Renal cell carcinoma

Definitions & Key takeaways

Renal cell carcinoma (RCC) is a type of kidney cancer that originates in epithelial cells in the proximal convoluted tubule of the kidney. RCCs are the most common type of malignant kidney cancer in adults, generally affecting older men. RCCs can arise sporadically or as part of a genetic condition like von Hippel-Lindau's disease. Symptoms may include blood in the urine, abdominal pain, and a mass in the kidney area. Treatment options include surgery, radiation therapy, and immunotherapy.

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Introduction0:00–0:20

Renal cell carcinomas (or RCC’s) are the most common type of malignant kidney cancer in adults, generally affecting older men.
Unfortunately, RCC is often considered a “silent” cancer because symptoms don’t typically get noticed until the tumor has grown pretty large.

Pathology0:20–2:41

Renal cell carcinomas form from epithelial cells in the proximal convoluted tubule of the kidney; this is the section of the nephron that is usually located in the renal cortex—the outer rim of the kidney.
The most common type of renal cell carcinoma is composed of polygonal epithelial cells, which have funny angular shapes with at least four sides and are filled with clear cytoplasm full of carbohydrates and lipids.
It’s those lipids that give the tumors their yellow color. At a genetic level, renal cell carcinomas have been linked to mutations on the short arm of chromosome 3, or 3p.
An easy way to remember this is that RCC has three letters and it’s linked to chromosome 3. One of the main genes involved in renal cell carcinomas is the VHL gene, which codes for the von Hippel-Lindau tumor suppressor protein, or pVHL which is normally expressed in all tissues.
Mutations in pVHL can allow IGF-1, the type 1 insulin-like growth factor, pathway to go into overdrive. This does two things.
First, there is dysregulated cell growth, and second it upregulates specific transcription factors called hypoxia-inducible factors, which in turn help generate more vascular endothelial growth factor or VEGF, as well as VEGF receptor, leading to growth of new blood vessels, or angiogenesis.
Dysregulated cellular growth and angiogenesis are a recipe for tumor formation. Renal cell carcinomas can arise sporadically or they can be a part of an inherited syndrome.
Sporadic tumors are usually solitary tumors in the upper pole of the kidney, and most often happen among older men that smoke cigarettes.
Inherited syndromes, like von Hippel-Lindau disease, can also give rise to renal cell carcinomas, and in this situation the tumors typically affect younger men and women and often involve both kidneys.
Von Hippel Lindau disease is a rare autosomal dominant disorder characterized by a mutation in a tumor suppressor gene which leads to the formation of cysts and benign tumors in various parts of the body like the eye and central nervous system.
The number one cause of death in patients with von Hippel-Lindau disease, though, is the development of renal cell carcinomas.

Symptoms2:41–3:57

Individuals with renal cell carcinoma typically have one or more of the following symptoms: hematuria, or red blood cells in the urine, which is most common, a palpable mass in the abdomen or lower back, and pain in the flank or near the hip bone.
Since the cancer causes a state of chronic inflammation, other classic symptoms include fever and weight loss. Renal cell carcinoma is also frequently responsible for causing various paraneoplastic syndromes, which is where the tumor cells generate a hormone that causes it’s own set of symptoms.
For example, these tumors can release the hormone erythropoietin which increases the production of new red blood cells, and this can lead to polycythemia or too many red blood cells, which can cause the blood to start sludging or slow down its normal flow.
Another paraneoplastic syndrome involves the release of renin a hormone that is part of the renin-angiotensin-aldosterone system and is involved in raising blood pressure.
Some other hormones that renal cell carcinomas are known for releasing include parathyroid hormone-related peptide (or PTHrP) which causes hypercalcemia and adrenocorticotropic hormone (or ACTH) which increases release of the stress hormone cortisol and can lead to Cushing’s syndrome.

Complication3:57–4:59

Finally, in rare cases, a large renal cell carcinoma affecting the left kidney can butt up against the left renal vein and impede normal venous drainage of the left testes.
This leads to dilation of the testicular veins and formation of a varicocele. Since the right testicular vein drains directly into the inferior vena cava, a blockage of the right renal vein by a large tumor does not have the same effect.
An especially dangerous progression of a renal cell carcinoma is its ability to invade the renal vein, where it literally grow within the vein, eventually reaching the inferior vena cava.
This dramatically increases the risk of cancer spreading through the bloodstream with the most likely targets being the lungs since that’s the first capillary bed that the tumor cells would reach if they broke free of the growing mass, but also the bones because the tumor cells have an affinity for that tissue.
To determine the risk of renal cell carcinomas, each one is individually staged by the TNM system. ‘T’ indicates the size of the tumor and whether or not it has grown in nearby areas, for example, the renal vein.

Diagnosis4:59–5:28

‘N’ describes the degree to which the cancer has spread to retroperitoneal lymph nodes. And finally ‘M’ indicates the degree to which the cancer has spread to other sites or metastasized.
Each of these categories is ranked from 0–4 with four being the most severe. Renal cell carcinomas are stubbornly resistant to both traditional chemotherapy and radiation therapy.
So if the tumor is localized to the kidney, surgical resection may be appropriate. In addition, renal cell carcinomas sometimes regress when they are attacked by the immune system, and are sensitive to immunomodulatory agents like certain chemokines and monoclonal antibodies.

Treatment5:28–6:04

Molecular targeted therapies specifically aimed at inhibiting the VEGF receptor are particularly effective because it reduces tumor vascularization, thereby cutting off the blood supply and killing the tumor.
Alright, as a quick recap, renal cell carcinomas form from epithelial cells in the proximal convoluted tubule of the kidney.
These tumors can arise sporadically or as part of a genetic condition like von Hippel-Lindau disease. Renal cell carcinomas can be tricky to treat because they are resistant to traditional chemotherapy and radiation therapy, and they are known to cause paraneoplastic syndromes.

Review6:04–6:29

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