Classic angiomyolipoma / PEComa of the kidney

• Benign mesenchymal neoplasm of the PEComa family.
• Variable proportions of dysmorphic vessels, smooth muscle-like cells and mature fat (triphasic); not every component is visible in every tumour or section.
• Myoid cells often radiate around or wrap vessels; vessels are thick-walled, irregular, with deficient elastic tissue.
• Tumour cells coexpress melanocytic and smooth muscle markers: HMB45, Melan-A, SMA, desmin.
• Usually PAX8 and keratin negative.
• Most carry TSC1/TSC2 alterations with mTORC1 activation.
• May show locally infiltrative growth, renal vein or lymph node involvement without being malignant.
• Main complication: haemorrhage. Separate it from epithelioid AML, which has a potentially aggressive spectrum.

Diagnostic pearl: dysmorphic vessels + myoid cells + mature fat, supported by a dual melanocytic and smooth muscle phenotype.

Clinical

• Adults, particularly middle-aged women; mostly sporadic and solitary.
• TSC-associated tumours: younger, bilateral, multifocal; may coexist with pulmonary LAM.
• Often incidental; larger tumours cause pain, haematuria, a mass or haemorrhage.

Gross

• Circumscribed, unencapsulated; yellow when fat-rich (lipoma-like), tan-white and solid when smooth muscle-rich, red-brown when vessel-rich.
• Large tumours: haemorrhage and degeneration; may protrude beyond the capsule or into the sinus.

Imaging

• Macroscopic fat is characteristic; fat-poor tumours lack it and mimic RCC.
• Hyperattenuation on unenhanced CT and low T2 signal suggest a dominant smooth muscle component.

Diagnostic pearl: a solid tan-white renal mass does not exclude AML.

• Angio: thick-walled, tortuous, variably hyalinised vessels with abnormal walls and poor elastic tissue.
• Myo: bland spindle or plump myoid cells in fascicles, short bundles and perivascular arrangements.
• Lipo: mature adipocytes, from scattered cells to broad lipomatous areas.

Interpretation

• Components are unevenly distributed; small tumours or biopsies may show only one or two.
• Vascular and myoid components often merge; fat may be sparse or absent in fat-poor AML, so a limited sample can look monophasic.

Diagnostic pearl: absence of one component on biopsy does not exclude AML; recognise the myoid and vascular morphology.

• Variably sized thick-walled channels with irregular, branching contours and disorganised myoid walls.
• Abrupt changes between thick and thin wall segments; hyalinisation; occasional aneurysms.
• Concentric muscle organisation is disrupted; myoid cells spill from the wall into the tumour; elastic lamina deficient or fragmented.
• Tumour cells radiate from or wrap around vessels: perivascular differentiation.
• Elastic stains rarely needed; useful when the lesion resembles a vascular or smooth muscle neoplasm.
• Fragile vessels bleed: haemosiderin, fibrosis, histiocytes; aneurysms relate to bleeding risk.

Diagnostic pearl: these are not normal thick arteries: irregular vessels blending into a perivascular myoid proliferation are characteristic.

• Bland spindle cells with fibrillary or finely granular eosinophilic cytoplasm, tapered or blunt nuclei, fine chromatin, low mitotic activity.
• Short fascicles, leiomyoma-like bundles, circumferential or radiating perivascular arrangements, haphazard areas mixed with fat.
• Plump myoid cells: polygonal, more cytoplasm, mild size variation; not automatically an epithelioid malignant component.
• Stroma: collagen, oedema, perivascular hyalinisation, occasional myxoid change.

Caveat

• Smooth muscle-predominant AML can mimic renal leiomyoma; SMA/desmin cannot separate them; HMB45 or Melan-A proves PEComa differentiation.

Diagnostic pearl: in a renal smooth muscle tumour, look for abnormal vessels, rare adipocytes and melanocytic markers before calling leiomyoma.

• Mature univacuolated adipocytes with peripheral bland nuclei; no significant atypia.
• Diffusely admixed, islands surrounded by myoid cells, predominant, or only a few peripheral cells.
• Fat-predominant AML can resemble lipoma: find the vessels and HMB45/Melan-A+ perivascular cells; sample more if needed.
• AML can extend into perirenal fat, and ccRCC can entrap or invade fat: fat next to a renal mass is not necessarily tumour.

Diagnostic pearl: do not call a fatty renal tumour AML on adipocytes alone; demonstrate the vascular and PEComa-type myoid component.

• Mostly bland myoid spindle cells; fat sparse or absent; vessels may be limited; solid, cellular, fascicular.
• Occasional plump or polygonal cells without meeting criteria for epithelioid AML.
• Uniform nuclei, fine chromatin, eosinophilic cytoplasm, few mitoses, no necrosis.
• Papilla-like (pseudopapillary) structures: myoid fascicles separated by blood-filled clefts can mimic papillae; there is no epithelial lining and the cells are PAX8/keratin negative.
• Mimics renal leiomyoma and, on imaging and small biopsies, papillary RCC.
• SMA positive; HMB45 or Melan-A supports PEComa (HMB45 may be absent when another melanocytic marker is positive); PAX8 and keratins negative; cathepsin K often positive.
• A small minority of renal AMLs; can be hyperattenuating on CT and T2-hypointense; imaging may not separate it from RCC.

Pseudopapillary and micropapillary-like changes were described in a 60-case series of classic renal AML (Virchows Arch 2025).

Diagnostic pearl: in a bland renal myoid tumour with odd thick-walled vessels or papilla-like clefts, melanocytic IHC beats repeating smooth muscle markers.

• Myxoid change: can obscure the triphasic pattern; extensive myxoid areas → consider the wider PEComa spectrum.
• Hyalinisation: vascular or stromal sclerosis, almost scar-like.
• Inflammation: lymphocytes, plasma cells, histiocytes; giant cells in fat necrosis.
• Haemorrhage and degeneration: haemosiderin, fat necrosis, fibrosis; post-embolisation necrosis and treatment change.
• Cystic change: degenerative cysts occur; true epithelial-lined cysts → AML with epithelial cysts (AMLEC).
• Pseudopapillary / micropapillary-like change: clefted myoid fascicles mimicking papillary architecture.

Diagnostic pearl: sclerosis, myxoid change or treatment effect can make a conventional AML look atypical; assess the component architecture before suspecting malignancy.

• HMB45: granular cytoplasmic, uneven, often perivascular; a negative result does not exclude AML when Melan-A is convincingly positive.
• Desmin negativity does not exclude AML; the melanocytic-myoid combination is more specific than either alone.
• Entrapped native tubules are PAX8 positive: assign staining to the right cells.

Diagnostic pearl: HMB45/Melan-A and SMA in tumour cells strongly support AML; PAX8/keratin in entrapped tubules is not neoplastic epithelium.

• Uneven melanocytic staining: limited HMB45 in smooth muscle-predominant AML; add Melan-A.
• Smooth muscle markers are not specific: leiomyoma, leiomyosarcoma and others express SMA and desmin.
• Cathepsin K is not diagnostic: also in other PEComas, EVT, ESC RCC and MiT RCC.
• CD117 is not decisive: variable in AML; mast cells stain.
• Epithelial markers may reflect entrapment: scattered PAX8+ structures are native tubules.
• Epithelioid morphology needs separate assessment: plump bland cells are fine; a substantial atypical polygonal population means epithelioid AML work-up.

Diagnostic pearl: ask which cells stain, not just whether the slide has positive cells.

• TSC1 (hamartin) and TSC2 (tuberin) with TBC1D7 restrain RHEB-dependent mTORC1; loss of the complex activates mTORC1.
• Sporadic and syndromic AMLs mostly show TSC2, sometimes TSC1, inactivation: an inherited variant plus a somatic hit, or two somatic events.
• A somatic TSC alteration in the tumour does not establish tuberous sclerosis; mosaicism complicates detection.
• TFE3-rearranged PEComas are a distinct subset, often epithelioid and strongly melanocytic, not equivalent to TSC-driven classic AML.

Diagnostic pearl: the TSC-RHEB-mTORC1 pathway gives the rationale for mTOR inhibition in selected cases.

• Bilateral, multifocal, younger patients; renal cysts and TSC-associated renal epithelial tumours may coexist; pulmonary LAM possible.
• Morphology similar to sporadic AML; small multifocal lesions may show limited triphasic differentiation.
• Multiple AMLs are not malignant dissemination.
• Not every renal mass in TSC is AML: an unusual, rapidly growing or nonresponsive lesion may be RCC.

Diagnostic pearl: bilateral multifocal AML raises TSC; a single sporadic AML does not mandate hereditary testing without other indications.

• Sinus and perinephric extension: not equivalent to metastatic potential.
• Renal vein / IVC: benign classic AML can form intravascular tumour with triphasic histology, mimicking RCC with thrombus.
• Regional lymph nodes: occasional involvement, attributed to multicentricity or benign spread, with long progression-free follow-up.
• Caveat: applies only to convincing classic AML, not to tumours with a substantial atypical epithelioid component, necrosis or brisk mitoses.

Diagnostic pearl: vein or node involvement does not make classic AML malignant; morphology and any aggressive epithelioid component decide.

Diagnostic pearl: if only bland spindle cells are sampled, abnormal vessels or melanocytic markers make the diagnosis.

Favours AML

• Arises from or is continuous with the kidney; abnormal thick-walled vessels; myoid cells within fat; melanocytic markers; no atypical hyperchromatic stromal cells.

Favours well-differentiated liposarcoma

• Retroperitoneal epicentre displacing the kidney; variable-sized adipocytes; atypical stromal cells in septa; MDM2 amplification.

Dedifferentiated liposarcoma

• Nonlipogenic spindle or pleomorphic areas can overlap with smooth muscle-rich AML; test MDM2 when site and morphology suggest it.

Diagnostic pearl: a fatty mass near the kidney is not automatically AML, especially with atypical stromal cells or an extrarenal epicentre.

• Assess the epithelioid percentage, atypia, atypical mitoses, necrosis, vascular invasion, size and stage.
• Both often HMB45 and Melan-A positive; smooth muscle markers variable in epithelioid tumours; both lack renal epithelial differentiation.

Diagnostic pearl: focal plump cells do not upgrade classic AML; a predominant atypical epithelioid component must not be dismissed because some triphasic areas exist.

• Epithelial-lined cysts with cellular subepithelial stromal condensation, smooth muscle-rich or PEComa-like stroma, thick-walled vessels, little or no fat.
• Mesenchymal cells melanocytic marker positive and myoid; cyst lining PAX8 and keratin positive; stromal ER/PR may be positive.
• Differential: MEST, adult cystic nephroma, MCRNLMP, other cystic RCCs.

Diagnostic pearl: epithelial lining does not establish MEST; melanocytic markers in the stroma identify AMLEC.

• RCC with entrapped or invaded fat: peripheral fat is not neoplastic; PAX8, keratins and RCC markers show epithelial lineage.
• RCC with myoid stroma: ccRCC, ELOC-mutated RCC and TSC/mTOR RCC with fibromyomatous stroma; the stroma lacks the dual melanocytic-myoid phenotype.
• Sarcomatoid RCC: spindle cells, may be keratin-poor or focally PAX8+; sampling reveals carcinoma; HMB45 and Melan-A negative.
• Papillary RCC: true fibrovascular cores lined by PAX8+/keratin+ epithelium, unlike the clefted myoid pseudopapillae of fat-poor AML.

Diagnostic pearl: localise PAX8 and keratin to the suspected tumour cells, or entrapped tubules will mislead you.

1. Dominant morphology: fat, abnormal vessels, myoid cells; triphasic, fat-predominant or myoid-predominant?
2. Vessels: irregular tortuous vessels with abnormal walls blending into myoid cells.
3. Focused IHC: HMB45 or Melan-A plus SMA; add desmin, h-caldesmon or cathepsin K selectively.
4. Lineage in atypical cases: PAX8 and keratins exclude carcinoma; separate entrapped tubules from tumour cells.
5. Epithelioid transformation: substantial atypical epithelioid component, necrosis, mitoses, pleomorphism, destructive growth.
6. Molecular: TSC1/TSC2 in unusual tumours; MDM2 for a liposarcoma differential.
7. Report: classic vs epithelioid; haemorrhage, necrosis, vascular extension.

• Cores may contain only smooth muscle or only fat; vessels may be unsampled; a focal epithelioid component may be missed.
• Fat-poor AML can look like a smooth muscle neoplasm; HMB45 may be limited (add Melan-A); entrapped PAX8+ tubules are not carcinoma.
• Imaging and the distribution of fat help.

Suggested wording

• Classic: “Angiomyolipoma, classic type. Mature fat, thick-walled dysmorphic vessels and bland smooth muscle-like cells; no significant atypia, mitoses or necrosis.”
• Fat-poor: “Angiomyolipoma, smooth muscle-predominant (fat-poor) type. Bland myoid cells with melanocytic and smooth muscle differentiation.”
• Limited biopsy: “Bland myoid renal neoplasm, favour angiomyolipoma. Triphasic architecture incompletely represented; melanocytic IHC and clinicoradiologic correlation may help.”

• Benign; does not ordinarily metastasise; often stable or slow-growing; most small asymptomatic lesions are observed.
• Haemorrhage is the main risk: size, intralesional aneurysms (about 5 mm or more is an important imaging risk feature) and vascular complexity matter; bleeding can be severe in a benign tumour.
• The historical 4 cm threshold is not a standalone indication; symptoms, growth, aneurysms and patient factors guide treatment.
• Options: observation, selective arterial embolisation, mTORC1 inhibitors (everolimus) in selected TSC-associated AML, surgery when indicated or when malignancy cannot be excluded.
• In TSC, cumulative tumour burden and renal function preservation are central.

Diagnostic pearl: the major clinical risk of classic AML is haemorrhage, not carcinoma-like spread.

• Fat-poor AML still causes unnecessary surgery: it lacks detectable fat, mimics papillary RCC, and histology prevents overtreatment.
• mTORC1 inhibition: the 2024 ERKNet/ERA consensus recommends considering it for TSC-associated AMLs needing nonurgent intervention, especially growing lesions above 3 cm or with substantial bleeding risk.
• Vascular extension into the renal vein or IVC can occur with entirely bland triphasic morphology; do not diagnose malignancy on that alone.
• Classic vs epithelioid AML: atypia, necrosis, atypical mitoses and a substantial epithelioid component matter; lineage and TSC alterations are shared.
• Cell-specific IHC: HMB45 may be negative; another melanocytic marker can reveal the phenotype; PAX8+ native tubules can be entrapped.

• Benign PEComa with variable vascular, smooth muscle and fat components, not all present in every field.
• Dysmorphic thick-walled vessels with deficient elastica; myoid cells radiate from or wrap vessels.
• Fat-predominant AML mimics lipoma; smooth muscle-predominant AML mimics leiomyoma; clefted myoid fascicles can mimic papillae.
• HMB45/Melan-A plus SMA supports PEComa; desmin not required; HMB45 can be negative when Melan-A is positive.
• PAX8 and keratins negative in tumour cells; entrapped tubules are positive. Cathepsin K helps but is not specific.
• TSC1/TSC2 loss and mTORC1 activation; sporadic AML does not imply TSC, but multifocal bilateral lesions should raise it.
• Sinus, vein or node involvement does not make classic AML malignant; a substantial atypical epithelioid component needs separate assessment.
• Haemorrhage is the main complication.