Papillary renal cell carcinoma

• A malignant renal epithelial neoplasm with papillary or tubulopapillary architecture and fibrovascular cores.
• The second most common RCC — approximately 10–20%.
• Classic morphology: thin papillae lined by uniform cuboidal cells with scant basophilic or amphophilic cytoplasm.
• Papillae may be inconspicuous where tubular, compact or solid growth predominates.
• The type 1/type 2 subdivision is no longer recommended (WHO 2022); the former type 1 phenotype is the classic pattern.
• Graded with the WHO/ISUP system.
• High-grade papillary tumours require exclusion of FH-deficient, TFE3-rearranged and TFEB-altered RCC.

Architecture

• Delicate, branching papillae with thin fibrovascular cores, lined by a single layer of small cuboidal cells.
• Papillae may be elongated or tightly packed; tubules are frequently admixed.
• Often well circumscribed with a pseudocapsule.

Cells

• Scant to moderate basophilic, amphophilic or pale eosinophilic cytoplasm; round to oval uniform nuclei.
• Classic-pattern tumours are frequently WHO/ISUP grade 1–2.

Associated findings

• Foamy macrophages in papillary cores — particularly characteristic.
• Psammoma bodies, haemosiderin, haemorrhage and cystic degeneration.
• Cores may be oedematous, fibrotic or hyalinised; necrosis in larger or aggressive tumours.

Diagnostic pearl: papillae + foamy macrophages + psammoma bodies is the classic triad — none is mandatory or entirely specific.

Tubulopapillary / predominantly tubular

• Tubules may be round, elongated or packed; tubular-predominant tumours can mimic papillary adenoma or MTSCC.
• Look for conventional papillary areas.

Solid / compact

• Packed papillae and tubules look solid; high power reveals compressed cores or minute lumina.
• True solid growth occurs, especially in high-grade tumours — consider metanephric adenoma and non-papillary RCCs.

Complex papillary

• Broad, fused, cellular papillae with multilayering — historically “type 2”, not a separate subtype.

Cystic / tubulocystic

• Haemorrhagic, proteinaceous or colloid-like contents may obscure papillae.

Micropapillary-like

• Tufts without cores, often degenerative; not specific.

Diagnostic pearl: a predominantly solid or tubular tumour should not be excluded just because well-formed papillae are scarce.

Classic low-grade

• Small cuboidal basophilic/amphophilic cells, uniform nuclei, inconspicuous nucleoli.

Eosinophilic / oncocytic

• Abundant granular cytoplasm, pseudostratification, variable nucleoli.
• Extensive eosinophilia → exclude FH-deficient RCC and other molecularly defined tumours.

Clear cell change

• Focal or extensive clearing or vacuolisation may mimic ccRCC or CCPRCT — architecture and IHC decide.

High grade

• Grade 3–4 features demand care: several aggressive molecular RCCs look similar.

Sarcomatoid / rhabdoid

• Uncommon; either feature establishes WHO/ISUP grade 4.

Diagnostic pearl: eosinophilic cytoplasm and pseudostratification are descriptive findings, not evidence of a “type 2” entity.

• Glomeruloid structures — relevant to biphasic squamoid/alveolar PRCC and metanephric adenoma.
• Hyalinised cores — with basement membrane-like material, biphasic cells and psammoma bodies, consider biphasic hyalinizing psammomatous RCC.
• Prominent vacuolisation — a bubbly, nearly clear appearance can mislead in solid or complex tumours.
• Colloid-like secretions — extensive follicles suggest thyroid-like follicular RCC.
• Lymphoid stroma — oncocytic epithelium with Warthin-like stroma suggests Warthin-like PRCC.

Diagnostic pearl: unusual architecture can be the first clue to an emerging variant or a molecularly distinct tumour.

Confirm papillary renal differentiation and exclude mimics — not a broad routine panel.

• CK7 — frequently diffuse · supports classic PRCC; may be patchy in eosinophilic/high-grade areas.
• AMACR — frequently strong · helps against metanephric adenoma and CCPRCT; not specific.
• PAX8 — positive · renal epithelial origin.
• CAIX — negative or focal · diffuse box-like favours ccRCC; cup-like with CK7 favours CCPRCT.
• CD10 — frequently positive · nonspecific.

Differential-directed markers

• FH / 2SC → FH-deficient RCC · GATA3 → PRNRP · WT1 → metanephric adenoma
• Cyclin D1 → squamoid cells of biphasic squamoid/alveolar PRCC · TFE3/TFEB testing → MiT family RCC

Diagnostic pearl: CK7/AMACR co-expression is characteristic, but neither marker alone establishes the diagnosis.

Chromosome 7 and 17 gains

• Characteristic of conventional PRCC, often with loss of Y in men; shared with papillary adenoma.

MET pathway

• MET (chromosome 7) — activating mutations or copy gains in a subset.
• Germline MET mutations cause hereditary papillary renal carcinoma.
• Not every PRCC has an identifiable MET alteration.

Other alterations

• CDKN2A loss is linked to aggressive tumours; SETD2, BAP1 and PBRM1 alterations occur but are not defining.
• Historical “type 2” molecular data included entities now classified separately.

Diagnostic pearl: 7/17 gains and MET alterations support conventional biology but are neither required nor able to separate PRCC from papillary adenoma.

Biphasic squamoid/alveolar PRCC

• Small basophilic cells lining alveolar/glomeruloid spaces around central large eosinophilic “squamoid” cells, often with emperipolesis.
• Large cells are cyclin D1+; p63 negative; 7/17 gains present.

Papillary renal neoplasm with reverse polarity

• Thin papillae with oncocytic cells and apically placed nuclei; foamy macrophages scarce.
• GATA3+, CD10 and vimentin negative; KRAS mutations; 7/17 gains usually absent.

Warthin-like PRCC

• Oncocytic papillae in dense lymphoid stroma; occasional aggressive behaviour reported.

Biphasic hyalinizing psammomatous RCC

• Small cells with basement membrane-like material, larger epithelial cells, sclerosis and psammoma bodies.
• Biallelic NF2 alterations with Merlin loss — biologically distinct from classic PRCC.

• Papillary adenoma — identical but ≤15 mm, low grade; CK7/AMACR cannot separate them.
• ccRCC — degenerative pseudopapillae; nests with delicate capillaries and diffuse box-like CAIX.
• Clear cell papillary renal cell tumour — clear cells with nuclei aligned away from the basement membrane; CK7 diffuse, cup-like CAIX, AMACR negative.
• FH-deficient RCC — papillary, tubulocystic, cribriform or solid; viral inclusion-like nucleoli with halos (may be focal); FH loss / 2SC positive; hereditary implications.
• TFE3-rearranged RCC — papillary/nested, clear or eosinophilic, psammoma bodies; CK7/AMACR may overlap; confirm molecularly.
• TFEB-altered RCC — biphasic with basement membrane material (rearranged) or high-grade eosinophilic (amplified); melanocytic markers, cathepsin K.
• MTSCC — anastomosing tubules merging with spindle cells in mucinous stroma.
• Metanephric adenoma — primitive small cells; WT1/CD57+, CK7/AMACR negative; BRAF V600E.
• Urothelial carcinoma of the renal pelvis — urothelial cytology, CIS; GATA3, p63/p40, uroplakin; PAX8 usually negative.

Diagnostic pearl: in a high-grade papillary tumour the task is not “type 1 vs type 2” but excluding a molecularly defined renal tumour.

• 1 · Confirm papillary renal morphology — fibrovascular cores, epithelial differentiation, admixed tubular or solid areas.
• 2 · Phenotype and grade — bland basophilic cells favour classic PRCC; marked eosinophilia or unusual nuclei broaden the differential.
• 3 · Selective IHC — CK7 and AMACR; add markers directed at the specific mimic.
• 4 · Exclude molecular RCCs — FH-deficient, TFE3-rearranged, TFEB-altered in high-grade or unusual tumours.
• 5 · Recognise distinctive patterns — reverse polarity, biphasic squamoid, hyalinisation with psammoma bodies, Warthin-like stroma.

• A narrowing concept — abandoning type 1/2 reflects the heterogeneity of old “type 2”; a 2025 review stressed morphology-directed ancillary testing.
• PRNRP as a distinct entity — an April 2026 study: all 15 PRNRPs KRAS-mutated, diffusely GATA3+, without 7/17 gains, versus none of 16 oncocytic PRCCs.
• Biphasic squamoid PRCC — 10 tumours (Virchows Arch 2025/2026): all trisomy 7/17, NOTCH1 mutations in 9/10; no progression over a median 55 months (small cohort).
• NF2-associated biphasic tumours — biphasic cells, hyalinisation and psammoma bodies point to biallelic NF2 inactivation.
• Molecular clarification — classic PRCC follows a 7/17–MET pathway; distinctive patterns carry KRAS, NF2 or other alterations, so unusual morphology should trigger focused testing.

• Type 1/type 2 subclassification is no longer recommended (WHO 2022).
• Classic PRCC: delicate papillae lined by small basophilic/amphophilic cells.
• Foamy macrophages and psammoma bodies are characteristic but not obligatory.
• Solid, tubular, cystic, eosinophilic or clear cell morphology can occur.
• CK7/AMACR co-expression supports the classic pattern.
• High-grade eosinophilic papillary tumours → exclude FH-deficient and MiT family RCC.
• Apical nuclei + diffuse GATA3 → PRNRP.
• Glomeruloid structures with central cyclin D1+ squamoid cells → biphasic squamoid/alveolar PRCC.
• Hyalinisation + psammoma bodies + biphasic cells → NF2-associated biphasic hyalinizing psammomatous RCC.
• Oncocytic cells in dense lymphoid stroma → Warthin-like PRCC.
• 7/17 gains and MET alterations are characteristic but not individually diagnostic.