Renal cell carcinoma NOS

• A malignant renal epithelial neoplasm that cannot be confidently assigned to a recognised subtype after appropriate evaluation.
• A category of exclusion, not a single histogenetic or molecular entity.
• Covers tumours with widely divergent morphology, immunophenotype, molecular alterations and behaviour.
• Some are unusual variants of established RCCs; some belong to new molecularly defined entities; some stay unclassified only because the needed tests are unavailable; some are genuinely unclassifiable after full work-up.
• Separating these situations matters clinically and scientifically.

Diagnostic pearl: RCC, NOS should describe the limits of classification, not erase the morphological information already available.

The label can hide very different situations

• Incompletely investigated: morphology suggests an entity, but IHC or molecular tests are unavailable; referral may resolve it.
• Morphologically overlapping: resembles several entities and the available IHC does not settle it; molecular work may be needed.
• Genuinely unclassifiable: complete morphological, IHC and molecular work-up, still no fitting category; a legitimate final diagnosis.
• Highly dedifferentiated: sarcomatoid, rhabdoid or undifferentiated change obscures the subtype; more sampling may reveal it.

Why it matters

• These groups do not share prognosis: some are indolent oncocytic tumours, others aggressive carcinomas.
• Some carry hereditary or actionable alterations.
• Pooling them in studies adds major biological heterogeneity and blurs multidisciplinary communication.

Adapted from Yildirim et al., Virchows Arch 2026. Proposed descriptive categories, not WHO entities.

Diagnostic pearl: minor focal variation is common in RCC and does not make a tumour “mixed”; the mixed group needs two or more substantial, roughly co-dominant components.

Morphology

• Solid sheets, compact nests, acini, tubules, small cysts or tubulocystic growth; variable oedema or fibrosis.
• Abundant granular eosinophilic cytoplasm, variable vacuoles, uniform or atypical nuclei; prominent nucleoli do not necessarily mean aggressive behaviour.

Worth documenting

• Perinuclear halos and irregular membranes; coarse basophilic stippling; large sharp vacuoles; flocculent inclusions; apical nuclei; thick-walled vessels or stromal transitions; true sarcomatoid or rhabdoid areas.

Differential

• Oncocytoma, eosinophilic ChRCC, LOT, EVT, ESC RCC, SDH-deficient RCC, low-grade oncocytic FH-deficient RCC, TSC/mTOR-altered and FLCN-associated neoplasms, eosinophilic TFE3/TFEB RCC.

Report

• “Renal cell carcinoma, NOS, with oncocytic/eosinophilic features.”
• May include indolent tumours and aggressive molecular ones; FLCN, FH, SDHx or TSC/mTOR germline alterations can matter beyond the index mass.

Diagnostic pearl: an eosinophilic tumour without the features of oncocytoma or ChRCC should not simply be called RCC, NOS without a morphological qualifier.

Morphology

• Solid, nested/alveolar, acinar or tubular growth; delicate capillaries in some; papillary or pseudopapillary foci; fibrous or fibromyomatous stroma.
• Optically clear cytoplasm, distinct or indistinct borders, round to irregular nuclei, focal granular eosinophilic change.

Sources of uncertainty

• Absent or atypical CAIX: ccRCC is usually diffuse box-like; negativity alone does not exclude it.
• True papillae: suggest PRCC, MiT RCC or another clear cell neoplasm; separate them from degenerative pseudopapillae.
• Fibromyomatous stroma: ELOC-mutated RCC, TSC/mTOR-altered RCC and some ccRCC-related tumours.

Differential

• Unusual ccRCC, TFE3 and TFEB RCC, ELOC RCC, TSC/mTOR RCC with fibromyomatous stroma, CCPRCT, PRCC with clear cell change.

Report

• “Renal cell carcinoma, NOS, with clear cell features.”

Diagnostic pearl: clear cytoplasm is a cytological description, not proof of ccRCC; integrate architecture, vessels, CAIX distribution, other IHC and molecular findings.

Morphology

• Branching papillae with fibrovascular cores, short or delicate projections, single or pseudostratified lining, tufting; foamy macrophages, psammoma bodies.
• Tubules and papillae together; papillae projecting into dilated lumina; packed acini merging with papillae; solid foci.
• Clear, eosinophilic, amphophilic or oncocytic cells; stratification; variable nucleoli; hobnail cells or vacuoles.

Clues

• Complex papillae with prominent eosinophilic nucleoli and halos (FH); psammoma-rich clear papillae (MiT); mucinous stroma; tubule-to-spindle transitions; abrupt papillary-solid changes.

Differential

• PRCC, TFE3 and TFEB RCC, FH-deficient RCC, MTSCC, CCPRCT, ALK-RCC and other molecular carcinomas with papillae.

Report

• “Renal cell carcinoma, NOS, with papillary/tubulopapillary architecture.”

Diagnostic pearl: papillary architecture is not papillary RCC; several molecular carcinomas have papillae, some with hereditary implications.

• Pleomorphic: large polygonal cells, irregular nuclei, macronucleoli, giant cells, atypical mitoses, sheets with little gland formation.
• Sarcomatoid: malignant spindle cells in fascicles, collagenous or myxoid stroma, abrupt or gradual transition to carcinoma, sometimes complete loss of epithelial architecture.
• Rhabdoid: eccentric nuclei, abundant eosinophilic cytoplasm, globular inclusions; may coexist with sarcomatoid change.
• Necrotic: extensive geographic necrosis can leave only peripheral viable tumour.

Work-up

• Search extensively for a conventional component; decide whether this is dedifferentiation of an established RCC.
• Exclude primary or metastatic mesenchymal tumours when lineage is uncertain; consider aggressive molecular carcinomas.

Differential

• Sarcomatoid ccRCC, PRCC, ChRCC or other RCC; FH-deficient RCC; SMARCB1-deficient medullary carcinoma; CDC; high-grade ALK-RCC; TFE3 or TFEB-amplified RCC; metastasis; mesenchymal tumour.

Report

• “Renal cell carcinoma, NOS, with high-grade pleomorphic/sarcomatoid features”, adding rhabdoid change and extensive necrosis where present.

Diagnostic pearl: sarcomatoid change is a progression pattern, not a lineage; identify and retain the underlying subtype whenever possible.

• Infiltrative angulated glands, small tubules, cords, cribriform aggregates and solid nests in native parenchyma.
• High-grade cuboidal, columnar or polygonal cells with prominent nucleoli and mitoses.
• Dense desmoplasia, myxoid areas, neutrophilic or lymphoplasmacytic inflammation, entrapped tubules, necrosis.
• Medullary-like: reticular or microcystic networks, cords in loose stroma, cribriform areas, rhabdoid cells, yolk sac tumour-like patterns.

Differential

• CDC, SMARCB1-deficient medullary carcinoma, FH-deficient RCC, ALK-RCC, upper tract urothelial carcinoma, metastasis.

Report

• “Renal cell carcinoma, NOS, with collecting duct-like/medullary-like features (high-grade infiltrative).”

Diagnostic pearl: an infiltrative high-grade carcinoma with desmoplasia is not automatically CDC; exclude the molecular mimics, urothelial and metastatic carcinoma first.

• Two or more distinct components in roughly comparable proportions with no dominant pattern.
• Examples: clear + oncocytic; papillary + solid eosinophilic; clear + papillary; oncocytic + tubulocystic; tubular + cribriform with different cytology.

Criteria

• Components are substantial and reproducible; a minor papillary focus does not make a solid tumour mixed.
• Components are morphologically distinct, not differences from degeneration, necrosis or sampling.
• Consider known heterogeneous entities first: ALK-RCC, FH-deficient RCC and TFE3 RCC routinely combine patterns.

Composite vs collision

• Composite: different components of a biologically related lesion. Collision: two separate neoplasms; divergent drivers or lineages help.

Report

• “Renal cell carcinoma, NOS, with mixed clear cell and oncocytic/eosinophilic patterns.”

Diagnostic pearl: list only the principal coexisting patterns; “mixed” must not become another wastebasket.

1. Morphology: if characteristic of a recognised entity, make that diagnosis.
2. Dominant subgroup: oncocytic, clear cell, papillary, high-grade pleomorphic/sarcomatoid, collecting duct-like/medullary-like or mixed.
3. Available tests: choose a focused, morphology-driven panel; avoid indiscriminate staining.
4. Specific entity? If IHC and molecular results establish one, report it.
5. Still unresolved: report RCC, NOS with the dominant subgroup and adverse features.
6. Essential tests unavailable: consider the proposed RCC, NOS (i).

Adapted from the algorithm in Yildirim et al., Virchows Arch 2026.

Where available

• FH and 2SC; SDHB and SDHA; cathepsin K and GPNMB; TFE3/TFEB testing; validated fusion or sequencing assays.

These are menus, not orders to run every stain. FH, cathepsin K and GPNMB were left out of the minimal panels only because they are often unavailable in resource-limited laboratories, not for lack of value.

• Proposed suffix (i): one or more essential tests needed for classification were unavailable or not feasible.
• A proposed reporting convention, not an official WHO suffix.

Use it when

• Morphology suggests a molecularly defined RCC but the necessary IHC, FISH or sequencing cannot be obtained, technically or financially.

Do not use it when

• Full work-up is complete and the tumour is genuinely unclassifiable; a subtype can already be diagnosed; the missing test would not change the classification.

Examples

• “RCC, NOS (i), with oncocytic/eosinophilic features.” Comment: tests needed to separate emerging oncocytic neoplasms were unavailable.
• “RCC, NOS (i), with collecting duct-like/medullary-like features.” Comment: essential ancillary testing was unavailable.
• “RCC, NOS, with mixed clear cell and eosinophilic features.” Comment: comprehensive work-up did not assign a subtype.

Diagnostic pearl: RCC, NOS and RCC, NOS (i) communicate different levels of investigation and certainty.

Architecture

• Solid, nested/alveolar, acinar, tubular, tubulopapillary, papillary, tubulocystic, cribriform, reticular/microcystic, trabecular, infiltrative glandular, sarcomatoid.

Cytology

• Clear, eosinophilic/oncocytic, amphophilic, vacuolated, rhabdoid, spindle, pleomorphic, signet-ring-like, small or primitive.

Stroma and background

• Fibromyomatous, desmoplastic, myxoid/mucinous, sclerotic; prominent vessels; foamy macrophages; neutrophils; psammoma bodies and other calcifications.

Adverse findings

• Coagulative necrosis, sarcomatoid or rhabdoid differentiation, marked pleomorphism, brisk mitoses, lymphovascular invasion, infiltrative or destructive growth.

Diagnostic pearl: state the dominant morphology in the diagnosis; put the rest in the description and comment rather than an unwieldy label.

• WHO/ISUP grading was built mainly for ccRCC and PRCC; RCC, NOS mixes tumours with different biology.
• Some emerging entities have prominent nucleoli yet behave indolently; some bland-looking molecular carcinomas are aggressive.

Examples

• Tubulocystic RCC: conspicuous nucleoli, usually favourable.
• EVT: striking nucleoli, usually indolent.
• Low-grade oncocytic FH-deficient RCC: bland nuclei do not guarantee benign behaviour.
• SDH-deficient RCC: mostly low grade; high-grade change and necrosis are the important adverse findings.

Reporting

• Document nuclear morphology, necrosis and dedifferentiation; do not assume a grade carries validated prognostic meaning in every entity; state context and limits if you grade.

Diagnostic pearl: a prominent nucleolus is an observation; its prognostic meaning depends on the entity.

• Historical RCC, NOS cohorts mix indolent oncocytic tumours, atypical ccRCC, molecular mimics, high-grade infiltrative and sarcomatoid carcinomas.
• These differ in prognosis, metastatic potential, hereditary risk, drivers and treatment response.

Analysing them as one group

• Distorts survival estimates; produces biomarkers that reflect case mix; hampers interinstitutional comparison; hides entities that morphology would already have flagged.

Morphological stratification

• More coherent retrospective cohorts, easier selection for molecular reassessment, better comparability and transparency about historical limits.

A research argument of the proposal, not a survival benefit shown by prospective validation.

Diagnostic pearl: subgrouping does not make RCC, NOS homogeneous, but it makes it interpretable and reclassifiable.

Structure

• Diagnosis: RCC, NOS, with [dominant subgroup].
• Adverse findings: necrosis, sarcomatoid/rhabdoid change and others.
• Comment: main differentials, what testing established or excluded, what remains unavailable.

Diagnostic pearl: a good RCC, NOS report says what the tumour looks like, why it is unclassified, and what could resolve it.

• Subgroups are not disease entities; observers may disagree on the dominant pattern; mixed patterns add reproducibility problems.
• Dedifferentiated tumours may lose the phenotype of their origin; one molecular carcinoma can fall in several subgroups.
• Morphology cannot establish hereditary status or reliably predict prognosis and treatment response.
• The (i) suffix is not WHO-recognised; the six-group framework has not been prospectively validated for interobserver agreement, diagnostic yield or prognosis.
• Critics argue that formalising subgroups of an indeterminate category has its own pitfalls (Chen and Li, Virchows Arch 2026).

Principle

• An adequately supported specific diagnosis (FH-deficient, TFE3-rearranged, ALK-rearranged RCC and others) always takes precedence over a descriptive NOS subgroup.

Diagnostic pearl: the aim is better communication when classification fails, not a competing taxonomy.

• RCC, NOS is a heterogeneous residual category, not a defined subtype, and tells little about behaviour on its own.
• Incomplete work-up and genuine unclassifiability are different situations.
• A morphological subgroup gives more information than NOS alone; the proposal has six.
• Oncocytic: think emerging oncocytic and metabolic neoplasms. Clear: exclude ccRCC and its molecular mimics. Papillary is not necessarily PRCC.
• High-grade/sarcomatoid: look for the underlying subtype. Collecting duct-like: exclude FH-deficient RCC, RMC, ALK-RCC, urothelial and metastatic carcinoma.
• “Mixed” requires co-dominant components; (i) flags incomplete essential testing and is a proposal, not WHO.
• Report necrosis, desmoplasia and mitotic activity; WHO/ISUP grade is not equally meaningful across emerging entities.
• Molecular testing should follow morphology; NOS is a record of unresolved classification, not the end of reasoning.