Epithelioid angiomyolipoma / epithelioid PEComa of the kidney

• Potentially malignant variant of renal AML in the PEComa family.
• Substantial or predominant rounded to polygonal epithelioid cells with abundant eosinophilic or clear cytoplasm.
• Triphasic vessels, smooth muscle and fat may be inconspicuous or absent.
• Carcinoma-like sheets, nests, trabeculae, alveolar structures, occasional pseudoglands.
• Atypia from minimal to striking: pleomorphism, multinucleated giant cells, prominent nucleoli, atypical mitoses, necrosis.
• HMB45 and Melan-A positive; smooth muscle markers variable; cathepsin K and GPNMB useful; PAX8 and keratins negative.
• Mostly TSC1/TSC2 with mTORC1 activation; a subset of renal epithelioid PEComas has TFE3 rearrangements.
• Behaviour ranges from indolent to recurrence, metastasis and death; epithelioid morphology alone does not establish malignancy.

Diagnostic pearl: EAML can look almost identical to RCC. Diagnosis needs PEComa differentiation; prognosis needs a separate assessment of adverse features.

• Classic AML with focal epithelioid change: mostly triphasic or myoid; scattered plump cells; no expansile epithelioid component, atypia, atypical mitoses or necrosis.
• Epithelioid AML: appreciable or predominant epithelioid population forming solid, nested or carcinoma-like regions.
• Pure epithelioid PEComa: almost entirely epithelioid; may lack any classic AML; mimics RCC or melanoma.

• Studies used 5%, 10% or predominant thresholds; contemporary descriptions often use about 80% for pure or predominant epithelioid tumours.
• No reproducible percentage separates benign classic AML from aggressive EAML.

Diagnostic pearl: ask three separate questions: is it epithelioid PEComa, how much is epithelioid, and which adverse features are present?

Clinical

• Adults, often middle-aged; sporadic or TSC-associated; may arise with a known classic AML.
• Flank pain, haematuria, mass or haemorrhage; often read radiologically as RCC because fat is limited.
• Regional or distant metastasis may be present at diagnosis.

Gross

• Solid tan-white, grey-white, tan-brown or haemorrhagic; little or no fat; circumscribed or infiltrative.
• Yellow fatty foci may be a coexisting classic AML; necrosis and haemorrhage can be prominent; sinus, perinephric or renal vein extension in large tumours.

Diagnostic pearl: a solid fat-poor mass with haemorrhage or necrosis can look like high-grade RCC; confirm histologically and immunophenotypically.

Architecture

• Expansile sheets; large solid nests with delicate vessels or fibrous septa; alveolar, organoid, trabecular or cord-like areas; discohesive clusters; perivascular arrangements.

Cells

• Large round to polygonal cells with abundant granular eosinophilic cytoplasm, some clear; distinct borders; central or eccentric nuclei; frequent prominent nucleoli.

Stroma

• Delicate vascular septa, perivascular hyalinisation, sclerosis, occasional myxoid change; haemorrhage and necrosis in aggressive examples.

Transition

• Gradual transition from classic spindle-cell AML into epithelioid regions is a valuable clue; fat and dysmorphic vessels may be confined to one area.

Diagnostic pearl: solid sheets of large polygonal eosinophilic cells with limited fat and no epithelial differentiation should raise EAML even without classic AML.

• Bland epithelioid: uniform nuclei, fine chromatin, small nucleoli, few mitoses; can be indolent.
• Ganglion-like: voluminous eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli; resemble ganglion or rhabdoid cells.
• Pleomorphic: marked enlargement, irregular contours, coarse chromatin, large nucleoli; usually with other adverse findings.
• Multinucleated giant cells: bizarre or osteoclast-like; significance depends on the associated atypia.
• Clear cell: mimics ccRCC or MiT family RCC if melanocytic and muscle markers are not considered.
• Rhabdoid-like: eccentric nuclei, dense cytoplasm; does not mean epithelial differentiation.

Diagnostic pearl: EAML can be bland, oncocytic, clear or markedly pleomorphic; eosinophilic cytoplasm tells you neither lineage nor risk.

• Carcinoma-like solid: cohesive sheets, high-grade nuclei; mimics high-grade RCC.
• Nested / alveolar: nests with vascular septa, central discohesion; mimics ASPS or TFE3 RCC.
• Trabecular / organoid: cords between delicate vessels; may suggest neuroendocrine tumour.
• Hyalinised perivascular: cords or nests around hyalinised vessels; prominent in TFE3-rearranged PEComa, with reduced myoid markers.
• Spindle-to-epithelioid transition: strongly supports continuity with classic AML.
• Pseudoglandular: gland-like spaces from discohesion or degeneration; not true epithelium.

Diagnostic pearl: glandular, nested or alveolar architecture does not prove renal epithelial origin; a PEComa can reproduce these patterns.

• Dysmorphic vessels: thick, irregular, disorganised walls, perivascular myoid proliferation, hyalinisation, aneurysms.
• Mature fat: islands within epithelioid areas, often limited or peripheral.
• Spindle myoid areas: short fascicles merging with plump epithelioid cells; marker expression may differ between components.

Limits

• A classic component is not required for EAML.
• A small classic component does not remove the malignant potential of the epithelioid part.
• Entrapped perirenal fat is not a classic AML component.

Diagnostic pearl: classic AML supports the PEComa diagnosis, but risk assessment must cover the whole tumour, especially atypia, mitoses and necrosis in epithelioid areas.

• HMB45/Melan-A: often stronger and more extensive than in classic AML; granular cytoplasmic; can be heterogeneous.
• Cathepsin K: valuable when myoid markers are weak, but also positive in TFE3/TFEB RCC, ESC RCC and EVT.
• Absent SMA with strong melanocytic markers occurs, especially in TFE3-rearranged PEComa.
• Convincingly negative PAX8 argues against RCC; entrapped native tubules keep PAX8.

Diagnostic pearl: HMB45/Melan-A+, cathepsin K+ and PAX8/keratin− strongly supports EAML in the right setting.

• Negative smooth muscle markers do not exclude EAML, particularly TFE3-rearranged PEComa.
• Cathepsin K is not lineage specific: MiT RCC, EVT and ESC RCC are positive.
• Entrapped PAX8+ tubules: localise PAX8 and keratin to the atypical epithelioid cells.
• Melanocytic markers do not mean melanoma: melanoma is usually S100+/SOX10+; EAML is not; exclude metastatic melanoma clinically.
• TFE3 protein does not prove rearrangement: confirm molecularly.

Diagnostic pearl: in an RCC-like epithelioid tumour, start with PAX8, PanCK, HMB45, Melan-A and cathepsin K, then add markers by result.

• TSC1 (hamartin) and TSC2 (tuberin) inhibit RHEB-dependent mTORC1; inactivation drives growth, anabolic metabolism and survival.
• TSC2 frequently, TSC1 less often altered; biallelic inactivation by mutation, deletion or LOH; sporadic and syndromic tumours.
• Shared pathway with classic AML; some EAMLs probably progress from a classic component; extra genetic and epigenetic events likely drive aggressiveness and are not fully defined.
• A somatic TSC alteration does not establish hereditary TSC; separate tumour from constitutional findings.

Diagnostic pearl: EAML shares the TSC/mTOR foundation of classic AML, but its malignant potential reflects additional biology.

• TFE3 fusions (SFPQ, NONO and rarer partners); some lack the TSC1/TSC2 profile.
• Large clear or eosinophilic epithelioid cells; nested, alveolar or organoid; perivascular arrangements; hyalinised stroma; no triphasic AML.
• HMB45 often strong, cathepsin K frequent, strong nuclear TFE3; SMA/desmin negative or limited; PAX8 and keratins negative.

vs TFE3-rearranged RCC

• Both can be TFE3+, HMB45+ and cathepsin K+ with clear and eosinophilic cells.
• PAX8 positivity and genuine tubular differentiation favour RCC; absence of renal epithelial lineage supports PEComa; no single marker is infallible; some partners occur in both.

Diagnostic pearl: a TFE3 fusion identifies a molecular alteration, not a renal carcinoma; lineage still has to be established.

• Epithelioid proportion: record overall epithelioid percentage and, separately, the percentage of markedly atypical epithelioid cells.
• Marked atypia: enlargement, pleomorphism, hyperchromasia or large vesicular nuclei with nucleoli, atypical multinucleated cells.
• Mitoses: count them and record atypical mitoses separately; historical HPF thresholds depend on field area.
• Coagulative necrosis: key; separate from haemorrhagic degeneration or treatment effect.
• Carcinoma-like pattern: extensive solid expansile growth (a Nese variable).
• Extrarenal or renal vein extension: record it, remembering that classic AML can also grow into veins.

Diagnostic pearl: necrosis, atypical mitoses, marked atypia and extensive epithelioid growth matter more than epithelioid cytology alone.

• 0–2: below the proposed high-risk threshold. 3–4: substantially higher probability of malignant behaviour.
• In the original 40 atypical EAMLs it classified about 78% of malignant and all benign tumours correctly.

Limits

• Selected cohort; a low score does not guarantee benign behaviour; HPF-based mitotic threshold; performance may differ in broader populations.

Diagnostic pearl: a practical histological risk tool, not a binary benign/malignant test.

• 0–1 lower, 2–3 intermediate, 4–5 higher risk.
• Original 41 pure epithelioid PEComas: recurrence 17%, metastasis 49%, disease-related death 33% among evaluable patients; these reflect a selected pure epithelioid cohort.

Limits

• Includes clinical and anatomical variables; TSC/concurrent AML is a model variable, not proof of aggressiveness; referral bias; thresholds not interchangeable with Brimo.

Diagnostic pearl: report Brimo and Nese accurately by name; never combine them into an unofficial score.

• State the actual adverse features; name the model; do not mix criteria; low-risk tumours can still recur; sample completely and follow up.

Pecoraro et al., Urologic Oncology 2026: 76 patients, 15 centres, median follow-up 30 months; 5 metastases (6.7%), 4 deaths. Adverse features were associated with outcome for both models; high risk was about 4% by Nese and 14% by Brimo; too few events for multivariable analysis.

Diagnostic pearl: the models support adverse-feature reporting, but their very different high-risk rates show they are not equivalent.

• ccRCC: nested clear cells overlap; diffuse box-like CAIX and epithelial markers favour ccRCC.
• Eosinophilic ChRCC: halos, irregular nuclei, CD117/CK7.
• ESC RCC: eosinophilic, solid, TSC-altered; stippling, CK20 and PAX8 favour it; cathepsin K/GPNMB overlap.
• TFEB-altered RCC: can be HMB45, Melan-A and cathepsin K positive; PAX8 and epithelial differentiation favour RCC; TFEB testing may be needed.

Diagnostic pearl: cathepsin K, GPNMB or TSC alterations do not separate EAML from RCC; lineage does.

• TFE3-rearranged RCC: solid, alveolar, papillary or clear; often PAX8+; keratins may be weak; cathepsin K and melanocytic markers can overlap.
• TFE3-rearranged PEComa: strongly melanocytic and cathepsin K+, may lack myoid markers, usually PAX8−.
• Alveolar soft part sarcoma: alveolar nests with central discohesion, large eosinophilic cells, PAS-D+ crystals, ASPSCR1::TFE3, cathepsin K+, PAX8 and keratin negative.
• Some TFE3-associated renal tumours sit on the boundary between PEComa, RCC and ASPS.

Diagnostic pearl: a TFE3-rearranged renal tumour without epithelial differentiation is not RCC just because it is in the kidney.

• Shared: epithelioid cells, atypia, prominent nucleoli, HMB45 and Melan-A, aggressive potential.
• Melanoma: strong S100 and SOX10, history of melanoma, pigment or a primary site, melanoma molecular context.
• EAML: perivascular PEComa architecture, any classic AML component, myoid markers, usually S100/SOX10 negative, TSC alterations.

Diagnostic pearl: melanocytic markers alone do not make a renal epithelioid tumour melanoma; EAML is the key mimic when S100 and SOX10 are negative.

• Epithelioid leiomyosarcoma: smooth muscle markers, no melanocytic PEComa phenotype; atypia and necrosis overlap.
• Epithelioid sarcoma: keratin and EMA positive, frequent INI1 loss; EAML retains INI1 and is melanocytic.
• Inflammatory myofibroblastic tumour: spindle to epithelioid cells with inflammation, ALK in a subset, no melanocytic profile.
• Angiosarcoma: haemorrhagic, pleomorphic; CD31 and ERG; check for malignant endothelial lining.

Diagnostic pearl: a PAX8- and keratin-negative renal epithelioid malignancy needs a directed mesenchymal work-up, not automatic RCC, NOS.

1. Recognise expansile sheets or nests of polygonal eosinophilic or clear cells, with or without atypia, necrosis or fat.
2. Search for classic AML: dysmorphic vessels, spindle myoid areas, fat, transitions.
3. Prove PEComa: HMB45 and Melan-A, plus cathepsin K or GPNMB; SMA/desmin if helpful.
4. Exclude RCC: PAX8 and PanCK in the actual tumour cells; consider MiT RCC when melanocytic markers overlap.
5. TFE3: test strong TFE3+ tumours lacking triphasic AML or myoid markers.
6. Adverse histology: epithelioid and atypical epithelioid %, mitoses, atypical mitoses, necrosis, size, extension.
7. Risk models: name Brimo or Nese and their thresholds; neither guarantees behaviour.

• Biopsy may show only epithelioid cells; a solid eosinophilic tumour may be called RCC; strong cathepsin K may suggest MiT RCC or ESC RCC.
• Limited myoid markers do not exclude EAML; entrapped PAX8+ tubules mislead.
• Necrosis, mitotic hotspots and pleomorphism may be missed; the epithelioid proportion cannot be estimated; resection-based risk models apply poorly to biopsies.

Suggested wording

• Biopsy: “Epithelioid angiomyolipoma (epithelioid PEComa) of the kidney. Epithelioid cells with melanocytic differentiation and no convincing renal epithelial differentiation. Malignant potential needs evaluation of the entire tumour for atypia, mitoses, necrosis and extension.”
• Resection with adverse features: “Epithelioid angiomyolipoma with adverse histopathological features: [specify]. These have been associated with increased risk of recurrence or metastasis in published risk stratification studies.”

Diagnostic pearl: do not call EAML malignant on epithelioid morphology alone; without metastasis, describe adverse features and model-based risk.

• Much more variable than classic AML: many localised tumours stay disease-free; others recur or metastasise (liver, lung, lymph nodes, bone), sometimes years later.
• Published aggressiveness varies with epithelioid thresholds, pure vs mixed tumours, referral bias, size, stage and follow-up.

These are not comparable risk estimates: inclusion criteria, populations and follow-up differ.

• Several adverse features are more concerning than any single one; no model predicts individual outcome perfectly; risk is a continuum; staging and surveillance matter.

• mTOR inhibitors: everolimus, sirolimus and related agents are active in selected PEComas and TSC-associated AMLs; evidence for advanced renal EAML is limited; a TSC alteration gives a rationale, not a guarantee.
• Nab-sirolimus: prospective evidence in advanced malignant PEComa; trial populations were not limited to renal EAML.
• Investigational: VEGF pathway inhibitors, immune checkpoint inhibitors, combinations, strategies against mTOR resistance.

Diagnostic pearl: the right PEComa diagnosis can change treatment, but the evidence base is much thinner than for common RCCs.

• 76-patient international cohort (Pecoraro, Urol Oncol 2026): median age 48, about 70% female, TSC in 19, median size 4.5 cm, 5 metastases, 4 deaths; more adverse features meant worse metastasis-free and cancer-specific survival.
• Beyond TSC2: a 2025 whole-exome study of 35 renal AMLs (15 EAML) found TSC2 most often altered, with candidate POLDIP2, NEFH and MUC2 alterations needing validation.
• Cathepsin K and GPNMB highlighted in a 2026 Histopathology review (Trpkov, Siadat, Saleeb): useful when myoid markers are weak, but overlap with renal epithelial tumours.
• TFE3-rearranged renal PEComas: the fusion does not decide epithelial versus mesenchymal lineage.

• EAML is a potentially malignant epithelioid PEComa, not an RCC variant; fat and dysmorphic vessels may be absent; carcinoma-like growth is common.
• Cells may be eosinophilic, clear, vacuolated, rhabdoid-like or pleomorphic; a classic AML component helps but is not required.
• HMB45 and Melan-A are key; SMA/desmin may be absent; cathepsin K and GPNMB help but overlap with RCCs.
• PAX8 and keratins negative in tumour cells; entrapped tubules stain.
• TSC1/TSC2-mTORC1 is the main pathway; TFE3-rearranged PEComas are a separate subset.
• Epithelioid morphology alone is not malignancy. Brimo: atypical epithelioid ≥70%, mitoses, atypical mitoses, necrosis. Nese: TSC/concurrent AML, >7 cm, carcinoma-like growth, extension, necrosis.
• Recurrence and metastasis can occur years later.
• Sequence: epithelioid morphology → PEComa lineage → exclude RCC and melanoma → document adverse features.