Definition/General

Introduction:
-Clear cell RCC is the most common type of renal cell carcinoma
-Represents 70-75% of all RCCs
-Arises from proximal tubular epithelium
-Shows characteristic clear cytoplasm due to lipid and glycogen accumulation.
Origin:
-Originates from proximal tubular epithelial cells
-Associated with VHL gene mutations
-Shows loss of chromosome 3p
-Develops through multistep carcinogenesis
-Can be sporadic or hereditary.
Classification:
-WHO 2022 classification: Clear cell renal cell carcinoma
-Grading: WHO/ISUP grade 1-4
-Nuclear grade based on nucleolar prominence
-Sarcomatoid/rhabdoid differentiation possible.
Epidemiology:
-Peak incidence 6th-7th decades
-Male predominance (2:1)
-Most common RCC in adults
-Associated with von Hippel-Lindau syndrome
-Smoking and obesity risk factors.

Clinical Features

Presentation:
-Asymptomatic mass (incidental finding 60%)
-Classic triad: hematuria, flank pain, palpable mass (10%)
-Hematuria (40%)
-Flank pain (40%)
-Weight loss
-Fever.
Symptoms:
-Hematuria (gross or microscopic)
-Flank pain
-Abdominal mass
-Constitutional symptoms (fever, weight loss, fatigue)
-Paraneoplastic syndromes (hypercalcemia, polycythemia)
-Varicocele (left-sided).
Risk Factors:
-Smoking (2-fold risk)
-Obesity
-Hypertension
-Chronic kidney disease
-von Hippel-Lindau syndrome
-Acquired cystic kidney disease
-Family history
-Occupational exposures.
Screening:
-CT/MRI imaging
-Ultrasound for screening
-Genetic counseling (familial cases)
-VHL syndrome surveillance
-Regular imaging in high-risk patients.

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Gross Description

Appearance:
-Well-circumscribed mass
-Golden-yellow color
-Soft, friable consistency
-Hemorrhage and necrosis common
-Cystic areas frequent
-Pseudocapsule present.
Characteristics:
-Variegated cut surface
-Golden-yellow to tan color
-Soft consistency
-Hemorrhage, necrosis, cystic change
-Well-demarcated from normal kidney
-Renal vein extension possible.
Size Location:
-Any location in kidney
-Upper pole slightly more common
-Size: Variable 2-20 cm
-Bilateral in VHL syndrome
-Multifocal in hereditary cases
-Cortical origin.
Multifocality:
-Usually solitary (sporadic)
-Multiple/bilateral in VHL syndrome
-Synchronous tumors in 3-5%
-Metachronous tumors possible
-Satellite nodules indicate higher stage.

Microscopic Description

Histological Features:
-Clear cells with abundant clear cytoplasm
-Well-defined cell membranes
-Round nuclei
-Delicate capillary network
-Alveolar/acinar architecture
-Hyalinized stroma.
Cellular Characteristics:
-Large polygonal cells
-Abundant clear cytoplasm (lipid, glycogen)
-Well-defined cell boundaries
-Round to oval nuclei
-Variable nuclear grade
-Prominent nucleoli (high grade).
Architectural Patterns:
-Solid, alveolar, acinar patterns
-Delicate vascular network
-Cystic areas common
-Papillary areas (<10%)
-Sarcomatoid differentiation (poor prognosis)
-Rhabdoid features (aggressive).
Grading Criteria:
-WHO/ISUP grading: Grade 1: Nucleoli invisible/basophilic at 400x
-Grade 2: Nucleoli visible at 400x
-Grade 3: Nucleoli visible at 100x
-Grade 4: Extreme pleomorphism, sarcomatoid/rhabdoid features.

Immunohistochemistry

Positive Markers:
-CA9 - positive (membranous, characteristic)
-CD10 - positive
-RCC marker - positive
-Vimentin - positive
-EMA - positive (apical)
-PAX8 - positive (nuclear).
Negative Markers:
-Cytokeratin 7 - negative (usually)
-p63 - negative
-TTF1 - negative
-CDX2 - negative
-PSA - negative
-Melanoma markers - negative.
Diagnostic Utility:
-CA9 most useful (90% positive)
-CD10 supports renal origin
-PAX8 confirms renal epithelial origin
-CK7 negativity helps distinguish from other RCC types
-Triple positive: CA9+, CD10+, RCC+.
Molecular Subtypes:
-VHL-mutated (80%): Classic clear cell morphology
-PBRM1-mutated (40%): Better prognosis
-SETD2-mutated (15%): Higher grade
-BAP1-mutated (15%): Poor prognosis.

Molecular/Genetic

Genetic Mutations:
-VHL mutations (90% sporadic, 100% VHL syndrome)
-3p deletion (chromosome 3p loss)
-PBRM1 mutations (40%)
-SETD2 mutations (15%)
-BAP1 mutations (15%)
-KDM5C mutations (7%).
Molecular Markers:
-HIF pathway dysregulation
-VHL/HIF-α axis disruption
-VEGF overexpression
-Chromatin remodeling defects
-mTOR pathway activation
-Angiogenesis increased.
Prognostic Significance:
-Grade most important prognostic factor
-Stage critical
-BAP1 loss: Poor prognosis
-PBRM1 mutations: Better response to immunotherapy
-Sarcomatoid features: Very poor prognosis
-Necrosis: Adverse factor.
Therapeutic Targets:
-VEGF inhibitors (sunitinib, pazopanib)
-mTOR inhibitors (everolimus, temsirolimus)
-Immunotherapy (nivolumab, pembrolizumab)
-Anti-angiogenic therapy
-Combination therapies
-HIF-α inhibitors (investigational).

Differential Diagnosis

Similar Entities:
-Papillary RCC
-Chromophobe RCC
-Oncocytoma
-Xanthogranulomatous pyelonephritis
-Adrenal cortical carcinoma
-Metastatic clear cell carcinoma.
Distinguishing Features:
-Clear cell RCC: CA9+, clear cytoplasm, delicate vasculature
-Papillary RCC: CK7+, papillary architecture
-Chromophobe RCC: CK7+, perinuclear halos
-Oncocytoma: Eosinophilic cytoplasm, nested pattern
-Adrenal cortical: SF1+, inhibin+
-Metastatic: Organ-specific markers.
Diagnostic Challenges:
-Low-grade clear cell vs oncocytoma
-Cystic RCC vs benign cysts
-Papillary areas in clear cell RCC
-Sarcomatoid transformation
-Metastatic disease vs primary RCC.
Rare Variants:
-Multilocular cystic RCC
-Clear cell RCC with smooth muscle stroma
-Clear cell RCC with leiomyomatous stroma
-Tubulocystic carcinoma.

Sample Pathology Report

Template Format

Sample Pathology Report

Complete Report: This is an example of how the final pathology report should be structured for this condition.

Specimen Information

[Kidney specimen type], weighing [X] grams

Tumor Description

Clear cell renal cell carcinoma measuring [X] cm in greatest dimension, located in [upper/middle/lower] pole

Microscopic Features

Tumor shows classic clear cell morphology with abundant clear cytoplasm, well-defined cell membranes, and delicate capillary network

WHO/ISUP Grade

WHO/ISUP Grade [1/2/3/4] based on nucleolar prominence and nuclear features

Pathologic Stage

pT[stage] - [staging details]

Margins

Surgical margins: [negative/positive], closest margin [X] mm

Lymphovascular Invasion

Lymphovascular invasion: [present/absent]

Immunohistochemistry

CA9: Positive, CD10: Positive, CK7: Negative, PAX8: Positive

Prognostic Factors

Grade [X], Stage [X], Size [X] cm, [Sarcomatoid features present/absent], [Necrosis present/absent]

Final Diagnosis

Clear cell renal cell carcinoma, WHO/ISUP Grade [X], pT[stage]