Internal Medicine

Renal cell carcinoma (RCC)

Heterogeneous group of cancers derived from renal tubular epithelial cells.

Heterogeneous group of cancers derived from renal tubular epithelial cells.

  • ‘Silent Cancer’
  • RCC is >90% of cancers in the kidney


Therapeutic evolution and survival outcome of metastatic ccRCC through the four different eras
Therapeutic evolution and survival outcome of metastatic ccRCC through the four different eras: a) Prior to 2004, two drugs were available to treat RCC (with a median survival of ~15 months). This so-called dark age of treatments was followed by the modern age (2005–2014), which saw seven additional regimens gain approval (increasing median survival to ~30 months). Currently, the golden age has already witnessed the introduction of three drugs, with more anticipated over the next decade. b) These advances promise to be translated to a significant number of patients (~50%) achieving durable remissions under active surveillance by 2025 with a median survival of ~5 years. The ultimate goal is the future diamond age of drug approvals is >80% of patients with metastatic ccRCC long-term survival. Dashed lines represent predicted survival. | Hsieh, J., Purdue, M., Signoretti, S. et al. Renal cell carcinoma. Nat Rev Dis Primers 3, 17009 (2017).


  • 2% of all cancer diagnoses and cancer deaths worldwide
  • Median age: 64 years
Global kidney cancer incidence
Global kidney cancer incidence: Estimated age-standardized rates (ASRs) of incidence for both sexes (per 100,000 persons) in 2012. Rates are generally higher in developed countries, with the highest incidence the Czech Republic (reasons unknown). | Data from GLOBOCAN database;


Major subtypes:

  • Clear cell RCC (ccRCC): M/C, 75% cases & M/cancer-related deaths
  • Papillary RCC (pRCC) (15% cases)
  • Chromophobe RCC (chRCC) (5% cases): Best prognosis

Remaining subtypes (15%):

  • Transitional cell carcinoma (8%)
  • Nephroblastoma or Wilms’ tumour (5–6%)
  • Collecting duct tumoursBellini type” (<1%): Worst prognosis
  • Renal sarcomas (<1%)
  • Renal medullary carcinomas (RMC) (<1%): Seen in sickle cell anaemia affected cases
Distinct subtypes of RCC
Distinct subtypes of RCC: Approximately 75% of renal cell carcinomas (RCCs) are a) Clear cell RCC (ccRCC). b) Papillary RCCs make up ~15% of all kidney cancers and are divided into two types based on staining features: b) type 1 (basophilic) and c) type 2 (eosinophilic). d) Chromophobe RCCs make up ~5% of kidney tumours. Other minor subtypes include e) MiT family translocation RCCs and f) collecting duct RCCs. Additional minor subtypes include medullary RCC, clear cell papillary RCC, acquired cystic disease-associated RCC, tubulocystic RCC, mucinous tubular and spindle RCC, succinate dehydrogenase-deficient RCC, hereditary leiomyomatosis, renal cell carcinoma-associated RCC and oncocytoma. Tumours not fitting into any of these categories are designated unclassified RCC. | Scale bar = 200 μm. | Hsieh, J., Purdue, M., Signoretti, S. et al. Renal cell carcinoma. Nat Rev Dis Primers 3, 17009 (2017).


Major risk factors:

  • Obesity
  • Hypertension
  • Cigarette smoking

Associated conditions:

  • Chronic kidney disease (CKD)
  • Haemodialysis
  • Kidney transplantation
  • Acquired kidney cystic disease
  • Previous RCC diagnosis
  • Diabetes mellitus

Occupational exposure:

  • AsbestosCd, Pbchlorinated solvents, petrochemicals, & PAH (Polycyclic aromatic hydrocarbon)

Genetic conditions (often multiple lesions):

  • Hereditary papillary renal carcinoma
  • Hereditary leiomyomatosis
  • Birt-Hogg-Dube syndrome
  • Hyperparathyroidism-jaw tumour syndrome
  • Familial papillary thyroid carcinoma
  • von Hippel-Lindau disease (autosomal dominant)
    • RCC is M/C cause of death in VHL cases
  • Sickle cell disease


VHL (Von Hippel-Lindau) tumour suppressor gene (chromosome 3): M/C mutated gene

VHL mutation

↑ IGF-1 (growth factor) → Dysregulation of cell growth

Upregulation of
Hypoxia-inducible factors (HIF)

Upregulation of
Vascular Endothelial growth factor (VEGF)
↑ Platelet-derived growth factor (PDGF)


VHL inactivation in ccRCC and its implication in targeted therapy
VHL inactivation in ccRCC and its implication in targeted therapy: Loss of VHL is the most frequent genetic feature of clear cell renal cell carcinoma (ccRCC). Its loss relieves the cell of negative regulation of the hypoxia-inducible factors (HIFs), which results in increase HIF target gene expression and ensuing changes in cellular metabolism and signaling that enhances cell survival. For example, increased vascular endothelial growth factor (VEGF) expression increases angiogenesis in concert with increased signaling from growth factor receptors in endothelial cells in the tumor microenvironment (including fibroblast growth factor (FGF) and hepatocyte growth factor (HGF)). Collectively, these changes provide the targets for therapeutic agents to impede tumor growth, as indicated. | FGFR, FGF receptor VEGFR, VEGF; TSC, tuberous sclerosis complex; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; AKT, RAC-α serine/threonine-protein kinase; Rheb, GTP-binding protein Rheb; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; S6K1, ribosomal protein S6 kinase; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; HRE, HIF response element; MET, hepatocyte growth factor receptor. | Hsieh, J., Purdue, M., Signoretti, S. et al. Renal cell carcinoma. Nat Rev Dis Primers 3, 17009 (2017).
Cancer evolution and tumor heterogeneity in ccRCC
Cancer evolution and tumor heterogeneity in ccRCC: Although VHL mutation and 3p loss of heterozygosity are early events that are evident in all clear cell renal cell carcinoma (ccRCC) cells regardless of the region of the tumor sampled, common driver mutations (for example, SETD2, MTOR, and KDM5C mutations) are present heterogeneously — suggestive of subclonal evolution of the tumor. a) Cancer subclones originate from the most recent common ancestor cell (MRCA) in which a normal cell acquires all functional capacities to become cancer cell. b) Genomic heterogeneity can result from the sequential, parallel accumulation of mutations, contributing to the heterogeneity and the evolution of ccRCC. In this example, ‘R’ represents the genomic characteristics of the primary tumor and ‘M’ represents the genomic characteristics of the metastatic sites, numbered accordingly. The major genetic lesions acquired after VHL mutation feature in different samples and are indicated on the branches. c) However, some evidence suggests that tumors can converge by way of parallel evolution. Here, a hypothetical beaded river model depicts the sequential convergence of SETD2 and KDM5C mutations through different spatiotemporally distinct genetic events. | Hsieh, J., Purdue, M., Signoretti, S. et al. Renal cell carcinoma. Nat Rev Dis Primers 3, 17009 (2017).


Classic triad (10% cases):

RCC is known as a silent cancer as > 40% present with none of these three symptoms. Currently, more than 60% of RCC are detected incidentally in patients not suspected of harbouring a genitourinary malignancy.
  1. Flank pain
  2. Gross haematuria
  3. Palpable abdominal mass

Paraneoplastic syndromes:

  • Endocrine paraneoplastic syndromes:
    • Erythropoietin → Polycythemia → Sludging of blood vessels (M/C)
    • Renin → HTN
    • Parathyroid hormone-related peptide (PTHrP) → Hypercalcemia
    • ACTH →  ↑ Cortisol → Cushing’s Syndrome
  • Non-endocrine paraneoplastic syndromes:
    • Amyloidosis, anaemia, neuromyopathies, vasculopathy, nephropathy, coagulopathy, prostaglandin elevation


Tumour locally invades and blocks venous drainage of testes (usually left because left testicular vein drains into left renal vein & right testicular vein drains into IVC)
A Tumor Or. (2020) Varicocele ~ Pasindu’s Archives. Retrieved January 23, 2020, from

Stauffer syndrome:

Rare paraneoplastic syndrome classically associated with renal cell carcinoma (RCC) characterized by a reversible anicteric elevation of liver enzymes, alkaline phosphatase, erythrocyte sedimentation rate (ESR), thrombocytosis, prolongation of prothrombin time, and hepatosplenomegaly in the absence of direct hepatobiliary obstruction or jaundice.



Imaging modality of choice
  • Chromophobe RCC: Central stellate lesion

Renal core biopsy:

  • Polygonal epithelial cells
  • Clear cytoplasm
  • Contain carbohydrates & lipids (lipids impart yellow colour)
  • Psammoma bodies (seen in papillary type)

International Society of Urological Pathology (ISUP) histological grading:

  • Grade 1: Tumor cell nucleoli invisible or small and basophilic at 400x magnification
  • Grade 2: Tumor cell nucleoli conspicuous at 400 x magnification but inconspicuous at 100x magnification
  • Grade 3: Tumor cell nucleoli eosinophilic and clearly visible at 100x magnification
  • Grade 4: Tumors showing extreme nuclear pleomorphism and/or containing tumor giant cells and/or the presence of any proportion of tumor showing sarcomatoid and/or rhabdoid dedifferentiation


StageDescription5 Year Survival Rate
ITumor is no bigger than 7cm and is limited to the kidney; there is distant metastasis but no lymph node metastasis.81%
IITumor is limited to the kidney, but its dimension is above 7cm.74%
IIITumor has spread to perinephric tissue, major veins, renal veins or vena cava.53%
IVTumor has spread further, beyond the Gerota fascia and possibly into the lungs.8%
Stages of kidney cancer and recommended treatments
Stages of kidney cancer and recommended treatments: Staging renal cell carcinoma (RCC) is based on size, position and lymph node involvement. For example, a stage I or II tumour is enclosed wholly in the kidney. Stage III tumours can extend into major veins or adrenal glands within Gerota’s fascia (the layer of connective tissue encapsulating the kidneys and adrenal glands) or can involve one regional lymph node involvement. Stage IV tumours can invade beyond Gerota’s fascia and/or have distant metastases. *Until the introduction of newer targeted therapies beginning in 2005, the 5-year survival of stage IV RCC was <10%. Treatment is largely guided by stage. For example, those with stage I RCC who are fit for surgery are recommended partial nephrectomy. However, radical nephrectomy is also an option; for elderly patients or those who cannot undergo surgery owing to comorbidities, active surveillance or ablative therapies are recommended. In patients with stage III RCC, radical nephrectomy is recommended with lymph node dissection in those with clinical enlarged lymph nodes, but systemic therapies might be the only available option for those with extensive disease and poor performance status. | Renal cell carcinoma. (2017). Nature Reviews Disease Primers, 3, 17010.


Treatment algorithms for renal cell carcinoma
Treatment algorithms for renal cell carcinoma: Given the advances in renal cell carcinoma (RCC) research, how patients are treated — based on their individual tumour characteristics — will likely change in the future. | Renal cell carcinoma. (2017). Nature Reviews Disease Primers, 3, 17010.

Surgical management:

RCC’s are radioresistant & chemoresistant.
  • Partial nephrectomy: Indicated only if tunmor < 7cm in size, located at poles or if bilateral
  • Radical nephrectomy: Indicated in all other cancers
Indications for radical nephrectomy
Indications for radical nephrectomy: a) Radical nephrectomy could be considered in cases with multiple small renal tumours (circled). b) Conversely, radical nephrectomy and contextual excision of neoplastic thrombus into renal vein or cava vein tumour thrombus is the gold standard treatment for patients with venous involvement. | Renal cell carcinoma. (2017). Nature Reviews Disease Primers, 3, 17010.

Metastatic cancer:

  • Sunitinib
  • Sorafenib


Performed in cases not able to undergo surgery or as palliative treatment in metastatic disease


Renal cell carcinoma
Renal cell carcinoma is a common cancer that is treated with surgery in localized cases and systemic targeted therapies in metastatic cases. Renal cell carcinoma (RCC) is a heterogeneous group of cancers derived from renal tubular epithelial cells | Renal cell carcinoma. Nat Rev Dis Prim [Internet]. 2017 Mar 9 [cited 2017 Apr 2];3:17010. Available from:

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