Thyroid-like follicular renal cell carcinoma

• Exceptionally rare renal epithelial tumour closely resembling thyroid follicular tissue; an emerging/provisional entity in WHO 2022.
• Packed follicles and dilated tubules filled with dense eosinophilic colloid-like material; micro- and macrofollicles.
• Bland cuboidal to low-columnar cells.
• PAX8 and keratin positive; TTF-1 and thyroglobulin negative (against metastatic thyroid carcinoma); PAX8 alone cannot prove renal origin.
• EWSR1::PATZ1 fusion in several molecularly studied cases, but few tumours are rigorously tested and the morphology-defined group may be heterogeneous.
• Most conventional cases indolent after resection; regional and distant metastases occur, especially with sarcomatoid differentiation.

Diagnostic pearl: thyroid-like follicles alone do not make TLF-RCC: you need predominant follicular architecture, exclusion of a thyroid primary and of other renal entities.

• Names: thyroid-like follicular RCC (TLF-RCC), thyroid-like follicular carcinoma of the kidney, follicular (thyroid-like) RCC.
• First described in the early 2000s from case reports and small series; listed among emerging entities; about 60 cases by a 2026 review.

Two overlapping concepts

• Morphology-defined TLF-RCC: predominant follicular architecture after exclusion of mimics; includes untested historical tumours.
• EWSR1::PATZ1-positive thyroid-like renal neoplasm: a molecularly defined, probably more coherent subset.
• Whether all historical TLF-RCCs belong to the fusion-positive group is unknown.

Diagnostic pearl: the morphology is reproducible, but the molecular boundaries are still evolving.

Clinical

• Broad age range; slight female predominance; no syndrome; solitary; often incidental; haematuria, flank pain or discomfort; no thyroid disease in confirmed primary cases.

Gross

• Well demarcated; tan, grey-white or yellow-tan; solid with micro- or multicystic areas; cysts with dense proteinaceous material; spongy surface; calcification, haemorrhage, fibrosis.
• Rare aggressive tumours infiltrate, are necrotic or have large nonfollicular components.

Diagnostic pearl: no radiological or gross feature is specific; the diagnosis is histological with IHC correlation.

Architecture

• Numerous round to irregular follicles, tightly packed with little stroma; marked size variation; micro- and macrofollicles; uniform follicular pattern throughout.

Lining

• Single layer of cuboidal or flattened, occasionally low-columnar cells; scant to moderate eosinophilic or amphophilic cytoplasm; round nuclei, fine chromatin, small nucleoli; minimal pleomorphism.

Lumina

• Dense, homogeneous, glassy, bright eosinophilic colloid-like secretions with cracks or retraction.

Stroma

• Delicate fibrovascular septa; focal fibrosis or hyalinisation; no infiltrative desmoplasia in conventional tumours.

Diagnostic pearl: the key clue is a diffuse population of variably sized colloid-filled follicles, not a few colloid-filled tubules in another tumour.

• Microfollicular: small, crowded lumina; mimics thyroid microfollicular neoplasia and the packed acini of metanephric adenoma.
• Macrofollicular: large dilated follicles with flattened lining and abundant secretions.
• Mixed: both in one region; irregular or elongated follicles.
• Cystic: large cysts with retracted colloid-like material; mimics cystic renal neoplasms.

Diagnostic pearl: variation in follicle size is typical, but extensive nonfollicular architecture should prompt evaluation for another subtype.

• Homogeneous or finely granular, dense, glassy; fissured; retracts from the lining; can look exactly like thyroid colloid.
• Not true thyroid colloid: primary tumours lack thyroglobulin; proteinaceous material in dilated renal tubules looks similar.
• PAS and mucin stains can characterise unusual contents but cannot separate TLF-RCC from metastatic thyroid carcinoma.

Diagnostic pearl: “colloid” starts the differential; it is not a lineage marker.

• Conventional: bland cuboidal cells, uniform nuclei, fine chromatin, small nucleoli, low mitotic activity.
• Focal atypia: mild enlargement and nucleoli; not necessarily aggressive.
• Papillary or tubulopapillary areas: occasional; extensive true papillae suggest PRCC with thyroid-like follicles.
• Solid areas: small nests occur; expansile solid regions need work-up for sarcomatoid change or another tumour.
• Stroma: sclerosis, haemorrhage, calcification, ossification; not diagnostic.

Diagnostic pearl: follicular architecture must be the dominant, reproducible phenotype, not an incidental feature of an otherwise classifiable tumour.

Historical GUPS summary: CK7 89%, RCC marker 14%, AMACR 17%, CD10 23%, CK20 40%; small, variably characterised cohorts.

Diagnostic pearl: PAX8+, keratin+, TTF-1−, thyroglobulin− with convincing follicular morphology is the expected profile, but it does not exclude every renal tumour with secondary follicles.

• Primary TLF-RCC: PAX8+, but PAX8 is not origin-specific.
• Metastatic differentiated thyroid carcinoma: PAX8+, usually TTF-1+ and thyroglobulin+, and can look identical.
• So a PAX8+ colloid-filled follicular lesion still needs TTF-1, thyroglobulin, thyroid evaluation when appropriate, and radiological correlation.
• Dedifferentiated thyroid carcinoma can lose TTF-1 and thyroglobulin: negativity is most reassuring in a bland, well-differentiated lesion.

Diagnostic pearl: PAX8+/TTF-1−/Tg− supports renal origin; PAX8+/TTF-1+/Tg+ favours thyroid; resolve discordance with clinical context and broader testing.

• EWSR1 (22q12) and PATZ1 lie close together on chromosome 22; the fusion can arise intrachromosomally; its oncogenic mechanism is unclear.
• Al-Obaidy et al. (Mod Pathol 2021) found it in three TLF-RCCs; further cases followed, including aggressive ones.

Colef et al., Hum Pathol 2026: 39 EWSR1-rearranged renal neoplasms; 34 Ewing sarcoma, 2 DSRCT, 2 sclerosing epithelioid fibrosarcoma, 1 TLF-RCC with EWSR1::PATZ1.

• Not every historical TLF-RCC was tested; prevalence in strictly defined tumours is unknown; the fusion also occurs in nonrenal mesenchymal and CNS tumours.

Diagnostic pearl: EWSR1::PATZ1 supports a thyroid-like renal neoplasm, but EWSR1 rearrangement alone never establishes TLF-RCC.

• Break-apart FISH detects EWSR1 rearrangement but not the partner, and many unrelated tumours carry EWSR1 fusions.
• Cryptic intrachromosomal events: EWSR1 and PATZ1 are close, so break-apart FISH can be negative or equivocal.
• RNA-based NGS identifies the partner and separates Ewing sarcoma, DSRCT and others; needs good RNA and coverage.

Strategy

• Establish epithelial and follicular morphology → exclude thyroid carcinoma → RNA fusion testing when it changes classification → interpret with histology and IHC.

Diagnostic pearl: prefer RNA-based testing when the partner matters or a cryptic rearrangement is suspected.

• Both have packed micro- and macrofollicles with bland cells; thyroid follicular carcinoma can metastasise to the kidney; consider an occult primary; poorly differentiated thyroid carcinoma may lose thyroid markers.

Diagnostic pearl: follicles plus PAX8 do not establish renal origin; TTF-1 and thyroglobulin are the essential first discriminators.

Favours PRCC

• Dominant true papillary or tubulopapillary growth, fibrovascular cores, foamy macrophages, conventional PRCC cytology, diffuse CK7/AMACR, PRCC genomic changes.

Favours TLF-RCC

• Predominantly follicular throughout, markedly variable follicle size, abundant colloid-like secretions, no substantial conventional PRCC component, EWSR1::PATZ1.

Diagnostic pearl: a PRCC with follicular areas is not automatically TLF-RCC; the dominant architecture and molecular findings decide.

• Packed atrophic tubules with microcystic or follicle-like spaces, eosinophilic secretions, bland flat or cuboidal cells, fibrotic or hyalinised stroma.
• Overlap: follicle-like spaces, proteinaceous contents, little atypia; very hard on biopsy.
• Assess true expansile neoplasia vs remodelled parenchyma, native glomeruli and tubules, sclerosis or background atrophy, and any defining driver.
• Terminology is evolving; some historical TLF-RCCs may belong here; not all such lesions have a defining alteration.

Diagnostic pearl: densely packed colloid-filled tubules without a convincing neoplastic follicular pattern should prompt review for an atrophic kidney-like lesion.

• Thyroidization: chronic injury with interstitial fibrosis, inflammation and glomerulosclerosis; no expansile mass.

Diagnostic pearl: thyroid-like morphology is a shared pattern, never entirely entity-specific.

• Follicles coexisting with expansile spindle-cell areas in short or long fascicles; sometimes deceptively bland; aggressive ones with pleomorphism, mitoses and necrosis; abrupt or gradual interface.

A 2026 Histopathology review: three patients with sarcomatoid differentiation, all metastatic at presentation, two died; EWSR1::PATZ1 in one. Bhardwaj et al. (Histopathology 2026) showed a shared clonal origin of follicular and spindle-cell components in a low-grade sarcomatoid TLF-RCC.

Diagnostic pearl: do not dismiss a bland spindle-cell component; it is tumour progression, not a collision, and has clinical implications.

• Most conventional cases are localised and recurrence-free after resection, though follow-up is often limited.
• Documented: regional nodes, lung, retroperitoneum, bone or skull, meninges, extensive abdominal soft tissue.
• Zhang et al. (Hum Pathol 2026): a metastatic TLF-RCC with EWSR1::PATZ1, so fusion-positive tumours are not necessarily indolent.
• No entity-specific grading or staging; use standard RCC staging and document adverse findings.

Diagnostic pearl: TLF-RCC is not uniformly benign.

1. Follicular phenotype: predominantly variably sized follicles with dense colloid-like material.
2. Epithelial lineage: PAX8 and keratins (PAX8 does not separate renal from thyroid).
3. Exclude thyroid carcinoma: TTF-1, thyroglobulin, clinical thyroid correlation.
4. Exclude follicular mimics: PRCC, metanephric adenoma, tubulocystic RCC, FH-deficient RCC, atrophic kidney-like lesions, thyroidization.
5. Molecular: RNA-based NGS for EWSR1::PATZ1 when uncertain or with nonfollicular areas.
6. Adverse features: necrosis, infiltration, sarcomatoid/spindle areas, mitoses, metastasis.
7. Report: thyroid-like follicular RCC, with the fusion partner if confirmed.

• A core may show only colloid-filled follicles; metastatic thyroid carcinoma can be identical; PAX8 cannot separate them; TTF-1 and thyroglobulin are essential.
• A PRCC component, an atrophic kidney-like lesion or a sarcomatoid component may be missed; EWSR1 FISH can be falsely negative.

Suggested wording

• Characteristic: “Thyroid-like follicular renal cell carcinoma. Predominantly follicular architecture with dense eosinophilic secretions; renal epithelial markers positive; TTF-1 and thyroglobulin negative.”
• Molecularly confirmed: “Thyroid-like follicular renal cell carcinoma, EWSR1::PATZ1-rearranged (RNA-based analysis).”
• Uncertain core: “Renal epithelial neoplasm with thyroid-like follicular architecture. Differential includes TLF-RCC and other renal tumours with secondary follicles; thyroid-specific IHC and molecular testing recommended.”

Diagnostic pearl: on a small biopsy, a descriptive diagnosis is more defensible than naming a rare entity before its mimics are excluded.

• EWSR1::PATZ1 is the leading molecular finding; may be cryptic on FISH; also nonrenal, so interpret by lineage; fusion-positive tumours may be a more homogeneous subset.
• Misclassification (2025 review): small numbers, heterogeneous IHC, limited molecular testing, inclusion of other follicular renal tumours, incomplete follow-up.
• Clonal sarcomatoid transformation confirmed molecularly (Histopathology 2026).
• Metastatic fusion-positive disease established (Hum Pathol 2026).
• EWSR1 renal cohort: 1 of 39 EWSR1-rearranged renal tumours was TLF-RCC; partner and lineage are crucial.

• Exceptionally rare emerging WHO 2022 entity: packed thyroid-like micro- and macrofollicles with dense colloid-like material and bland cuboidal cells.
• PAX8 and CK7 positive; TTF-1 and thyroglobulin negative; PAX8 cannot separate it from metastatic thyroid carcinoma, the key differential.
• PRCC can contain follicular areas; atrophic kidney-like lesions and thyroidization mimic it; a substantial nonfollicular component means reassessment.
• EWSR1::PATZ1 is recurrent but the historical group is molecularly incomplete; break-apart FISH can miss it; RNA NGS names the partner; EWSR1 rearrangement is not specific.
• Usually indolent, but nodal and distant metastases occur; sarcomatoid/spindle transformation is the key adverse feature; no validated grading.
• Sequence: follicular morphology → renal epithelial lineage → exclude thyroid primary and mimics → molecular testing when appropriate.