative vs usually lost / aberrantly positive (FH can be retained).
• Proliferation and behaviour: low and indolent vs often elevated and aggressive.

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

• TC-RCCs were <4 cm, pT1a, low Ki-67, FH retained and 2SC negative.
• All 10 FH-deficient tumours had halos, FH loss, 2SC positivity and at least a focal non-tubulocystic component; they were larger and more proliferative.
• Size or Ki-67 cannot replace FH/2SC.

Diagnostic pearl: a tubulocystic FH-deficient RCC is not a variant of TC-RCC; it is a distinct carcinoma with possible hereditary implications.

Papillary RCC

• Can be tubular, microcystic or tubulocystic; eosinophilic PRCC can look similar cytologically.
• Both often express AMACR and CD10; CK7 is more often diffuse in PRCC but overlaps.
• Well-formed fibrovascular papillae, foamy macrophages and psammoma bodies favour PRCC.
• PRCC often gains 7 and/or 17; pure TC-RCC showed 9 loss with 17 gain.
• Under strict criteria, a tumour with a substantial true papillary component is not pure TC-RCC.

Acquired cystic disease-associated RCC

• Relevant in end-stage kidneys; both may be eosinophilic, cystic and AMACR+.
• ACD-RCC shows cribriform/sieve-like, papillary, acinar or solid growth and calcium oxalate crystals.
• End-stage kidney disease alone establishes neither diagnosis.

Diagnostic pearl: AMACR and chromosome 17 gain do not separate TC-RCC from PRCC; in an end-stage kidney, look for oxalate crystals and sieve-like growth.

• Tubulocystic oncocytoma: tubules and cysts lined by granular oncocytic cells without the conspicuous nucleoli; CD117 and E-cadherin often positive, AMACR focal.
• MCRNLMP: cysts lined by low-grade clear cells; CAIX strong, AMACR negative.
• Clear cell papillary renal cell tumour: clear cells with apical nuclear polarisation; diffuse CK7, cup-like CAIX.
• Collecting duct carcinoma: infiltrative, desmoplastic, high grade, destructive, with substantial non-tubulocystic areas.

Diagnostic pearl: tubulocystic architecture is a pattern shared by many renal tumours; TC-RCC needs morphology, cytology and exclusion of specific mimics.

1. Architecture: uniform tubules and cysts with delicate septa; check for separate solid, papillary or cribriform areas.
2. Lining: flattened, cuboidal or hobnail eosinophilic cells, conspicuous nucleoli, low mitoses.
3. Exclude FH-deficient RCC: FH and 2SC, mindful of internal controls and retained FH.
4. Limited panel: PAX8, AMACR; add CK7, CD10, CAIX or CD117 as the differential requires.
5. Background kidney: end-stage disease, acquired cysts, papillary adenomas, other RCCs.
6. Certainty: most secure when extensive sampling confirms pure morphology.

On biopsy

• A core may show classic tubulocystic morphology yet miss focal non-tubulocystic areas of an FH-deficient RCC.
• Retained FH and negative 2SC do not prove the whole lesion is pure; definitive diagnosis on biopsy is discouraged.
• Suggested wording: renal epithelial neoplasm with tubulocystic features; see comment.

Diagnostic pearl: a classic-looking core is not proof that the whole tumour is purely tubulocystic.

• Very low malignant potential: Harik et al. (AJSP 2025), 31 strictly defined FH-proficient tumours in 30 patients, median 2.3 cm, all pT1, median follow-up 35 months (1 to 294): no evidence of disease in any patient. Not proof of zero lifetime risk.
• Renaming proposal: a 2024 series of 28 cases (mean 1.2 cm, 68% multifocal, 96% end-stage kidney, 54% papillary adenomas, all indolent) proposed “tubulocystic renal cell tumour”. Not adopted by WHO.
• Pseudoinvasion: protrusion toward perinephric fat in 36% of that series; distinguish expansile protrusion from true destructive fat invasion and do not dismiss it if other atypical features exist.
• FH-deficient mimic: in the 2024 multicentre study all FH-deficient tumours had focal additional patterns, FH loss, 2SC positivity and halos; sampling and FH/2SC are complementary.
• Historical metastatic rates: a 2026 scoping review of 30 published cases includes tumours classified before strict criteria and FH-deficient RCC recognition; do not quote them as the risk of pure FH-proficient TC-RCC.

• Pure tubulocystic architecture is the central requirement; bubble-wrap or sponge-like at low power.
• Packed tubules and cysts separated by delicate fibrous septa.
• Flattened, cuboidal or hobnail eosinophilic cells; prominent nucleoli with very low mitotic activity.
• Substantial papillary, solid, cribriform or infiltrative components exclude straightforward pure TC-RCC.
• FH-deficient RCC is the key differential; FH retained and 2SC negative in TC-RCC, though retained FH alone is not absolute.
• AMACR usually positive; CK7 often negative or focal but variable.
• Chromosome 9 loss with 17 gain in a small pure cohort.
• Frequent end-stage kidney disease, papillary adenomas and multifocality in some cohorts.
• Fat protrusion can be pseudoinvasive.
• Avoid a definitive diagnosis on biopsy.
• Strictly defined tumours: no evidence of disease in 31/31 (AJSP 2025).
• Best combination: pure morphology, eosinophilic hobnail cells, low proliferation, FH-proficient phenotype.