Chromophobe renal cell carcinoma

• A malignant renal epithelial neoplasm with irregular nuclear membranes, prominent cell borders and pale or eosinophilic cytoplasm.
• About 5–7% of RCCs — the third most common subtype.
• Thought to arise from intercalated cells of the collecting duct.
• Two forms: classic (pale reticular cytoplasm, crisp borders, halos, wrinkled nuclei) and eosinophilic (granular cytoplasm, oncocytoma-like).
• Hallmark: multiple whole-chromosome losses — 1, 2, 6, 10, 13, 17, 21.
• Usually favourable; sarcomatoid change, necrosis and advanced stage are adverse.
• WHO/ISUP grading is not recommended for ChRCC.

Diagnostic pearl: wrinkled nuclear membranes, conspicuous borders and perinuclear clearing are more useful than cytoplasmic colour.

Architecture

• Solid, nested, alveolar or trabecular sheets with delicate vessels or septa; often well circumscribed.

Cells

• Large polygonal cells with pale, finely reticular or flocculent cytoplasm.
• Sharp membranes — the plant-cell appearance; pale and eosinophilic cells may coexist.

Nuclei

• Irregular, wrinkled, raisinoid; binucleation; coarse chromatin; nucleoli usually inconspicuous.

Perinuclear halos

• Distinct clearing around nuclei — characteristic but also seen in LOT, EVT and others.

Diagnostic pearl: borders + raisinoid nuclei + halos together are characteristic; no single feature is pathognomonic.

• Predominantly granular eosinophilic cells, nested/acinar/solid — closely mimics oncocytoma.
• Chromophobe nuclear changes may be subtle or focal; borders less crisp.
• Fibromyxoid or oedematous stroma may increase the resemblance.
• CK7 often patchy, focal or absent; CD117 retained.
• Usually shares the multiple-loss profile, with some heterogeneity.

Diagnostic pearl: scattered-cell CK7 does not exclude eosinophilic ChRCC — look at the distribution and quality of nuclear irregularity.

• Solid / sheet-like — mosaic, plant-cell look; common in classic ChRCC.
• Nested / alveolar — common in eosinophilic ChRCC; hardest against oncocytoma.
• Tubular / acinar — may mimic other low-grade tumours.
• Trabecular — cords in oedematous or fibrous stroma.
• Microcystic / cystic — extensive cysts → exclude other cystic tumours.
• Pseudopapillary — focal is acceptable; extensive true papillae → PRCC or molecular RCC.

Diagnostic pearl: ChRCC is defined by cellular phenotype and genome rather than one pattern.

• Classic pale cells and oncocytic cells often coexist.
• Binucleation — characteristic but nonspecific.
• Nuclear atypia — enlargement and pleomorphism are often intrinsic, not dedifferentiation.
• Stromal hyalinisation, calcification, ossification — nonspecific.
• Sarcomatoid differentiation — aggressive; document presence and proportion.

Diagnostic pearl: marked nuclear irregularity is expected; necrosis, sarcomatoid change and invasive progression matter more.

• CK7 — diffuse in classic; variable/focal in eosinophilic · first discriminator from oncocytoma.
• CD117 — strong membranous · shared with oncocytoma and EVT.
• S100A1 — often negative/limited · supportive against oncocytoma.
• CAIX — usually negative · against ccRCC.

Key points

• Diffuse CK7 is not specific — LOT is also diffusely positive.
• CD117 negative with diffuse CK7 → think LOT.

Diagnostic pearl: diffuse CK7/CD117 co-expression supports classic ChRCC; eosinophilic ChRCC may look oncocytoma-like (CK7-low/CD117+).

• Multiple whole-chromosome losses (1, 2, 6, 10, 13, 17, 21, ± Y) — hypodiploid genome; eosinophilic tumours may be less extensive.
• TP53 — among the most frequently altered genes; relevant to progression.
• PTEN — mutations/deletions affecting PI3K–AKT–mTOR.
• TERT — promoter alterations and rearrangements in a subset.
• Versus oncocytoma — oncocytoma has 1/Y loss, CCND1 rearrangement or a simple genome.

Diagnostic pearl: a multiple-loss profile strongly supports ChRCC when eosinophilic morphology and low CK7 overlap with oncocytoma.

• Borders — prominent in ChRCC, indistinct in oncocytoma.
• Nuclei — wrinkled raisinoid vs smooth round.
• Halos — conspicuous vs absent/focal.
• Stroma — compact vs oedematous/myxoid.
• CK7 — diffuse (classic) or variable vs scattered cells; CD117 positive in both.
• Genome — multiple losses vs limited losses / CCND1.

Oncocytoma may show striking but focal, smudged degenerative atypia — not the widespread uniform membrane irregularity of ChRCC.

Diagnostic pearl: assess the nuclear phenotype across several regions, not only the most atypical or most oncocytoma-like area.

• LOT — small compact nests, oedema, bland round nuclei; CK7 diffuse, CD117 negative; L1CAM, GATA3; MTOR/TSC1; no multiple losses.
• EVT — large vacuoles, big nucleoli, thick-walled vessels; CD117+, cathepsin K+, CK7 limited; TSC/MTOR.
• Hybrid oncocytic/chromophobe tumour — mixed features; Birt–Hogg–Dubé, oncocytosis.
• ESC RCC — solid and cystic, coarse basophilic stippling; CK20+; TSC1/2.
• SDH-deficient RCC — flocculent inclusions; SDHB loss; CD117 and CK7 negative.

Diagnostic pearl: let morphologic clues decide which second-line stain to use: cathepsin K, CK20, SDHB, L1CAM.

• Limited CK7 — a CK7-low/CD117+ tumour is not automatically oncocytoma.
• Degenerative vs chromophobe atypia — focal smudged nuclei vs widespread membrane irregularity.
• Halos — not specific; combine with wrinkling and borders.
• Oncocytoma-like areas — biopsies may sample only these.
• Unusual genomics — some ChRCC-like tumours are emerging entities.
• Apparent high grade — intrinsic atypia ≠ progression; look for mitoses, necrosis, sarcomatoid change.

No universally accepted grading system — report adverse findings individually.

• Coagulative tumour necrosis — adverse; distinguish from ischaemia and haemorrhage.
• Sarcomatoid differentiation — malignant spindle cells; markedly increased risk of metastasis and death.
• Anaplastic transformation — pleomorphic undifferentiated carcinoma with mitoses.
• Glandular dedifferentiation — atypical gland-forming component that may look unrelated.

• Dedifferentiation is broader — a 2024 multiregion study described sarcomatoid, anaplastic and glandular patterns, with loss of lineage markers in aggressive areas.
• TP53/PTEN and genome doubling — whole-genome duplication of the hypodiploid genome accompanies aggressive morphology.
• L1CAM separates LOT — 2024 Modern Pathology: L1CAM marks LOT, not eosinophilic ChRCC; ancillary, not stand-alone.
• Grading under study — four-tiered and Paner chromophobe grading stratify risk in small series; not universally adopted.
• Molecularly atypical eosinophilic tumours — FOXI1/LINC01187 and MTOR findings suggest distinct subgroups within former eosinophilic ChRCC.

• Prominent borders, perinuclear halos and raisinoid nuclei define classic ChRCC.
• Eosinophilic ChRCC mimics oncocytoma; CK7 may be limited.
• CD117 is positive in both ChRCC and oncocytoma.
• Widespread membrane irregularity favours ChRCC; focal smudged atypia fits oncocytoma.
• CK7 diffuse / CD117 negative → LOT. Vacuoles + thick vessels + cathepsin K → EVT.
• Losses of 1, 2, 6, 10, 13, 17, 21 are highly characteristic; TP53 and PTEN recur.
• No WHO/ISUP grade; report necrosis, sarcomatoid and anaplastic change.
• Multifocal or bilateral oncocytic/chromophobe tumours → Birt–Hogg–Dubé.