Renal cell carcinoma – causes, symptoms, diagnosis, treatment, pathology


Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to create
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much more. Try it free today! 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. 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. 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. 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 usually have the same effect. However, very rarely, in people whose right
spermatic vein drains into the right renal vein, renal cell carcinoma affecting the right
kidney may cause a varicocele of the right testis. 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. ‘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. 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.

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