Author: PathologyMCQ Editorial Team
Category: Uropathology / Oncopathology
Last Updated: October 2026
Read Time: 10 minutes
Difficulty: Moderate (MD/DNB, FRCPath, NEET-SS)
Clear cell renal cell carcinoma (RCC) can be differentiated from clear cell papillary RCC based on morphology, immunohistochemistry and molecular genetics. Prognosis also varies between the two.
Key differences between the two conditions are elaborated below.
Both tumours are built from cells with clear cytoplasm, so the diagnosis rests on architecture, nuclear position, a small immunohistochemistry panel and, when needed, genetics, not on cytoplasmic clearing alone. Getting it right matters: clear cell RCC needs grading, staging and follow-up for metastasis, whereas clear cell papillary RCC is indolent.
At a glance
- Clear cell RCC (ccRCC): the commonest RCC (about 70%), driven by VHL loss on chromosome 3p, with nests and a delicate capillary network, ISUP grading and metastatic potential.
- Clear cell papillary RCC (CCPRCC): an uncommon, small, encapsulated tumour with tubules and papillae, nuclei lined up away from the basement membrane, CK7 positivity and cup-shaped CAIX. WHO 2022 renamed it a clear cell papillary renal cell tumour because of its indolent course.
- Deciding features: architecture, nuclear polarity, CK7 and CAIX pattern, and 3p/VHL status.
- In this post: schematic comparisons, three comparison tables, an annotated virtual slide of a key mimic (xanthogranulomatous pyelonephritis), 5 MCQs and the renal pathology quiz.
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Key differences: infographic and table
| Feature | Clear cell RCC | Clear cell papillary RCC |
|---|---|---|
| Frequency | Commonest RCC (about 70%) | Uncommon, a few percent of renal epithelial tumours |
| Gross | Golden-yellow, variegated, haemorrhage, necrosis and cysts; may invade the renal vein | Usually small, well circumscribed, fibrous capsule, solid and cystic |
| Architecture | Solid nests, alveolar and acinar patterns in a delicate capillary network | Branching tubules, cysts and short papillae in fibromuscular stroma |
| Nuclei | Central; ISUP grade 1 to 4; high-grade and sarcomatoid change occur | Low grade, lined up at the luminal pole away from the basement membrane |
| CK7 | Negative or focal | Diffuse and strong |
| CAIX | Diffuse membranous (box-like) | Cup-shaped, sparing the luminal border |
| Genetics | 3p loss with VHL inactivation | No 3p loss or VHL mutation |
| Behaviour | Can recur and metastasise; stage and grade dependent | Indolent |
Morphology: what you see on H&E
Schematic drawings for teaching, not photomicrographs.
Clear cell RCC
- Gross: a solid, golden-yellow tumour (lipid) with a variegated cut surface from haemorrhage, necrosis and cystic change. It bulges from the cortex and may grow into the renal vein.
- Architecture: solid nests, alveolar and acinar patterns, separated by a delicate, thin-walled capillary network.
- Cells: polygonal cells with distinct borders and optically clear cytoplasm, because glycogen and lipid are removed during processing.
- Nuclei and grade: ISUP grade is based on nucleoli. Grade 1 has no visible nucleoli at 400x, grade 2 has nucleoli visible at 400x, grade 3 at 100x, and grade 4 shows extreme pleomorphism, sarcomatoid or rhabdoid change.
- Pitfall: cystic change and papillary-like architecture can occur in ccRCC, so a papillary look alone does not make it papillary RCC or CCPRCC.
Clear cell papillary RCC
- Gross: usually small and well circumscribed with a fibrous capsule, solid and cystic.
- Architecture: branching tubules, cysts and short papillae with a fibromuscular stroma.
- Nuclear polarity: low-grade nuclei are aligned in a row at the luminal pole, away from the basement membrane (reverse polarity), with clear cytoplasm beneath. The look is often likened to secretory endometrium.
- Absent features: necrosis, solid sheets of high-grade cells and sarcomatoid change argue against CCPRCC.
- Pitfall: ccRCC with tubulopapillary architecture can mimic CCPRCC, so confirm with CK7 and CAIX rather than relying on H&E.
Immunohistochemistry
| Marker | Clear cell RCC | Clear cell papillary RCC |
|---|---|---|
| PAX8 | Positive | Positive |
| CK7 | Negative or focal | Diffuse, strong |
| CAIX | Diffuse membranous, box-like | Cup-shaped (basolateral), luminal border spared |
| CD10 | Positive | Usually negative or focal |
| AMACR | Negative | Negative |
| CK 34ฮฒE12 (HMWCK) | Usually negative | Often positive |
| GATA3 | Negative | Frequently positive |
| TFE3 | Negative | Negative (positive TFE3 points to an Xp11 translocation RCC) |
Practical panel: CK7 plus CAIX separates the two in most cases. Add AMACR if you also need to exclude papillary RCC, and TFE3 if the cells are clear to eosinophilic with a papillary pattern in a young patient.
Molecular genetics, prognosis and reporting
| Clear cell RCC | Clear cell papillary RCC | |
|---|---|---|
| Genetics | Loss of 3p with VHL inactivation in most cases; frequent PBRM1, SETD2 and BAP1 mutations. VHL syndrome predisposes to multifocal ccRCC. | Lacks the 3p loss and VHL mutations of ccRCC, and lacks the trisomy 7 and 17 of papillary RCC. No single defining driver. |
| Prognosis | Depends on stage (renal vein, perinephric fat) and ISUP grade. Sarcomatoid or rhabdoid change and tumour necrosis are adverse. | Indolent. Strictly defined cases are not known to recur or metastasise. |
| Reporting | Report ISUP grade, necrosis, sarcomatoid or rhabdoid change, extent of invasion and margins. | State the diagnosis only when the architecture and the CK7 and CAIX pattern fit. If features overlap, say so and add the differential. |
Differential diagnosis
| Mimic | Clue | Deciding test |
|---|---|---|
| Papillary RCC with clear cells | True papillae with foamy macrophages and a fibrovascular core, nuclei not polarised away from the basement membrane | AMACR positive; CAIX not cup-shaped; trisomy 7 and 17 |
| Xp11 translocation RCC | Clear and eosinophilic cells, papillary and nested pattern, often in young patients | Nuclear TFE3, cathepsin K; TFE3 break-apart FISH |
| RCC with fibromyomatous stroma (often ELOC-altered) | Smooth muscle stroma and CK7 positivity overlap with CCPRCC | ELOC (TCEB1) alteration on molecular testing |
| ccRCC with papillary or tubular architecture | Atypia and necrosis, nuclei central | CK7 negative or focal; box-like CAIX; 3p loss |
| Xanthogranulomatous pyelonephritis (XGP) | Foamy macrophages resemble clear cells in a small biopsy, with plasma cells and neutrophils | CD68 positive; keratin and PAX8 negative |
Virtual slide ยท a key mimic
Xanthogranulomatous pyelonephritis (XGP)
Foamy macrophages can look like clear cells. Pan out, then zoom in on the nuclei.
What to look for ยท Xanthogranulomatous pyelonephritis
Sheets of foamy macrophages with abundant pale, vacuolated cytoplasm, mixed with plasma cells, lymphocytes, neutrophils and multinucleated giant cells, often around necrosis and destroyed tubules. Pitfall: the foamy cells resemble the clear cells of ccRCC, but their nuclei are small, round and bland, the infiltrate is mixed, and they are CD68 positive with keratin and PAX8 negative.
Drag to pan ยท pinch or double-tap to zoom ยท use the + / โ buttons
What’s new: WHO 2022
- Renamed: clear cell papillary RCC is now the clear cell papillary renal cell tumour, reflecting its indolent behaviour.
- Grading: the ISUP nucleolar grade is used for ccRCC. Sarcomatoid or rhabdoid change is graded as grade 4.
- Molecular classes: RCC with fibromyomatous stroma and other molecularly defined RCCs are recognised mimics that can need genetic testing.
Test yourself: 5 MCQs and the renal quiz
1. Which immunohistochemical pattern best supports clear cell papillary RCC over clear cell RCC?
- CK7 negative with diffuse box-like CAIX
- CK7 diffuse and strong with cup-shaped CAIX
- Diffuse CD10 with AMACR positivity
- Nuclear TFE3 positivity
- Vimentin positive, CK7 negative
Show answer
B. CCPRCC is CK7 diffuse and strong with cup-shaped (basolateral) CAIX. ccRCC is usually CK7 negative or focal with diffuse box-like CAIX and CD10 positive.
2. Which nuclear arrangement is typical of clear cell papillary RCC?
- Central nuclei with prominent nucleoli
- Nuclei aligned at the luminal pole, away from the basement membrane
- Nuclei pushed to the periphery by a large vacuole
- Multinucleated giant cells
- Nuclear grooves and pseudo-inclusions
Show answer
B. Low-grade nuclei line up away from the basement membrane (reverse polarity), with clear cytoplasm beneath, resembling secretory endometrium.
3. Which genetic change is characteristic of clear cell RCC?
- Trisomy 7 and 17
- TFE3 gene rearrangement
- Loss of 3p with VHL inactivation
- Loss of chromosomes 1, 2, 6, 10, 13 and 17
- FH mutation
Show answer
C. Loss of 3p with VHL inactivation is the hallmark of ccRCC. Trisomy 7 and 17 point to papillary RCC, TFE3 rearrangement to Xp11 translocation RCC, and multiple chromosomal losses to chromophobe RCC.
4. What is the expected behaviour of a strictly defined clear cell papillary renal cell tumour?
- Frequent early liver metastasis
- Indolent, with no known recurrence or metastasis
- Aggressive, with sarcomatoid transformation
- Always associated with VHL syndrome
- Needs ISUP grade 4 reporting
Show answer
B. It is indolent, which is why WHO 2022 uses the term tumour. ccRCC, in contrast, is graded and can metastasise.
5. A nephrectomy for chronic pyelonephritis shows sheets of foamy cells with plasma cells and neutrophils. Which pair of stains best excludes clear cell RCC?
- CD68 positive, keratin and PAX8 negative
- PAX8 positive, CD68 negative
- CK7 positive, CAIX cup-shaped
- AMACR positive, TFE3 positive
- CD10 positive, vimentin positive
Show answer
A. In xanthogranulomatous pyelonephritis the foamy cells are macrophages: CD68 positive, keratin and PAX8 negative. Clear cell RCC is PAX8 positive.
More practice: renal pathology quiz
Clear cell RCC vs clear cell papillary: 10 MCQs
Morphology, IHC, genetics and mimics, with instant explanations.
More practice: the renal pathology MCQ bank โ
Exam pearl and key takeaway
Exam pearl: clear cells in nests with a delicate capillary network, CK7 negative, box-like CAIX and 3p loss = clear cell RCC. Clear cells in tubules and papillae with nuclei away from the basement membrane, CK7 strongly positive and cup-shaped CAIX = clear cell papillary RCC.
Key takeaway: clear cytoplasm is not the diagnosis. Read the architecture and nuclear position, confirm with CK7 and CAIX, and remember that only ccRCC needs grading and metastatic follow-up.
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Related reads: Emerging renal tumours, WHO 2022 โ ยท Hereditary renal carcinoma syndromes โ ยท Paediatric renal tumours โ
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