ALK-rearranged renal cell carcinomas

• Rare, molecularly defined renal carcinoma with an oncogenic ALK rearrangement (2p23); provisional in WHO 2016, a distinct entity in WHO 2022.
• Many partners: VCL, EML4, TPM3, TPM1, STRN, HOOK1, PLEKHA7, CLIP1, KIF5B, KIAA1217, SLIT1, ARNT, NUMA1 and others.
• Exceptional heterogeneity: papillary, tubular, tubulocystic, solid, trabecular, cribriform, mucinous, metanephric adenoma-like and MTSCC-like patterns, often together.
• Cells eosinophilic, clear, rhabdoid, spindled or signet-ring-like; intra- and extracellular mucin and vacuoles are key clues.
• ALK IHC (D5F3 or 5A4) screens; an ALK fusion in a renal epithelial tumour establishes the diagnosis.
• Mostly indolent when localised, but metastasis and death occur; advanced tumours can respond dramatically to ALK inhibitors.

Diagnostic pearl: the clue is often an unusual combination of patterns, especially with mucin, rather than one pattern.

• Children to older adults, mostly adults; both sexes; usually solitary.
• VCL::ALK in young patients with sickle cell trait in a subset; no hereditary syndrome known.
• Circumscribed solid or solid-cystic, tan-white or variegated; gelatinous areas reflect mucin; haemorrhage, cysts, necrosis in high-grade tumours.

Lobo et al., AJSP 2026 (16 cases)

• Mean 7.1 cm (2.0–12.2); 9 men, 7 women; necrosis in 6/16.

Diagnostic pearl: a large tan-white tumour with gelatinous areas and heterogeneous histology should prompt ALK IHC.

• Solid nests merging into papillae; tubules and cysts beside cribriform sheets; mucinous glands beside eosinophilic solid areas.
• High-grade rhabdoid or pleomorphic areas beside bland areas; metanephric adenoma-like acini; MTSCC-like tubules and spindle cells.
• Cells: cuboidal, large eosinophilic with nucleoli, small uniform, vacuolated, signet-ring-like, spindled.
• Stroma: mucinous, fibrous, hyalinised, desmoplastic, inflamed; psammomatous calcification.

Diagnostic pearl: when a tumour seems to contain several unrelated subtypes, look for a unifying molecular entity rather than the predominant pattern.

• Papillary: delicate or broad cores, cuboidal to columnar or hobnail cells; can mimic PRCC.
• Tubular: branching or angulated tubules with secretions or mucin; bland forms mimic MA or MTSCC.
• Tubulocystic: cysts lined by flat or hobnail cells, sometimes with mucin.
• Solid: sheets of eosinophilic to clear cells; mimics high-grade RCC.
• Cribriform: mimics CDC or FH-deficient RCC.
• Trabecular: cords in fibrous or myxoid stroma; neuroendocrine- or hepatoid-like.
• Single cells in mucin with signet-ring forms: mimics metastatic mucinous adenocarcinoma.

Diagnostic pearl: a papillary or tubular RCC with unexpected mucin, vacuoles or a second unusual pattern deserves ALK.

• Clear or mucin-containing cytoplasmic vacuoles, focal or extensive.
• Signet-ring-like cells with displaced nuclei; do not assume mucin without histochemistry.
• Extracellular blue-grey mucin pools, sometimes dominant and grossly gelatinous.
• Alcian blue, mucicarmine or PAS help but do not establish ALK-RCC.
• Not all tumours contain mucin; mucin also occurs in non-ALK renal tumours.

Diagnostic pearl: mucin is a screening clue, not a requirement.

• Rhabdoid: discohesive cells, eccentric nuclei, prominent nucleoli, abundant eosinophilic cytoplasm.
• Sarcomatoid: malignant spindle cells; shared ALK expression links them to the carcinoma.
• Pleomorphic epithelioid cells, multinucleation, atypical mitoses; intranuclear pseudoinclusions occur.

AJSP 2026 (16 cases)

• Solid 12, tubular 7, papillary 5, tubulocystic 2, pleomorphic 6, rhabdoid 4, sarcomatoid 2 (overlapping).

Diagnostic pearl: high-grade, rhabdoid or sarcomatoid areas do not exclude ALK-RCC; ALK IHC helps in unclassifiable high-grade tumours.

Metanephric adenoma-like

• Packed small acini, small uniform cells, inconspicuous nucleoli, glomeruloid tufts, psammoma.
• PLEKHA7::ALK example: ALK, CK7, PAX8, AMACR positive; WT1, CD57, BRAF V600E, TFE3, CAIX, cathepsin K negative. Also seen with other partners.

MTSCC-like

• Elongated tubules, bland spindle cells, mucinous stroma (KIF5B::ALK, focal in KIAA1217::ALK).
• PAX8, CK7 and AMACR overlap with MTSCC.

Screening evidence

• ALK IHC on 49 metanephric adenomas and 202 MTSCCs found no further ALK-positive tumours.

Diagnostic pearl: test ALK in atypical MA- or MTSCC-like tumours (e.g. CK7/AMACR+, WT1−), not in every conventional one.

• Young patients with sickle cell trait, often VCL::ALK (not exclusive).
• Solid sheets and nests of polygonal or spindled eosinophilic cells, prominent nucleoli, vacuoles, lymphocytes; medullary location.
• ALK positive, PAX8 positive, INI1 retained (lost in renal medullary carcinoma).

Diagnostic pearl: in a young patient with sickle cell trait, retained INI1 plus ALK positivity points to VCL::ALK RCC.

• ALK (D5F3/5A4): usually strong, cytoplasmic; membranous or granular accentuation by partner; sometimes heterogeneous.
• PAX8: usually positive; gives lineage (ALK does not).
• CK7, AMACR: frequently positive, nonspecific; PanCK/EMA variable; CD10 variable; 34βE12 may be positive.
• INI1, FH, SDHB: retained.
• TFE3: focal nuclear staining without fusion in 4/13 (AJSP 2026), a pitfall.

Limits

• Weak or equivocal ALK does not establish the diagnosis; poor preservation can give false negatives.
• ALK expression does not name the partner and occurs in IMT and other ALK-driven tumours.

Diagnostic pearl: PAX8+/CK7+/AMACR+ is nonspecific; ALK is the major clue.

• Kinase domain of ALK fused to a partner gives constitutive activation (MAPK/ERK, PI3K/AKT/mTOR, JAK/STAT).
• VCL: young, sickle cell trait, medullary-like. EML4, TPM3, TPM1: heterogeneous. STRN: may mimic other entities. PLEKHA7: MA-like. KIF5B, KIAA1217: MTSCC-like.
• Rare: HOOK1, CLIP1, SLIT1, ARNT, NUMA1, RAB1A (2026).
• AJSP 2026 (14 sequenced): EML4 5, TPM1 4, TPM3 2, SLIT1 2, VCL 1.
• Identical partners can give very different architectures; partner is not a classification system.

Diagnostic pearl: do not split ALK-RCC into separate entities by partner.

• STRN::ALK has been found in tumours resembling other established entities (e.g. metanephric adenoma).
• Assess three levels: lineage (epithelial?), morphology (resembles what?), driver (pathogenic expressed ALK fusion?).
• In a renal epithelial tumour, a pathogenic fusion strongly supports ALK-RCC even with low-grade or conventional-looking morphology; document the resemblance.
• In a non-epithelial tumour (IMT, other ALK mesenchymal neoplasms), the fusion does not make it RCC.
• Where the boundaries lie remains debated; proof that the fusion is pathogenic and in tumour cells is essential.

• Break-apart FISH: partner-agnostic on FFPE; misses some atypical events; does not name the partner or establish lineage.
• RNA-based NGS: identifies the expressed fusion and junction; best for rare or surprising fusions; needs good RNA.
• DNA-based NGS: may miss intronic breakpoints.
• Not every candidate transcript is pathogenic; copy-number gain or nonspecific expression is not a fusion.

Diagnostic pearl: practical route: ALK IHC, then FISH or NGS; RNA-NGS for unusual cases.

• Metanephric adenoma: WT1, CD57, BRAF V600E; CK7/AMACR usually negative; ALK negative.
• MTSCC: multiple chromosomal losses; ALK negative.
• Papillary RCC: +7/+17; mucin, signet-ring cells, rhabdoid areas or mixed patterns suggest ALK.
• FH-deficient RCC / CDC: FH/2SC for FH; CDC only after ALK and FH are excluded.
• Renal medullary carcinoma: INI1 lost, ALK negative.
• Inflammatory myofibroblastic tumour: spindle myofibroblasts, lymphoplasmacytic inflammation, SMA, PAX8 negative; keratin can be positive.

Diagnostic pearl: the ALK fusion defines a driver, not a lineage: RCC requires an epithelial renal tumour.

1. Clues: unusual heterogeneity, mucin, vacuoles, signet-ring cells, atypical MA/MTSCC/medullary-like pattern.
2. Lineage: PAX8 and epithelial markers; exclude ALK+ mesenchymal or metastatic tumours.
3. Screen: validated ALK D5F3/5A4 IHC.
4. Confirm: ALK FISH and/or RNA-NGS.
5. Reconcile discordance (TFE3 staining, transcript validity).
6. Report ALK-rearranged RCC with the partner when known.

On biopsy

• A core may show only one pattern; mucin and signet-ring cells may be missed; high-grade areas may be missed.
• ALK IHC can rescue a non-specific biopsy; small FFPE samples may limit RNA testing.
• Wording: RCC with features suspicious for ALK rearrangement; molecular testing recommended.

• Many localised tumours are cured surgically; long-term data are limited.
• Nodal and distant metastases and deaths occur; rhabdoid, sarcomatoid and necrotic tumours are concerning; no validated grading system.
• 2020 series: 8 of 9 with follow-up disease-free; 2025 Mayo update: 3 metastatic, 2 deaths.
• ALK inhibitors (crizotinib, alectinib, brigatinib, ceritinib, lorlatinib) are not RCC standards, but case reports show striking responses: complete response to alectinib in an ALK-RCC first called CDC (2024); near-complete remission with first-line alectinib in a 23-year-old with VCL::ALK RCC (2026).

Diagnostic pearl: accurate classification has more immediate therapeutic relevance than in most rare RCCs.

• Expanding partners: ARNT and NUMA1 (Mayo 2025), RAB1A (2026); test broadly, not a fixed partner list.
• High-grade morphology: pleomorphic, rhabdoid and sarcomatoid tumours in the 2026 cohort.
• Focal TFE3 staining without TFE3 fusion can mislead toward MiT RCC.
• Entity mimicry: MA- and MTSCC-like tumours raise classification questions; lineage and driver evidence are needed.
• Targeted therapy: case-based but dramatic responses support molecular identification in metastatic disease.

• WHO 2022 molecular entity; ALK at 2p23; many partners.
• No single pattern; mixed papillary, solid, tubular, cribriform, trabecular and mucinous growth.
• Mucin, vacuoles and signet-ring cells are key clues.
• MA-like and MTSCC-like forms exist; VCL::ALK with sickle cell trait mimics medullary carcinoma (INI1 retained).
• Rhabdoid and sarcomatoid change occur.
• ALK D5F3/5A4 IHC screens; PAX8 gives lineage; CK7/AMACR nonspecific; focal TFE3 is a pitfall.
• Confirm with FISH or RNA-NGS; exclude IMT when lineage is uncertain.
• Variable prognosis; ALK inhibitors can work in advanced disease.