Clear cell renal cell carcinoma

by Trevor A. Flood, MD FRCPC
May 11, 2022


What is clear cell renal cell carcinoma?

Clear cell renal cell carcinoma is a type of kidney cancer. The tumour develops from the very small tubules in the kidney. Clear cell renal cell carcinoma is the most common type of kidney cancer in adults.

What syndromes are associated with clear cell renal cell carcinoma?

Most cases of clear cell renal cell carcinoma are sporadic. That is they happen by chance and are unrelated to any known genetic condition. Some patients, however, are born with a syndrome, a genetic condition, that makes them more likely to develop clear cell renal cell carcinoma. Often these patients are at risk of developing multiple tumours and they arise at a younger age compared to patients with sporadic tumours.

How is this tumour normally found and diagnosed?

Many clear cell renal cell carcinomas are detected incidentally at the time of abdominal imaging for other reasons.  Patients with these tumours may occasionally experience pain in their back or side or notice blood in their urine. The tumour will appear as a kidney mass on MRI or CT scan of the abdomen.

The diagnosis of clear cell renal cell carcinoma can be made after a small sample of tissue is removed in a procedure called a biopsy. Depending on the results of the imaging studies, your doctor may suggest removing the tumour without first performing a biopsy.

What does clear cell renal cell carcinoma look like under the microscope?

When examined under the microscope, the tumour is made up of large round cells that connect together to form large groups of cells. The tumour gets its name from the fact that the cytoplasm (cell body) of many of the tumour cells appears clear when examined under the microscope. Tumours made up mostly of clear cells are less likely to spread to other parts of the body and are associated with an excellent prognosis. The groups of tumour cells are often separated by small blood vessels that provide the tumour with a large amount of blood.

clear cell renal cell carcinoma

The microscopic appearance of clear cell renal cell carcinoma.

What is the WHO/ISUP grade and why is it important?

Pathologists divide clear cell renal cell carcinoma into four grades using a system developed by the World Health Organization (WHO) and the International Society for Urological Pathology (ISUP). Prior to 2016, these tumour types were graded using Fuhrman nuclear grading system.

The WHO/ISUP grading system and the Fuhrman nuclear grading system are similar and both employ a scoring system from 1 to 4. The WHO/ISUP grade is based on microscopic features of the tumour cells, in particular, the size and shape of the tumour cell nuclei and the presence of nucleoli.

The WHO/ISUP grade is important because it is can predict the future behaviour of the tumour. In general, high grade tumours (WHO/ISUP grades 3 and 4) are associated with a worse prognosis than low grade tumours (WHO/ISUP grades 1 and 2) and are more likely to spread to other parts of the body.

The WHO/ISUP grading system:

  • Grade 1 – The tumour cell nuclei are small and round. The nucleoli are difficult to see even when the cells are examined with a high magnification lens.
  • Grade 2 – The tumour cell nuclei are slightly larger and irregularly shaped. Nucleoli are easier to see but only after the cells are examined with a high magnification lens.
  • Grade 3 – The tumour cell nuclei are obviously irregular and enlarged. The nucleoli are very easy to see even when the cells are examined with a low magnification lens.
  • Grade 4 – The tumour cell nuclei are bizarre, extremely irregular and often multilobed. Tumours with sarcomatoid and rhabdoid cells are included in this category (see sections below for more details).
What are sarcomatoid cells and why are they important?

Sarcomatoid cells are tumour cells that have changed both their shape and their behaviour. Sarcomatoid tumour cells can be found in almost all types of renal cell carcinoma, including clear cell renal cell carcinoma. Instead of being round in shape, the sarcomatoid cells are now long and thin. Pathologists describe cells with this shape as spindle cells. Tumours with sarcomatoid cells are considered high grade (see WHO/ISUP grade above) and they are associated with a worse prognosis.

What are rhabdoid cells and why are they important?

Rhabdoid cells are tumour cells that have changed to look more like muscle cells. Rhabdoid tumour cells can be found in almost all types of renal cell carcinoma, including clear cell renal cell carcinoma. Tumours with rhabdoid cells are considered high grade (see WHO/ISUP grade above) and they are associated with a worse prognosis.

What if more than one tumour is found in the kidney?

Sometimes, more than one tumour is found in the same kidney. When only one tumour is found, pathologists call this unifocal. When more than one tumour is found, pathologists call this multifocal.

When multiple tumours are found, they are usually of the same type. For example, they are all clear cell renal cell carcinomas. However, different types of tumours can also be found in the same kidney. In that case, your report will list and describe each type of tumour found.

What does tumour necrosis mean?

Necrosis is a form of cell death and it commonly occurs in cancerous tumours. Your pathologist will closely examine the tumour for evidence of necrosis. The presence of necrosis is important because it is associated with a worse prognosis.

What does tumour extension mean and why is it important?

The normal kidney sits near the back of the body and is surrounded by fat. The adrenal gland sits directly above the kidney and the bladder is attached to the kidney by a long thin tube called the ureter which connects to the kidney in a region called the ‘renal sinus’. Clear cell renal cell carcinoma starts inside the kidney but as it grows, it can extend into any of these structures and organs. The growth of the tumour into surrounding organs is called tumour extension.

Your pathologist will carefully examine the specimen for any evidence of tumour extension and all structures or organs involved will be listed in your report. Tumour extension into any of these structures or organs is important because it is associated with a worse prognosis and it is also used to determine the pathologic stage (see Pathologic stage below).

Margins

A margin is the normal tissue that surrounds a tumour and is removed with the tumour at the time of surgery. If only part of the kidney was removed (a procedure known as a ‘partial nephrectomy’), the margins will include the fat surrounding that portion of the kidney and the area where the kidney was divided.

Margin

 

If the entire kidney was removed (a procedure known as a ‘total’ or ‘radical nephrectomy’) the margins will include the fat surrounding the kidney, the ureter (the tube that connects the kidney to the bladder), and some large blood vessels (usually arteries and veins). Some larger specimens may include additional margins.

A negative margin means that no cancer cells were seen at the cut edge of the tissue. In contrast, a positive margin means that cancer cells are seen at the cut edge of the tissue. Your pathologist will report any positive margins and the location of that margin. A positive margin is associated with an increased risk of the tumour coming back in the same area of the body.

Lymphovascular invasion

Blood moves around the body through long thin tubes called blood vessels. Another type of fluid called lymph which contains waste and immune cells moves around the body through lymphatic channels. The term lymphovascular invasion is used to describe tumour cells that are found inside a blood vessel or lymphatic channel. Lymphovascular invasion is important because once the tumour cells are inside a blood vessel or lymphatic channel they are able to metastasize (spread) to other parts of the body such as lymph nodes or the lungs.

lymphovascular invasion

What are lymph nodes?

Lymph nodes are small immune organs located throughout the body. Tumour cells can spread from the tumour to a lymph node through lymphatic channels located in and around the tumour (see Lymphovascular invasion above). The movement of tumour cells from the tumour to a lymph node is called lymph node metastasis.

Lymph node

Your pathologist will carefully examine each lymph node for tumour cells. Lymph nodes that contain tumour cells are often called positive while those that do not contain any tumour cells are called negative. Most reports include the total number of lymph nodes examined and the number, if any, that contain tumour cells.

How do pathologists determine the pathologic stage (pTNM) for clear cell renal cell carcinoma?

​The pathologic stage for clear cell renal cell carcinoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means more advanced disease and a worse prognosis.

Tumour stage (pT) for clear cell renal cell carcinoma

Clear cell renal cell carcinoma is given a tumour stage between 1 and 4 based on the size of the tumour and the growth of the tumour into organs attached to the kidney.

  • T1 – The tumour is less than or equal to 7 centimetres and is still entirely within the kidney.
  • T2 – The tumour is greater than 7 centimetres but is still entirely within the kidney.
  • T3 – The tumour is grown into the fat around the kidney or into a large vein attached to the kidney.
  • T4 – The tumour has grown well outside the kidney and through a barrier known as ‘Gerota’s fascia’ OR into the adrenal gland above the kidney.
Nodal stage (pN) for clear cell renal cell carcinoma

Clear cell renal cell carcinoma is given a nodal stage of 0 or 1 based on the presence of tumour cells in a lymph node. If no lymph nodes are involved the nodal stage is N0. If any tumour cells are seen in a lymph node the nodal stage is N1. If no lymph nodes are submitted for pathological examination, the nodal stage cannot be determined and the nodal stage is listed as NX.​

Metastatic stage (pM) for clear cell renal cell carcinoma

Clear cell renal cell carcinoma is given a metastatic stage of 0 or 1 based on the presence of tumour cells at a distant site in the body (for example the lungs). The metastatic stage can only be determined if tissue from a distant site is submitted for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined and is listed as MX.

Pathologic findings in the non-neoplastic kidney

The non-neoplastic kidney is the tissue outside of the tumour. Your pathologist will carefully examine the non-neoplastic tissue for evidence of other diseases that can commonly affect the kidney such as arterionephrosclerosis (high blood pressure) and diabetic nephropathy (diabetes).

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