SMARCB1-deficient renal medullary carcinoma

• Rare, highly aggressive renal carcinoma with loss of SMARCB1/INI1, typically in patients with sickle hemoglobinopathy (mostly sickle cell trait); WHO 2022 molecular entity.
• Centred on the medulla; infiltrative and heterogeneous: reticular, microcystic, cribriform, tubular, solid, nested and rhabdoid growth.
• Clues: yolk sac tumour-like reticular areas, desmoplasia, prominent neutrophils.
• Complete nuclear INI1 loss with intact internal controls; PAX8 usually positive; p63 and GATA3 usually negative.
• Without sickle hemoglobinopathy: SMARCB1-deficient medullary-like RCC.
• Other RCCs can show secondary INI1 loss and must not be reclassified automatically.
• Usually presents with regional or distant metastasis.

Diagnostic pearl: medullary morphology + INI1 loss + renal epithelial lineage + hemoglobinopathy status; INI1 loss alone is not enough.

• SMARCB1-deficient RMC: renal epithelial tumour with sickle hemoglobinopathy.
• SMARCB1-deficient medullary-like RCC: same phenotype without demonstrated hemoglobinopathy (formerly RCC unclassified with medullary phenotype).
• Established RCC with secondary SMARCB1 loss: keeps its primary subtype.
• Malignant rhabdoid tumour: distinct, mainly infants.

Diagnostic pearl: an unrecorded sickle cell history is not a negative test; consider haemoglobin electrophoresis in characteristic cases.

• Adolescents and young adults, wider range possible; male predominance about 2:1.
• Sickle cell trait in most; HbSC and other sickling disorders also.
• Haematuria, flank pain, constitutional symptoms, lymphadenopathy or metastatic symptoms; right kidney more often.
• Grey-white, firm, ill-defined medullary mass extending into the sinus; haemorrhage, necrosis, satellite nodules.
• Less than 0.5% of RCCs; a small primary may come with extensive metastasis.

Diagnostic pearl: a central infiltrative tumour in a young patient with sickle cell trait is characteristic, but medullary-like tumours occur outside that setting.

• Highly infiltrative, alternating hypercellular and hypocellular areas, desmoplastic or myxoid stroma, entrapped native tubules.
• Reticular and microcystic spaces, anastomosing cords, angulated glands, cribriform sheets, solid nests.
• Cuboidal, polygonal or spindled cells; eosinophilic to amphophilic cytoplasm; irregular nuclei, prominent nucleoli; discohesion.
• Neutrophilic and lymphoplasmacytic inflammation; necrosis; rhabdoid cells; sickled red cells in vessels; brisk mitoses; frequent lymphovascular invasion.

Diagnostic pearl: reticular/microcystic growth + high-grade cytology + desmoplasia + neutrophils together are far more telling than any one alone.

• Reticular / microcystic: lace-like networks of cords and small spaces, yolk sac tumour-like; architectural, not germ cell differentiation.
• Tubular / glandular: angulated tubules in desmoplasia, closely mimicking CDC.
• Cribriform: sieve-like sheets.
• Tubulocystic: dilated tubules with hobnail cells in more cellular stroma than pure TC-RCC.
• Solid / nested: sheets with pleomorphism, central discohesion or necrosis.
• Rhabdoid: eccentric nuclei, nucleoli, eosinophilic inclusions; not equivalent to malignant rhabdoid tumour.
• Spindle / sarcomatoid: rare; PAX8 and keratins help.

Diagnostic pearl: a PAX8-positive high-grade carcinoma with yolk sac-like reticular areas should prompt INI1.

• Desmoplasia: frequent, CDC-like, not specific.
• Myxoid stroma: accentuates reticular cords.
• Neutrophils: conspicuous in stroma and lumina, best seen at low and medium power; not always present.
• Lymphoplasmacytic inflammation may obscure the tumour.
• Sickled erythrocytes: supportive context; their absence does not exclude trait.

• SMARCB1 / INI1: complete nuclear loss in viable tumour cells; inflammatory, endothelial, stromal and tubular nuclei must stain.
• PAX8: usually positive (may weaken in dedifferentiated areas).
• AE1/AE3, EMA, CK7: generally positive, nonspecific.
• p63/p40, GATA3: usually negative (against urothelial carcinoma).
• 34βE12: often negative or limited (overlaps with CDC).
• FH retained, 2SC negative, ALK negative.

Diagnostic pearl: PAX8+ with complete INI1 loss is powerful in a medullary-pattern carcinoma, but secondary loss must be excluded.

• Internal controls are mandatory: a fully negative section may be technical failure; avoid necrotic or poorly fixed areas.
• Not unique: INI1 loss also occurs in malignant rhabdoid tumour, epithelioid sarcoma and as a secondary event in other RCCs.
• Mosaic staining: fixation, entrapped normal cells or true heterogeneity; if loss is confined to a dedifferentiated part, look for an underlying RCC.
• Genotype: some INI1-deficient tumours show no SMARCB1 variant on limited panels (structural events, coverage).
• Sickle trait and INI1 loss are not interchangeable.

Diagnostic pearl: INI1-negative is an immunophenotype, not a complete diagnosis.

• SMARCB1 (INI1, SNF5, BAF47) at 22q11.23: core SWI/SNF chromatin-remodelling subunit and tumour suppressor.
• Biallelic loss, mainly by structural events: in 38 tumours, hemizygous loss with rearrangement 52.6%, homozygous deletion 15.8%, deletion plus indel 13.2%, none found 15.8%.
• Few point mutations despite aggressiveness; sequence-only panels can miss the alteration.
• Hypoxic, hypertonic medulla favours sickling, ischaemia and iron-related stress; single-cell studies point to the thick ascending limb as cell of origin; INI1 loss may aid survival (ferroptosis resistance). Model still developing.

Diagnostic pearl: use assays that detect structural variants and copy number, not only SNVs.

• Same reticular/microcystic, cord-like, cribriform and nested high-grade morphology, often rhabdoid, with complete INI1 loss.
• Requires proven renal epithelial differentiation and exclusion of other SMARCB1-deficient tumours.
• 2026 series: 3 new cases (nested, cord-like, reticular; one focally rhabdoid), about 18 in the literature.

Diagnostic pearl: before calling medullary-like RCC, confirm that hemoglobinopathy was tested, not just unmentioned.

Collecting duct carcinoma

• Shared location, infiltration, desmoplasia, inflammation, PAX8.
• CDC: older adults, INI1 retained, HMWCK more often positive; reticular/microcystic and rhabdoid areas favour RMC.
• Rare CDCs show secondary INI1 loss.

FH-deficient RCC

• Macronucleoli with halos, papillary/tubulocystic mix, FH loss or 2SC.
• Dual-loss pitfall: FH-deficient RCC can also lose INI1; if FH driver is proven, it stays FH-deficient RCC.

ALK-rearranged RCC

• VCL::ALK in young sickle cell trait patients; ALK+, INI1 retained; stain both INI1 and ALK.

Upper tract urothelial carcinoma

• CIS, urothelial morphology, p63/p40 and GATA3, uroplakin, INI1 retained.
• PAX8 can be focally positive in UC and GATA3 negative in poorly differentiated UC: use a panel and imaging.

Malignant rhabdoid tumour

• Infants; diffuse rhabdoid/undifferentiated; PAX8 usually negative; INI1 lost; rhabdoid predisposition syndrome; methylation profiling helps.

Secondary SMARCB1 loss

• In ccRCC (often sarcomatoid parts), PRCC, ChRCC, FH-deficient and TFE3-rearranged RCC.
• Look for a conventional component, compare INI1 between components, test subtype-defining markers.

Diagnostic pearl: an independently established primary molecular diagnosis takes precedence over secondary INI1 loss.

1. Morphology: reticular, microcystic, cribriform, tubular or solid high-grade carcinoma with desmoplasia, neutrophils, rhabdoid cells.
2. Lineage: PAX8 and keratins; exclude urothelial and metastatic carcinoma.
3. INI1: complete tumour loss with intact controls.
4. Hemoglobinopathy: history and electrophoresis if needed.
5. Mimics: CDC, FH-deficient, ALK-RCC, urothelial carcinoma, rhabdoid tumour.
6. Secondary loss: is INI1 loss the primary event?
7. Report RMC or medullary-like RCC with uncertainties.

On biopsy

• May sample only solid or glandular high-grade carcinoma; reticular areas, neutrophils and sickled cells may be missing; necrosis limits evaluation.
• Wording: SMARCB1-deficient renal medullary carcinoma (with hemoglobinopathy) or SMARCB1-deficient medullary-like RCC (without).

• Among the most aggressive renal carcinomas; most present with nodal, lung, liver or bone metastases; rapid progression.
• Size is unreliable; stage and metastatic burden matter; no validated grading.
• Management differs from ccRCC: platinum-based chemotherapy has been the backbone; durable responses are uncommon.
• Investigational: nivolumab + relatlimab (NCT05347212), neddylation inhibition (pevonedistat with platinum), replication and proteotoxic stress targeting.

Diagnostic pearl: a small primary does not exclude disseminated disease; prompt classification matters.

• Thick ascending limb origin from single-cell studies, integrating hypoxia, sickling and ferroptosis; no routine lineage marker yet.
• Structural SMARCB1 events dominate; SNV panels can be falsely negative.
• Medullary-like RCC: growing literature of tumours reproducing RMC without hemoglobinopathy.
• Secondary INI1 loss in FH-deficient, TFE3-rearranged and other RCCs is a rising classification pitfall.
• Therapy research targets SMARCB1-related stress pathways and the immune microenvironment; still investigational.

• Highly aggressive, sickle hemoglobinopathy-associated, medullary, in young patients.
• Reticular/microcystic yolk sac-like growth with cribriform, tubular, solid patterns; desmoplasia; neutrophils; rhabdoid cells; sickled red cells.
• PAX8+, keratins+, p63/GATA3 usually negative; complete INI1 loss with intact controls.
• Key mimics: CDC, FH-deficient RCC, ALK-RCC (VCL), urothelial carcinoma, malignant rhabdoid tumour.
• INI1 loss is not specific; secondary loss occurs in established RCCs.
• Without hemoglobinopathy: SMARCB1-deficient medullary-like RCC.
• Structural SMARCB1 events; negative SNV panels do not exclude.
• Sequence: morphology → lineage → INI1 → hemoglobinopathy → mimics and secondary loss.