Subtypes of Renal Cell Carcinoma (RCC)
Not all kidney cancers are the same. There is an increasing understanding among clinicians and researchers that there are different subtypes of RCC and that they behave quite differently, both with regard to how aggressive they are in the patient and how they respond to treatment. Ten or fifteen years ago, it was common for a pathology report from a patient with kidney cancer to read simply “Renal Cell Carcinoma.” This simple diagnosis is now thought to be incomplete. Identification of the specific subtype or cell type (histology) of the kidney cancer can be as important in determining patient prognosis as knowing the stage or grade of the RCC. Your doctor should give you information regarding the histology, grade and stage of your kidney cancer. If not, you should feel comfortable asking for this information since it is an important part of your treatment planning.
The subtypes of RCC come from the description of the cell’s appearance and other characteristics. They include:
- Clear Cell (conventional) RCC: This is the most common form of kidney cancer and represents between 66% and 75% of all cases. Clear cell RCC is the cell type associated with the von Hippel Lindau (VHL) gene mutation in hereditary kidney cancer. In fact, approximately 70% of non-hereditary cases of clear cell RCC also have aVHL mutation. Much of today’s research, which is attempting to identify new effective treatments for patients with locally advanced or metastatic disease, is focused on this disease subtype since it is the most common type of RCC. When the tumor has not spread, prognosis is very good following surgical excision. Prognosis for the patient is directly related to both the cancer’s stage (tumor size and rate of growth) and grade (the characteristics of a tumor’s cell structure). Staging and grading are both explained later in this chapter. Patients with metastatic clear cell RCC – or a tumor that has spread to other parts of the body – have a significantly poorer prognosis.
- Papillary RCC: This is the second most common form of kidney cancer, making up approximately 15% of cases. Papillary RCC itself is divided into two subtypes based on cell appearance: Type I (5%) and Type II (10%). There is an increased incidence of papillary RCC in African Americans and an increased incidence of bilateral disease (involving both kidneys) associated with this subtype. There are also hereditary forms of both Type I and Type II papillary RCC. When papillary RCC has not spread, surgical removal is usually associated with an excellent prognosis. However, when papillary RCC metastasizes to other locations in the body, most conventional therapies for RCC, such as immunotherapy are ineffective.
- Chromophobe RCC: This rare form of kidney cancer represents approximately 5% of RCC cases. This type of RCC is thought to originate from the same cell type as those that form renal oncocytomas (see below). Hybrid tumors that contain features of both chromophobe RCC and renal oncocytoma have also been diagnosed. There is a familial or inherited form of chromophobe RCC (in association with renal oncocytoma) called Birt Hogg Dubé syndrome, which is also associated with a specific genetic mutation. Chromophobe RCC rarely metastasizes until very late in its clinical course, and surgical removal of localized or even locally advanced disease is usually associated with an excellent prognosis. Metastatic chromophobe RCC is quite rare, and no standard therapy currently exists.
- Renal Oncocytoma: This is a benign tumor of the kidney that makes up approximately 5% of all kidney tumors. These tumors do not metastasize, although they can grow to a large size in the kidney and invade local structures, which can result in symptoms requiring surgery. They are thought to be related to chromophobe RCC, and it can be quite difficult to differentiate the two. The tumor is treated by a partial or complete removal of the kidney.
- Unclassified RCC: Less than 1% of renal cell carcinomas are an unclassified type and are very rare. They don’t fit into one of the more common subtypes of RCC listed above. When examined under a microscope, these unclassified cancer cells have a structure and genetic features that don’t match the description of the more common RCC subtypes. This category usually includes aggressive tumors that do not respond to traditional therapy for RCC.
- Collecting Duct Carcinoma: This is a rare and very aggressive variant of kidney cancer that represents less than 1% of cases. This form of RCC is usually metastatic at the time of diagnosis, and is more common in younger individuals. Treatment has been directed at using chemotherapy-based regimens, similar to those used in the treatment of transitional cell carcinoma (see below), as these tumors do not respond to traditional RCC therapies such as bioimmunotherapy.
- Medullary RCC: This is also a very rare and aggressive variant of kidney cancer, thought to be a variant of collecting duct carcinoma. It is commonly associated with the sickle cell trait, and therefore is more common in the African-American population. It represents less than one percent of all kidney cancers diagnosed. Chemotherapy remains the main focus of treatment for this disease.
- Sarcomatoid RCC: This condition, known as “differentiation,” can occur with any of the common RCC subtypes. The term refers to the fact that the RCC cells -- when viewed under the microscope -- have the appearance of sarcoma cells. The percentage of sarcomatoid differentiation is usually reflected in the tumor’s pathology report and relates to the tumor’s aggressiveness. The prognosis associated with Sarcomatoid RCC is usually poor. The condition is found frequently in patients whose kidney cancer has metastasized widely. This form of kidney cancer is sometimes treated with chemotherapy.
- Transitional Cell Carcinoma of the Kidney: Transitional cell carcinoma (TCC) of the kidney is a rare and potentially very aggressive tumor that should not be considered a true kidney cancer, but instead should be grouped with those cancers that develop from cells that line the urinary tract. This includes TCC of the urinary bladder, which is far more common than TCC of the kidney. If the cancer has not spread, the tumor can be treated by surgical removal of both the kidney and its ureter, although recurrences of TCC in the bladder are common. When the tumor is large or has metastasized, the prognosis is extremely poor, and treatment options are similar to those for metastatic urinary bladder cancer, which includes chemotherapy.
Detection, Diagnosis and Staging
Because kidney cancer may spread to other parts of your body, it is important to be very thorough in testing for its presence. Your doctor may order some or all of a variety of tests that are available to determine the extent of your cancer and to develop your treatment plan.
Your doctor may use different approaches to diagnose RCC, depending on the symptoms you display. All approaches begin with a careful physical examination, combined with a complete discussion of past and present medical problems.
Certain tests may be done to assist your doctor in determining the correct diagnosis. The most common tests that may be ordered include:
Computed Tomography (CT scan)
A CT scan is a highly specialized x-ray that is used to visualize internal organs and provides a very accurate cross section picture of specific areas of the body. It is used as one of the primary imaging tools for the assessment of RCC. If the initial sign of the tumor is a mass or thickening in the kidney area detected on an x-ray taken for other reasons, or seen or felt from the outside of the body, a CT scan is often ordered.
CT scans are more detailed then ordinary x-rays, taking pictures of your organs one thin slice at a time from different angles. Then a computer puts the images together to show the size and location of any abnormalities. To enhance the image of the abdominal organs, dye may be taken orally (by mouth) before the scan. An IV may also be placed for injection of additional contrast dye. There is generally no pain associated with the CT scan, although the IV dye may cause a hot flushing sensation. Some people may also experience an allergic reaction to IV dye (also called IV contrast), especially individuals who are allergic to iodine. Depending on the part of the body visualized, dietary restrictions may be required prior to the procedure.
CT scanning technology has recently been improved by development of a method called spiral CT scanning. This type of CT scan is faster and gives a better image than older CT methods.
Magnetic resonance imaging (MRI)
An MRI is a highly specialized scan that is similar to a CT scan, but may be better suited for assessing certain areas of the body, such as the bones. It creates an accurate cross-section picture of specific organs within the body, to allow for a layer-by-layer examination. An MRI is usually not a painful procedure. Because it uses a powerful magnet to produce the images, people with metal within their body -- such as prosthetic hip replacements, pacemakers, or metal plates -- should discuss the use of an MRI with their physician and the MRI technician before the scan is performed. The test may require the patient to lie still for a long time usually in a narrow space, which may be difficult for some people who do not like closed in spaces. MRI scans are often used in cases where CT scans may not be able to view an area of the body well enough.
Bone scan
A bone scan is used to check for the spread of cancer to the bones. It is done by injecting small amounts of a special radioactive material through a vein into your bloodstream. This material is carried to the bone, where it collects in areas where there is a lot of bone activity. The test can identify both cancerous and non-cancerous diseases but the test can’t distinguish between cancer and other conditions such as arthritis when used it is used alone. Therefore other tests may be needed, such as x-rays or CT scans.
PET scan (Positron Emission Tomography)
A PET scan is a very specialized diagnostic study that provides information about how extensively a cancer has spread, based on certain activities of the cells. PET scans are typically used for breast, colorectal, ovarian, lymphoma, lung, melanoma, and head & neck cancer. The effectiveness of PET scans for kidney cancer is still being studied.
Unlike CT and MRI scans, which produce images of internal organs or other structures, a PET scan produces images based on the chemical and physiological changes related to a cell’s metabolism. This is important because chemical and physiological changes in the cells often occur before structural changes in tissues can be seen. The result is that PET scans can help distinguish benign from malignant tumors and help doctors determine the stage of cancer spread in the patient. PET scans can also measure whether or not treatment therapies are working. PET scans are quite often used in combination with CT and MRI scans. A PET scan can last from 15 minutes to 2 hours, depending on the area of the body being scanned.
Ultrasonography (ultrasound or US)
If there is blood in the urine, an ultrasound of the abdomen with special attention to the kidneys, ureters, and bladder may be ordered. Usually no preparation is needed for this test, and it is generally not uncomfortable. It utilizes sound waves to produce images of internal organs, helping the radiologist detect any masses that may be present. A wand called a transducer is passed over the skin, and emits sound waves that are detected as echoes bouncing back off internal organs. The echo-pattern images produced by kidney tumors look different from those of normal kidney tissue. This test may be used for initial diagnosis of a kidney mass or to help visualize a mass when a fine needle biopsy is done (see Biopsy Procedure).
Intravenous pyelogram (IVP)
An intravenous pyelogram (IVP) test may also be used. Special dye is injected into a blood vessel, usually in the arm. The dye circulates through the blood stream to the different organs of the body including the kidneys. X-rays are taken of the kidneys as the dye circulates through them. This will identify any abnormalities within the kidney. If either the ultrasound or IVP is abnormal, a CT scan may be ordered.
Chest x-ray
A plain x-ray of the chest may be done to see if the cancer has spread to the lungs. If something is seen on the x-ray, the doctor may order a CT scan of the chest to help determine what it is.
Angiography
This procedure is used to visualize location and function of arteries. A catheter is usually threaded up a large artery in the leg into an artery leading to your kidney (renal artery). A contrast dye is then injected into the artery to outline blood vessels. Angiography can outline the blood vessels that supply a kidney tumor, which can help a surgeon better plan an operation. Angiography may also help diagnose renal cancers since the blood vessels supplying tumors usually look different than the normal blood supply to the kidney.
Biopsy Procedure
If, after diagnostic tests are completed, there is a strong clinical suspicion that the kidney mass is cancerous (malignant), surgical removal of the kidney (nephrectomy) will be performed immediately. If the diagnostic test results are not clear, a biopsy may be performed. During a biopsy procedure a small sample of tissue is removed from the mass and examined to determine whether it is benign or malignant. There are several ways to perform a biopsy of a kidney mass, though the most common method is a procedure called a fine needle aspiration (FNA) or fine needle biopsy. Using ultrasound or a CT scanner for guidance, the doctor will insert a long thin needle through the skin, directly into the mass, and remove the sample tissue. This is generally not an uncomfortable procedure. A pathologist will evaluate the biopsy tissue under a microscope to determine whether it is benign or malignant. If it is malignant, the pathologist also will identify the histology, or cell type.
If there is clear evidence of widespread metastasis at the time of the discovery of the kidney mass, a biopsy may be taken from an area of metastasis, instead of from the kidney. This may be recommended to reduce risk of bleeding, if the metastatic area is more easily accessible than the kidney.
Other Tests
In addition to the tests described above, your doctor may order one or more of the following lab tests to complete your evaluation.
Urinalysis
Urinalysis is usually part of a complete physical exam. Microscopic and chemical tests are performed that will detect small amounts of blood and other substances not seen with the naked eye. About half of all patients with renal cell cancer will have blood in their urine. Microscopic examination of urine samples (called urine cytology) can also detect cancer cells in the urine.
Blood tests
A complete blood count and chemical test of the blood can detect findings associated with RCC. Anemia (too few red blood cells) is very common. Erythrocytosis (too many red blood cells) may also occur because some of these renal cancers produce a hormone (erythropoietin) that can increase red blood cell production by the bone marrow.
High levels of liver function enzymes in the blood (for reasons not known) and hypercalcemia (high calcium levels) sometimes occur.
The Role of Staging and Grading
Staging of a cancer is the process of classifying how far a cancer has spread, while grading determines the characteristics and make up of the cancer’s cells. The two systems play different roles, but both staging and grading are important predictors of the course of the disease and treatment effectiveness (prognosis). They are useful tools in determining what therapy is appropriate and the chance of treatment success.
Staging
Certain imaging tests, including CT and MRI scans, can help determine staging. Blood tests will also be done to evaluate your overall health and to detect whether the cancer has spread to certain organs.
A staging system is a standardized way in which the cancer care team describes the extent of the cancer. The most commonly used staging system was developed by the American Joint Committee on Cancer (AJCC)
American Join Committee on Cancer (AJCC) TNM Staging System
The AJCC staging system is based on the evaluation of the tumor size on the kidney (T), the number of lymph nodes (N) and the extent of metastisis (M). Evaluation of the T, N and M components is followed by a stage grouping.
The T component designates the size of the tumor. The numerical value increases with tumor size and extent of invasiveness. The letter T followed by a number from 0 to 3 describes the tumor's size and spread to nearby tissues. Some of these numbers are further subdivided with letters, such as T1a and T1b. Higher T numbers indicate a larger tumor and/or more extensive spread to tissues near the kidney.
The N component designates the presence or absence of tumor in the regional lymph nodes. In some sites there is an increasing numerical valued based on size, fixation, or capsular invasion. In other sites, numerical value is based on multiple node involvement or number of location and the regional lymph nodes. The letter N followed by a number from 0 to 2 indicates whether the cancer has spread to lymph nodes near the kidney and, if so, how many are affected. Lymph nodes are bean-sized collections of immune system cells that help fight infections and cancers.
The M component identifies the how distant the spread of the cancer has been, including lymph nodes that are not in the region of the original tumor. The letter M followed by a 0 or 1 indicates whether or not the cancer has spread (metastasized) to distant organs such as the lungs or bones, or to lymph nodes that are not near the kidneys.
Detailed Definitions of T, N, and M Categories
Primary tumor (T)
TX: Primary tumor cannot be assessed (information not available).
T0: No evidence of a primary tumor.
T1a: Tumor is 4 cm (about 11/2 inches) in diameter or smaller and is limited to the kidney.
T1b: Tumor is larger than 4 cm but smaller than 7 cm (about 2¾ inches) and is limited to the kidney.
T2: Tumor is larger than 7 cm but is still limited to the kidney.
T3a: Tumor has spread into the adrenal gland or into fatty tissue around the kidney, but not beyond a fibrous tissue called Gerota’s fascia, which surrounds the kidney and nearby fatty tissue.
T3b: Tumor has spread into the large vein leading out of the kidney (renal vein) and/or the part of the large vein leading into the heart (vena cava) that is within the abdomen.
T3c: Tumor has reached the part of the vena cava that is within the chest or invades the wall of the vena cava.
T4: Tumor has spread beyond Gerota’s fascia (fibrous tissue that surrounds the kidney and the fatty tissue next to the kidney).
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed (information not available).
N0: No regional lymph node metastasis.
N1: Metastasis to one regional (nearby) lymph node.
N2: Metastasis to more than one regional (nearby) lymph node. Distant metastasis (M):
Extent of Metastasis (M)
MX: Presence of distant metastasis cannot be assessed (information not available).
M0: No distant metastasis.
M1: Distant metastasis present; includes metastasis to non-regional (not near the kidney) lymph nodes and/or to other organs (such as the lungs, bones, or brain).
Renal Cell Cancer Stage Grouping
Once the T, N, and M categories have been determined, this information is combined in a process called stage grouping to determine a patient’s overall disease stage. This is expressed in Roman numerals from stage I (the least serious or earliest stage) to stage IV (the most serious or advanced stage).
Stage I: T1a-T1b, N0, M0. The tumor is 7 cm or smaller and limited to the kidney. There is no spread to lymph nodes or distant organs.
Stage II: T2, N0, M0. The tumor is larger than 7 cm but is still limited to the kidney. There is no spread to lymph nodes or distant organs.
Stage III: T1a-T3b, N1, M0 or T3a-T3c, N0, M0. Several combinations of T and N categories are included in this stage. These include any tumor that has spread to only one nearby lymph node but not to other organs. Stage III also includes tumors that have not spread to lymph nodes or distant organs but have spread to the adrenal glands, to fatty tissue around the kidney, and/or have grown into the large vein (vena cava) leading from the kidney to the heart.
Stage IV: T4, N0-N1, M0 or Any T, N2, M0 or Any T, Any N, M1. Several combinations of T, N, and M categories are included in this stage, which includes any cancers that have spread directly through the fatty tissue and beyond Gerota’s fascia, the fibrous tissue that surrounds the kidney. Stage IV also includes any cancer that has spread to more than one lymph node near the kidney, or to any lymph node distant from the kidney, or to any distant organs such as the lungs, bone, or brain.
Grading
The system for determining the characteristics of a cancer’s cells is called Fuhrman grading. The Fuhrman grade is determined by a pathologist, who will review the cellular details of your tumor. The grade is based on an examination of how closely the cancer cell’s nucleus (part of a cell in which DNA is stored) resembles a normal kidney cell’s nucleus.
Kidney cancers are usually given a Fuhrman grade on a scale of 1 through 4. Grade 1 kidney cancers have cell nuclei that look very much like a normal kidney cell nucleus. These cancers are usually slow growing and are slow to spread to other parts of the body (metastasize). They tend to have a good outlook (prognosis). Grade 4 kidney cancer, on the upper end of the Fuhrman scale, looks quite different from normal kidney cells and has a worse prognosis. Generally, the higher the Fuhrman grade the worse the prognosis.
