Eosinophilic solid and cystic renal cell carcinoma

• Distinct renal carcinoma recognised in WHO 2022.
• Abundant eosinophilic cytoplasm with coarse basophilic/amphophilic stippling, typically in solid and cystic architecture.
• Solid areas: compact nests, sheets or acini; cysts often lined by hobnail cells.
• Some tumours are almost entirely solid; focal papillary, tubular or other patterns occur.
• Characteristic profile: CK20+, CK7−, CD117−, frequent cathepsin K and GPNMB.
• Most harbour inactivating TSC1 or TSC2 alterations with mTORC1 activation.
• Mostly sporadic; a minority arise in tuberous sclerosis complex.
• Usually indolent, but nodal and distant metastases are documented.

Diagnostic pearl: solid/cystic architecture + eosinophilic cells with coarse stippling + CK20 positivity is highly characteristic.

Clinical

• Broad age range, including young adults.
• Marked female predominance in early series; recent cohorts include many men.
• Mostly sporadic; can occur with germline TSC and other TSC-associated renal tumours.
• Often incidental; sometimes haematuria, flank pain or a mass.

Gross

• Well demarcated, often nonencapsulated; tan to yellow-grey.
• Classic: intermixed solid tissue and cysts with serous or haemorrhagic fluid.
• Many appear completely solid, with cysts only microscopic.
• Necrosis, extensive haemorrhage or invasive growth need careful evaluation.

Diagnostic pearl: female sex and a solid-cystic gross appearance are useful clues, but neither is required.

Solid component

• Large polygonal cells in sheets, compact nests or packed acini with voluminous eosinophilic cytoplasm.
• May look oncocytoma-like or chromophobe-like at low power; scant stroma.

Cystic component

• Micro- and macrocysts lined by a single layer of eosinophilic cells, often hobnail.
• Contents: eosinophilic material, haemorrhage or macrophages.

Cytology

• Round to oval nuclei, often with visible nucleoli; limited pleomorphism.
• Scattered bi- or multinucleated cells.
• Coarse basophilic or amphophilic cytoplasmic inclusions (stippling).

Background

• Foamy macrophages and lymphocytes between nests; focal haemorrhage, oedema, occasional psammoma bodies or papillae.

Diagnostic pearl: the cytoplasmic stippling is often more informative than the proportion of solid versus cystic areas.

• Solid / nested: often predominant; mimics oncocytoma, eosinophilic ChRCC or EVT; cysts may be focal or microscopic.
• Compact acinar / tubular: packed acini and short tubules with small lumina; may resemble compact tubular PRCC.
• Microcystic: small spaces among nests, sieve-like, hobnail-lined.
• Macrocystic: large cysts separated by solid nodules or septa.
• Papillary / pseudopapillary: focal, cores may hold foamy macrophages; can resemble former “type 2” PRCC. Extensive papillae warrant excluding PRCC, FH-deficient and TFEB-altered RCC, but papillae alone do not exclude ESC RCC.
• Clear cell: focal clear or vacuolated cells; extensive clear cell morphology needs other RCCs excluded.

Diagnostic pearl: in papillary-rich cases the cytoplasmic phenotype and IHC are especially valuable.

Appearance

• Irregular coarse basophilic or amphophilic granules, dots or clumps in abundant eosinophilic cytoplasm.
• Diffuse or focal; produces a dirty, flocculent, heterogeneous oncocytic look.
• Also described as basophilic inclusions or Leishmania-like bodies.

Ultrastructure

• Aggregates of rough endoplasmic reticulum and granular material; not organisms or mucin.

Variation

• Usually seen at medium power; may be focal or subtle.
• Some cells have homogeneous granular cytoplasm; condensed eosinophilic material can form inclusion-like structures.

Diagnostic pearl: distinguish stippling from the large empty vacuoles of EVT and the flocculent inclusions of SDH-deficient RCC.

• Hobnail cells line cysts and tubules; supportive, not specific.
• Multinucleated tumour cells: not sarcomatoid change and not necessarily aggressive.
• Xanthomatous giant cells: large foamy multinucleated tumour cells blending with classic areas; separate from non-neoplastic histiocytes.
• Clear or vacuolated cells: overlap with EVT, ccRCC or TFEB-altered RCC.
• Nuclei: nucleoli may suggest WHO/ISUP grade 2 to 3; marked pleomorphism, brisk mitoses or extensive necrosis point to aggressive disease or another tumour.
• Stroma: foamy histiocyte clusters, lymphocytes, fibrosis or myxoid change.

Diagnostic pearl: multinucleated and xanthomatous giant cells belong to the expanding ESC RCC spectrum; their prognostic meaning is uncertain.

• PAX8: usually positive.
• CK20: positive in most, focal, patchy or diffuse; the most useful conventional marker. About 10–15% are CK20-negative, so a negative result does not exclude the diagnosis.
• CK7: usually negative or very limited; diffuse CK7 should prompt reconsideration.
• CD117: typically negative; helps against EVT, oncocytoma and ChRCC.
• Cathepsin K: frequently positive, variable; also in EVT, TFEB-altered RCC, epithelioid AML.
• GPNMB: usually strong; supportive, not specific.
• AMACR, CD10: often positive, nonspecific. Vimentin: usually positive.
• Melanocytic markers: HMB45 usually negative; rare focal Melan-A.

Diagnostic pearl: first-line panel: CK20, CK7 and CD117, then cathepsin K or GPNMB if needed.

TSC1 / TSC2

• Inactivating TSC1 or TSC2 alterations (hamartin, tuberin) lead to RHEB-driven mTORC1 activation.
• Biallelic inactivation by mutation plus loss of the other allele.

Wang et al., Human Pathology 2026 (80 molecularly characterised tumours)

• TSC2 50/80, TSC1 31/80, both 1/80.
• 110 distinct mutation sites, about 91% truncating (frameshift, nonsense, splice); hotspots uncommon.
• A selected cohort, not frequencies in unselected tumours.

Downstream and germline

• p-S6 and p-4EBP1 upregulation; GPNMB expression. Not specific.
• Most tumours are sporadic; a somatic TSC alteration does not establish hereditary tuberous sclerosis.

Diagnostic pearl: TSC1/TSC2 alterations are characteristic but shared with other mTOR-driven renal tumours; test whole genes, not hotspots.

• Cytoplasm: coarse basophilic stippling (ESC) vs large round empty vacuoles (EVT).
• Architecture: solid and cystic, hobnail cyst lining, sometimes papillary (ESC) vs predominantly solid, nested, compact acinar without extensive macrocysts (EVT).
• CK20: usually positive (ESC) vs negative or very focal (EVT).
• CD117: typically negative (ESC) vs usually positive (EVT).
• CK7: negative or focal in both. Cathepsin K, GPNMB: positive in both.
• Molecular: TSC1/TSC2 (ESC) vs TSC1/TSC2/MTOR (EVT); a shared pathway alteration does not settle the distinction.

Diagnostic pearl: stippling versus vacuoles, supported by opposite CK20/CD117 profiles.

Shared

• Eosinophilic cytoplasm; solid, nested, tubular or cystic growth; cathepsin K; occasional CK20.

Favours ESC RCC

• Tightly packed tubules, coarse stippling, hobnail cyst lining, numerous macrophages, TSC1/TSC2 alteration.

Favours TFEB-amplified RCC

• Loose tubular and pseudopapillary growth, dense granular cytoplasm without stippling, focal apical nuclei, extracellular magenta globules, TFEB amplification.

Molecular

• TFEB rearrangement and TFEB amplification are different events; TFEB-amplified RCC can be aggressive; overlap may require direct molecular testing.

Diagnostic pearl: cathepsin K and CK20 do not reliably separate ESC RCC from TFEB-altered RCC; confirm molecularly when features overlap.

Epithelioid angiomyolipoma

• Sheets of large eosinophilic cells with nucleoli; TSC-associated; cathepsin K positive.
• Melanocytic markers (HMB45, Melan-A) positive; PAX8 and keratins negative; beware entrapped tubules.
• Pitfall: TSC2 mutation or cathepsin K cannot separate ESC RCC from EAML.

Eosinophilic ChRCC

• Distinct borders, perinuclear halos, raisinoid nuclei; diffuse CK7 and CD117.

Oncocytoma

• Bland round nuclei, nests in oedematous stroma; CD117 diffuse; CK20 and cathepsin K not typical.

Papillary RCC

• CK7 and AMACR; stippling, hobnail cysts, CK20 and CD117 negativity favour ESC RCC.

SDH-deficient RCC

• Flocculent inclusions; SDHB loss (retained in ESC RCC); hereditary implications.

LOT

• Small uniform cells, oedematous transitions, diffuse CK7, CD117 negative; no stippling or extensive cysts.

Diagnostic pearl: a CK20+/CD117− eosinophilic tumour with coarse stippling strongly suggests ESC RCC, but TFEB-altered RCC and rare mimics must still be considered.

1. Architecture: solid nests, compact acini, variably sized cysts; cysts may be sparse, papillae may occur.
2. Cytoplasm: coarse stippling in abundant eosinophilic cytoplasm; not EVT vacuoles or SDH inclusions.
3. Supportive features: hobnail cysts, foamy macrophages, multinucleated cells.
4. IHC: CK20+/CK7−/CD117− supports ESC RCC; cathepsin K/GPNMB add support. CD117+/CK20− suggests EVT, oncocytoma or ChRCC; melanocytic markers without renal epithelial markers suggest EAML.
5. Molecular: TSC1/TSC2 supports; test TFEB rearrangement/amplification in atypical or aggressive cases.

On biopsy

• Often recognisable with stippling and CK20+/CK7−.
• Cores may be purely solid or papillary-rich; CK20 may be focal and missed; 10–15% are CK20-negative.
• Cathepsin K overlaps with TFEB-altered RCC and EAML; high-grade or necrotic areas may be unsampled.
• Suggested wording: oncocytic/eosinophilic renal neoplasm with features suggestive of eosinophilic solid and cystic RCC.

Diagnostic pearl: purely solid morphology does not exclude ESC RCC; the cytoplasm may be decisive.

• Most tumours do well after resection.
• Nodal and distant metastases, recurrence and tumour death are reported.
• A 2026 review estimated metastases in about 5–10% of published cases, often larger tumours; heterogeneous cohorts, not a validated rate.
• No histologic or molecular feature reliably predicts metastasis; routine RCC staging applies.

Diagnostic pearl: ESC RCC is generally indolent but genuinely malignant; it is not equivalent to oncocytoma or a tumour of uncertain malignant potential.

• Grossly solid tumours: in a 2024 series of 18, only one looked classically solid-cystic; all had microscopic cysts and consistent stippling.
• Condensed eosinophilic inclusions: 5/17 tumours in a 2026 study, all TSC1-mutated; a possible genotype-morphology link needing validation. Do not infer TSC1 status without testing.
• Xanthomatous giant cells: TSC2-altered xanthomatous giant cell tumours overlap strongly with ESC RCC (4/17 in the 2026 series); search for classic areas rather than classifying separately.
• ESC vs TFEB-amplified RCC (Zullow, Histopathology 2026; 9 vs 6): packed tubules, stippling, hobnail cysts and macrophages favour ESC; loose tubules, pseudopapillae, dense cytoplasm and magenta globules favour TFEB-amplified. TSC1/2 vs TFEB amplification is decisive, and the distinction matters because TFEB-amplified RCC can be aggressive.
• Broad mutation spectrum: 110 distinct, mostly truncating TSC1/TSC2 sites across 80 tumours; use assays covering whole genes and alteration types.

• WHO 2022 entity: eosinophilic cytoplasm with coarse stippling, usually solid-cystic.
• Female predominance is classic but not universal; sporadic cases far outnumber TSC-associated ones.
• Grossly solid tumours may have only microscopic cysts.
• Cysts lined by hobnail eosinophilic cells; focal papillae may occur.
• Foamy macrophages, multinucleated, clear and xanthomatous giant cells can be present.
• CK20 usually positive (10–15% negative); CK7 and CD117 negative.
• Cathepsin K and GPNMB frequent but nonspecific; they do not exclude TFEB-altered RCC or EAML.
• CK20+/CD117− favours ESC RCC over EVT.
• TSC1/TSC2 alterations drive mTORC1; a somatic alteration does not mean hereditary TSC.
• TFEB-amplified RCC overlaps and may need molecular exclusion.
• Mostly indolent, but metastases occur.