Acquired cystic disease-associated renal cell carcinoma

• A distinct malignant renal epithelial neoplasm arising in end-stage kidneys with acquired cystic kidney disease (ACKD).
• The most common RCC subtype in kidneys with acquired cystic disease.
• Classic morphology: large eosinophilic cells forming cribriform / sieve-like structures, often with papillary and tubulocystic areas.
• Cytoplasmic vacuolisation with intra- and intercellular lumina is characteristic.
• Intratumoral calcium oxalate crystals are a highly characteristic clue — their absence does not exclude the diagnosis.
• Enlarged nuclei with prominent nucleoli are common and do not by themselves suggest another high-grade subtype.
• Multifocal and bilateral tumours occur, sometimes alongside other subtypes; conventional RCCs can also arise in end-stage kidneys.

Diagnostic pearl: ACKD + eosinophilic cells + sieve-like architecture + intratumoral oxalate crystals is strongly suggestive of ACD-RCC.

Architecture

• Cribriform, microcystic or sieve-like sheets of closely apposed cells with numerous round “holes”.
• Papillary, tubular and cystic structures frequently coexist; often circumscribed, but infiltration occurs.

Cells

• Large polygonal cells with abundant granular eosinophilic cytoplasm and indistinct borders.
• Round to oval, often enlarged nuclei with conspicuous eosinophilic nucleoli; focal clearing possible.

Lumina

• The sieve-like look comes from intra- and intercellular vacuoles and microlumina, empty or with eosinophilic material.

Associated findings

• Oxalate crystals, haemorrhage, cystic degeneration, fibrosis.
• Background kidney: acquired cysts, tubular atrophy, interstitial fibrosis.

Diagnostic pearl: the “holes” are not simply dilated glands — they reflect packed cells forming cytoplasmic and intercellular microlumina.

• Cribriform / sieve-like — the most distinctive pattern; may involve only part of the tumour.
• Papillary — eosinophilic cells with prominent nucleoli on fibrovascular cores; may mimic old “type 2” PRCC.
• Tubulocystic — dilated tubules and cysts; can mimic tubulocystic RCC.
• Compact tubular — tightly packed tubules appear almost solid.
• Solid — sheets or nests that obscure the cribriform pattern; exclude other eosinophilic tumours.
• Mixed — the rule: in a 2024 series of 31 tumours, 23 combined sieve-like and papillary growth; 9 tubulocystic, 4 compact tubular, 1 solid.

Diagnostic pearl: pure sieve-like morphology is not required — even focal cribriform areas are valuable.

• Classic eosinophilic cells — large, granular, indistinct borders, prominent nucleoli.
• Vacuolated cytoplasm — coalescing vacuoles build the sieve-like look; may mimic eosinophilic vacuolated tumour.
• Clear cell change — focal or extensive; may resemble ccRCC.
• High-grade nuclear appearance — enlarged nuclei and nucleoli are frequent in conventional tumours and do not by themselves imply aggressive behaviour.
• Sarcomatoid / rhabdoid — rare, adverse; document when present.

Diagnostic pearl: prominent eosinophilic nucleoli are part of the classic phenotype — they should not automatically trigger a diagnosis of FH-deficient RCC.

Morphology

• Transparent, refractile, angular or sheaf-like crystals in stroma, epithelium or cysts.
• Strongly birefringent under polarised light.

Distribution & reaction

• Focal or extensive; may also be present in the background kidney — intratumoral crystals are more informative.
• Usually little or no foreign-body giant cell reaction; distinguish from dystrophic calcification and psammoma bodies.

Significance

• Strong support in the right morphology and background, but not absolutely specific.
• Absence does not exclude ACD-RCC; a 2024 series found crystals in all 31 tumours, other series report crystal-negative cases.

Diagnostic pearl: when ACD-RCC is suspected, look at the H&E under polarised light.

• ACKD — multiple cysts in chronically damaged kidneys, usually after prolonged renal replacement therapy, with atrophy and fibrosis.
• Atypical cyst epithelium — hyperplasia, stratification, tufting or eosinophilic lining; proposed precursor, but reactive change is not carcinoma.
• Multifocality — multiple, sometimes bilateral ACD-RCCs may arise independently with different alterations.
• Coexisting tumours — papillary adenoma, PRCC, ccRCC and others can share the same end-stage kidney; evaluate each lesion separately.

Diagnostic pearl: the background provides context, but the tumour’s own morphology decides.

Supportive, not defining — morphology and clinical background lead.

• AMACR — usually strong and diffuse · overlaps with PRCC.
• CK7 — usually negative or focal · helps against classic PRCC.
• CD10 — frequently positive · nonspecific.
• PAX8 — usually positive.
• CAIX — usually negative or limited · helps against ccRCC.

Additional markers

• FH / 2SC if FH-deficient RCC is suspected; TFE3/TFEB testing in unusual tumours.
• No extra stain is routinely needed when context and histology are characteristic.

Diagnostic pearl: strong AMACR with absent or focal CK7 supports ACD-RCC, but neither marker separates it from every PRCC.

• Recurrent gains of chromosomes 3, 7, 16 and 17 — chromosome 16 gain recurs across studies; unlike the ccRCC profile.
• No single driver — alterations in chromatin regulation, signalling and genome maintenance; different tumours in one kidney may differ (multiclonal).
• Chromatin regulators — SMARCB1 and SETD2 alterations reported; not required for diagnosis.
• mTOR pathway — MTOR and TSC2 alterations in subsets; not specific.

Diagnostic pearl: unlike TFE3-rearranged or FH-deficient RCC, ACD-RCC has no pathognomonic molecular alteration.

• Papillary RCC — the main differential; foamy macrophages and psammoma bodies, no sieve-like areas or oxalate crystals; CK7 usually diffuse.
• ccRCC — branching capillary network, conventional clear areas, diffuse box-like CAIX.
• Tubulocystic RCC — sponge-like tubules and cysts in fibrous stroma, without oxalate crystals or sieve-like cellular areas.
• FH-deficient RCC — papillary/tubulocystic/cribriform with inclusion-like nucleoli; FH loss / 2SC positive.
• Eosinophilic vacuolated tumour — cohesive solid/nested growth, thick-walled vessels; CD117+, cathepsin K+ (ACD-RCC usually CD117−).
• TFE3-rearranged RCC — psammoma bodies, hyaline nodules; confirm molecularly when atypical.

Diagnostic pearl: ACD-RCC is a clinicopathologic diagnosis — no single feature, marker or history of renal failure suffices.

• 1 · Clinical background — end-stage kidney with ACKD; dialysis history alone is not enough.
• 2 · Sieve-like architecture — packed eosinophilic cells with microlumina; check papillary and tubulocystic areas for cribriform foci.
• 3 · Oxalate crystals — inspect tumour tissue, use polarised light.
• 4 · Focused IHC — AMACR and CK7 vs PRCC; CAIX if ccRCC is a concern; FH/2SC for specific questions.
• 5 · Other lesions — sample distinct nodules separately; look for sarcomatoid or rhabdoid components.

• Broader architecture — 2024 series of 31: only 4 pure sieve-like, 23 sieve-like + papillary; crystals in all.
• SMARCB1 / SETD2 — 3 of 9 sequenced tumours had SMARCB1 alterations, yet INI1 was retained — not SMARCB1-deficient RCC.
• Heterogeneous biology — a 2024 meta-analysis (26 studies, 418 tumours) highlighted chromosomes 3 and 16, with KMT2C and TSC2 mutations; no defining alteration.
• Usually indolent, not harmless — pT3–4 in 8.7%, nodes 3.4%, distant metastasis 5.8%; sarcomatoid/rhabdoid change and high stage are adverse.
• Precursor model — atypical eosinophilic cyst lining and independent multifocal tumours suggest a renal field effect; stepwise progression is unproven.

• Arises in end-stage kidneys with acquired cystic kidney disease.
• Eosinophilic cells with cribriform / sieve-like architecture from intra- and intercellular microlumina.
• Papillary, tubulocystic, compact tubular, solid and clear cell patterns coexist; dominant cribriform growth is not mandatory.
• Intratumoral calcium oxalate crystals are highly characteristic but not required — use polarised light.
• Prominent nucleoli are common in conventional tumours.
• AMACR strong and diffuse; CK7 often negative or focal — overlapping with PRCC and tubulocystic RCC.
• Mimics: eosinophilic PRCC, FH-deficient RCC, tubulocystic RCC.
• Other RCCs may share the same kidney — assess each lesion independently.
• Gains of 3, 7, 16, 17; SMARCB1 alterations with retained INI1; no diagnostic alteration.
• Sarcomatoid or rhabdoid components are adverse.