Clear cell renal cell carcinoma

• The most common malignant renal epithelial neoplasm — approximately 70–80% of renal cell carcinomas.
• Driven by VHL pathway dysregulation, typically chromosome 3p loss with biallelic VHL inactivation.
• Classic morphology: nests or alveoli of clear cells separated by a delicate, branching capillary network.
• Cytoplasmic clearing reflects intracellular glycogen and lipid.
• Clear cytoplasm is not mandatory — some tumours are predominantly eosinophilic, granular or high grade.
• Characteristic vasculature + compatible cytology + diffuse membranous CAIX is highly supportive.
• Papillary, cystic, tubular or smooth muscle-rich patterns demand careful exclusion of other entities.

• Architecture: solid, nested, alveolar or acinar; variable-sized nests separated by thin fibrovascular septa.
• Vascular network: numerous delicate, thin-walled, branching capillaries — the “chicken-wire” pattern.
• Cytoplasm: abundant and optically clear; sometimes finely granular or eosinophilic.
• Cell borders: usually distinct, giving a well-defined polygonal appearance.
• Nuclei: size, nucleolar prominence and pleomorphism vary with WHO/ISUP grade.

Diagnostic pearl: the delicate vascular network often stays recognisable even when cytoplasmic clearing is minimal or absent.

• Stroma: usually scant, but fibrotic, hyalinised or desmoplastic-appearing areas occur.
• Haemorrhage: common — from focal extravasated erythrocytes to extensive intratumoral haemorrhage, often with haemosiderin.
• Necrosis: variable; more frequent in high-grade and advanced tumours.
• Tumour interface: often well circumscribed with a fibrous pseudocapsule, though infiltrative growth and vascular invasion may occur.

Nested / alveolar

• The prototype: rounded or irregular nests wrapped by branching capillaries.
• Nest size and shape vary; often mixed with solid, acinar or cystic areas.

Solid / diffuse

• Broad sheets with inconspicuous septa; may accompany higher grade or eosinophilic cytoplasm.
• The capillary network is often clearer at the periphery or in residual conventional areas.

Acinar / tubular

• Rounded acini, small glands or elongated tubules; lumina may hold erythrocytes or eosinophilic secretions.
• Extensive tubular growth can mimic other renal epithelial tumours.

Microcystic / macrocystic

• Cysts from dilated acini or degeneration, lined by flattened, cuboidal or clear polygonal cells.
• Expansile solid nodules or high-grade areas favour conventional ccRCC over MCRNLMP.

Pseudopapillary

• Degeneration and loss of cohesion expose vascular cores — a false papillary architecture.
• Extensive papillary-like growth requires exclusion of papillary RCC, clear cell papillary renal cell tumour and molecularly defined RCCs.

Trabecular / cord-like

• Elongated nests, thin cords or interconnecting trabeculae hugging delicate capillaries.
• Particularly misleading in metastatic specimens.

Diagnostic pearl: interpret any pattern in the context of the whole tumour — finding a conventional ccRCC component is especially valuable.

Clear cell

• Abundant optically clear cytoplasm (glycogen and lipid), distinct membranes, round to oval nuclei.
• Classically low- or intermediate-grade areas.

Eosinophilic / granular

• Finely granular, deeply eosinophilic cytoplasm, focal or predominant.
• Frequent in high-grade areas but not restricted to them.
• Can mimic oncocytoma, chromophobe RCC and other eosinophilic tumours.

Vacuolated / foamy

• Multiple intracytoplasmic vacuoles give a bubbly appearance and may obscure epithelial features.
• Vacuolation alone does not define a distinct subtype.

High-grade pleomorphic

• Enlarged nuclei, conspicuous nucleoli, irregularity and hyperchromasia.
• Marked pleomorphism and tumour giant cells may qualify as WHO/ISUP grade 4.
• Low-grade conventional areas may coexist with markedly atypical regions.

Rhabdoid

• Large polygonal cells with eccentric nuclei, prominent nucleoli and dense eosinophilic cytoplasmic inclusions.
• An aggressive dedifferentiated component.
• Any rhabdoid differentiation = WHO/ISUP grade 4.

Sarcomatoid

• Malignant spindle cells in fascicular, storiform or pleomorphic patterns.
• The conventional epithelial component may be very limited.
• Any sarcomatoid differentiation = WHO/ISUP grade 4.

Multinucleated syncytial-type giant cells

• Voluminous eosinophilic cytoplasm with numerous nuclei, coexisting with low-grade ccRCC.
• Not automatically osteoclast-like giant cells or sarcomatoid change.
• A 2014 series found this appearance in 13 tumours (~1.5% of the ccRCC cohort).

Intranuclear pseudoinclusions

• Cytoplasmic invaginations forming well-defined inclusions.
• Not specific for ccRCC and do not independently determine grade.

Intracytoplasmic hyaline globules

• Rounded eosinophilic globules; exceptionally numerous enough to obscure the conventional appearance.
• Should not by themselves redirect classification.

Stromal fibrosis / hyalinisation

• Extensive sclerosis may isolate small nests or tubules of clear cells; smooth muscle-rich areas may occur.
• When fibromuscular stroma dominates, consider ELOC-mutated RCC and other clear cell renal tumours.

Calcification / ossification

• Focal dystrophic calcification and rare ossification are nonspecific.
• They should not outweigh dominant morphology and immunophenotype.

Prominent inflammation

• Dense lymphocytic or mixed infiltrates can obscure epithelial architecture.
• Inflammation is not a defining feature of ccRCC.

These are heterogeneous, uncommon observations — some supported only by small series or case reports, not established subtypes.

A deliberately restricted panel:

• PAX8 — nuclear positive · supports renal epithelial origin.
• CAIX — strong, diffuse, complete membranous · the most useful characteristic pattern.
• CK7 — usually negative or focal · separates many ccRCCs from clear cell papillary renal cell tumour.
• CD10 — frequently positive · supportive, limited specificity.
• AMACR — usually negative or focal · mainly useful against papillary RCC.

CAIX

• Diffuse, complete, box-like membranous staining is typical.
• A basolateral, cup-like pattern favours clear cell papillary renal cell tumour.
• Not entirely specific — varies with differentiation, hypoxia and sampling.

CK7 & AMACR

• ~15% of ccRCCs are CK7-positive, depending on threshold and cohort — CK7 alone does not exclude ccRCC.
• ~35% AMACR positivity has been reported; use it within a panel, not in isolation.

Choose further markers by the suspected mimic — e.g. cathepsin K and melanocytic markers for PEComa-spectrum tumours; molecular testing for TFE3-, TFEB- or ELOC-altered tumours.

Chromosome 3p loss

• One of the earliest, most characteristic events; the region holds VHL, PBRM1, BAP1 and SETD2.

VHL inactivation

• The defining pathway: 3p deletion plus mutation or epigenetic silencing of the remaining allele.
• HIF stabilisation under normoxia drives VEGFA and CA9 — explaining the rich vascularity and CAIX expression.

Chromatin regulators

• PBRM1 (~30–45%) — PBAF complex; adds heterogeneity, not required for diagnosis.
• BAP1 (~10–15%) — loss linked to higher grade and adverse features; IHC is a surrogate in selected contexts, not routinely needed for subtyping.
• SETD2 (~10–20%) — H3K36 trimethylation; often emerges during progression.
• KDM5C — less frequent; contributes to epigenetic dysregulation.

Diagnostic pearl: VHL pathway abnormalities are highly characteristic but read alongside morphology; chromatin-regulator mutations are biologically important but not subtype-defining.

Clear cell papillary renal cell tumour

• Low grade; tubular, cystic, papillary or branching; nuclei aligned away from the basement membrane.
• Diffuse CK7 with cup-like CAIX; lacks the ccRCC molecular profile.
• Pitfall: focal apical nuclear alignment or CK7 does not exclude ccRCC.

ELOC-mutated RCC

• Clear cells with prominent fibromuscular stroma; CK7 common, CAIX may overlap.
• A pathogenic ELOC alteration is required.
• Pitfall: smooth muscle-rich stroma is not specific.

Papillary RCC with clear cell change

• True papillae, foamy macrophages, psammoma bodies; CK7 and AMACR positive.
• Pitfall: degenerative pseudopapillae in ccRCC mimic true papillae.

TFE3-rearranged RCC

• Broad spectrum — clear, eosinophilic, nested, papillary; psammoma bodies and hyaline nodules.
• Pitfall: TFE3 IHC alone is insufficient — confirm the rearrangement.

TFEB-altered RCC

• Biphasic populations and basement membrane-like material; cathepsin K and melanocytic markers help but are not universal.

MCRNLMP

• Exclusively cysts with thin septa holding low-grade clear cells; no expansile nodules, necrosis or high grade.
• Pitfall: cystic degeneration in conventional ccRCC does not qualify.

Epithelioid angiomyolipoma

• HMB45, Melan-A, cathepsin K positive; generally PAX8 negative.

• 1 · Dominant architecture — nested, alveolar, papillary, tubular, cystic or solid?
• 2 · Vasculature — delicate branching capillaries hugging the nests; often the best clue in eosinophilic or unusual tumours.
• 3 · Conventional areas — even a small focus of typical clear cells with characteristic vessels helps.
• 4 · Focused IHC — CAIX and CK7 first; add PAX8, AMACR or others for the specific problem.
• 5 · Selective molecular testing — for persistently ambiguous tumours or a suspected molecularly defined RCC.

Core principle: a single unusual feature should not override the overall morphologic and immunophenotypic profile.

• Heterogeneity beyond VHL — VHL loss is the founding event; PBRM1, BAP1 and SETD2 may sit in different subclones, so a single biopsy may under-represent the tumour.
• BAP1 vs PBRM1 phenotypes — BAP1-altered tumours behave more aggressively; combined loss may be worse. Relevant to risk stratification, not new WHO entities.
• Morphology as evolution — sarcomatoid and rhabdoid change are progression, not separate lineages; whether unusual patterns predict specific alterations is not settled.
• Molecular boundaries — ELOC-mutated RCC and other defined entities refine the differential; clear cells with smooth muscle-rich stroma or unusual tubules are not automatically ccRCC.
• Multi-omics — integrated genomic, epigenomic, transcriptomic and metabolic data link chromatin alterations to metabolism and the immune microenvironment; still investigational.

• Clear cytoplasm is neither necessary nor sufficient for ccRCC.
• The delicate branching capillary network is one of the most valuable clues.
• Diffuse, complete membranous CAIX is highly supportive but not absolutely specific.
• CK7 positivity does not independently exclude conventional ccRCC.
• Prominent eosinophilic cytoplasm occurs in conventional ccRCC, including high-grade tumours.
• Extensive pseudopapillary or tubular architecture should prompt consideration of competing entities.
• Fibromuscular stroma warrants evaluation for ELOC-mutated RCC.
• Sarcomatoid and rhabdoid change are high-grade transformation, not subtypes.
• Molecular heterogeneity may explain regional differences within one tumour.
• A coherent combination of morphology, IHC and — when indicated — molecular findings beats any isolated feature.