Thursday, March 29, 2012

Kidney cancer

Author: Dr Brent Yanke Urologist West Orange New Jersey 2008-07-28

The kidneys (or renal units) are organs responsible for cleansing the blood of waste.  Many byproducts of the metabolic processes in the body build up in the blood stream.  A microscopic tubular system within the kidney filters the blood and removes these byproducts before they can accumulate to dangerous levels.  Kidney tissue is separated into two layers, the outer cortex and the inner medulla.  Once the filtered waste passes through these layers, it collects in the renal pelvis which is an open space in the core of the kidney.  The urine then drains from the renal pelvis into the ureter and finally into the bladder. Surrounding the kidney are several protective layers.  A thin capsule encircles the renal cortex and comprises the outer surface of the kidney.  The kidney sits in a pocket of fat that is itself contained in another layer of tissue called Gerota’s fascia.
A renal tumor is an atypical growth of cells that can arise from different segments of the kidney.  Benign renal tumors are non-cancerous and rarely threatening to the patient while a malignant renal tumor, also known as renal cancer, has a more aggressive nature.  In 2007, there were an estimated 51,190 new cases of kidney cancer and 12,890 deaths due to kidney cancer in the United States.1 This represents 2% of all diagnosed cancers.2  



WHAT ARE THE DIFFERENT TYPES OF KIDNEY TUMORS?


Metastases from other cancers

            The most common kidney tumors are metastases (spreading of the disease) from primary cancers of other organs in the body.  This is often a late event in a terminally ill patient.   These tumors generally do not cause additional symptoms and do not require additional treatment.    

Benign renal tumors

            Benign renal tumors are far more common than their malignant counterparts.  These include simple cysts, oncocytomas, and angiomyolipomas among others.

The facts about renal cysts
            Renal cysts are thin walled structures filled with fluid that can vary from clear to bloody. They can be found in any region of the kidney and while often only a single cyst is present, there also can be multiple cysts in the same kidney, as well as cysts in both kidneys simultaneously.  Cysts can be diverse in appearance and can range from being benign simple cysts to cystic renal cancers.  The Bosniak classification system separates cysts into four categories and assesses the risk of malignancy for each based on Computerized Tomography (CT) scan imaging.3
Category I – These are simple benign cysts with a thin wall and only fluid inside.  By far, simple cysts are the most common benign renal lesion (another term for tumor or mass) and are twice as common in men as women.4  While growing an average of 2.82 mm a year and increasing in occurrence as we age (affecting 5.1% of the population in their thirties to 36.1% in their seventies), these cysts are never malignant.  They generally do not need treatment or observation.
Category II – While benign, cysts in this category have additional radiologic features.  They may have septations, defined as walls within the cyst, which are thin.  Additional findings may include small amounts of calcium in the wall of the cyst, infected cysts, and cysts with old or clotted blood within them (termed hyperdense cysts).  Risk of malignancy is 0% to 5% and while intermittent surveillance is recommended, surgical treatment is not necessary.
Category III – Cysts are complex in appearance and can have thick, irregular septations or walls with coarse calcium deposits.  Approximately 50% of these lesions are malignant and surgical removal is essential as imaging cannot reliably separate these from the benign Category III lesions.5 
Category IV – These cysts have a mixture of cystic and solid segments. Walls are thickened and highly irregular in appearance and, most importantly, they enhance (light up) when intravenous contrast dye is given to the patient.  They are presumed malignant and require surgical excision.
Oncocytomas
            These benign tumors are difficult to differentiate from malignant renal tumors radiographically.  They are comparable in size and are found at a similar average age as renal cancers.  As a result, these tumors should be treated the same as malignant renal tumors as described below.  When appropriately treated, long term observation is not needed.
Angiomyolipomas
What makes these tumors unique is that they are made up of three different tissue types: adipose (fat), blood vessels, and smooth muscle.  Almost one-third are found in patients suffering from tuberous sclerosis, a syndrome with the hallmark features of epilepsy, mental retardation, and characteristic skin lesions of the face.6  Traditionally, the most concerning presenting symptom was an acute bleed from the tumor.  More than 50% are now found incidentally, without symptoms, due to the widespread use of modern imaging.7  As opposed to most other benign tumors, the presence of fat allows these to be identified by CT scan making the exclusion of renal cancer possible.7  Angiomyolipomas that are asymptomatic and less than 4 cm rarely require treatment and can be observed at regular intervals by imaging studies.8  Larger tumors or patients with symptoms from tumors of any size require treatment, either by surgical removal or angioembolization.  Once treated, follow-up surveillance is required in patients with tuberous sclerosis and in patients with multiple lesions.

Malignant renal tumors 

            Approximately 85% of all primary renal cancers are renal cell carcinomas (RCCs) and most arise from the renal cortex.  Transitional cell carcinomas are tumors arising from the renal pelvis and represent slightly less than 10% of renal cancers.  Other uncommon renal cancers each represent less than 1% of the total. 
            Renal cell cancer incidence has continued to increase over the past 30 years despite the fact that tumor size has decreased.  From 1988 to 2002, average tumor size has decreased from 6.7 cm to 5.9 cm.9 However, from 1975 to 1995 incidence rates increased annually by 2.3% among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women.10  Over that same period, the incidence rates for renal pelvis cancer declined among white men and remained steady among white women and blacks.  As is discussed below under “Diagnosis and workup”, the increased use of radiographic imaging likely factors in these trends.  However, other as to now unknown causes must also play a role.
            Overall mortality rates from renal cancer have also steadily increased over the past 50 years.10,11  However, due to the widespread use of abdominal imaging, there has been a greater percentage of incidental tumors discovered, rising from 10% in the 1970s to 60% in 1998.11  These tend to be smaller and more localized within the kidney with improved five-year survival rates.11
            A majority of RCCs present as a single lesion in one kidney.  Involvement in the other kidney occurs 2% to 4% of the time.  Multiple tumors can be found in the same kidney in approximately 10% to 20% of cases and is more common with the papillary subtype (described further below).12

SUBTYPES OF RENAL CELL CARCINOMA

Clear cell RCC – Also termed conventional RCC, this is the most common subtype compromising 70% to 80% of all RCCs.13  Several genetic mutations have been found to be associated with clear cell cancers.  In comparison to the other RCC types, clear cell has the worst prognosis with approximately 30% of patients dying due to the cancer five years after diagnosis.14,15
Papillary RCC – These tumors, also called chromophilic RCC, are the second most common and account for 10% to 15% of all RCCs.  These cancers tend to be smaller with a better prognosis (over 87% of patients alive after five years).14,15  Often, patients with papillary RCC have multiple tumors present which can occur in one kidney or both at the same time. 
Chromophobe RCC – This subtype constitutes 3% to 5% of RCCs with a favorable prognosis similar to papillary RCC.14,15
Collecting duct (Bellini’s duct) RCC – This rare tumor comprises less than 1% of all RCCs.13 It tends to occur in younger patients and invariably is advanced at presentation with a poor prognosis.16
Renal medullary RCC – Also an extremely rare subtype, it is predominantly found in young African-Americans who carry the sickle cell trait.  These patients customarily present with metastatic disease and rarely live for more than a few months.17

RISK FACTORS FOR KIDNEY CANCER

            The majority of RCCs are diagnosed in patients in their fifties and sixties and are more common in men than in women.11 Incidence is higher in African-Americans than in Caucasians and it has been estimated that approximately 4% to 5% of all RCCs are inherited.10  Several risk factors have been identified for RCC and are listed below.
Tobacco – Smokers have been found to have an almost 1.4 times increase in RCC over non-smokers.18 This increases to double the risk in smokers consuming over a pack a day.  Notably, the increased risks begin to lessen when people quit smoking for over 10 years.
Occupational exposures – Employment in the blast-furnace and iron and steel industry have been found to be significantly associated with RCC.  Exposure to cadmium (two times increased risk), petroleum products (1.6 times increased risk), asbestos (1.4 times increased risk), and dry-cleaning solvents (1.4 times increased risk) were also significant.19
Dialysis and acquired cystic disease of the kidney – Many long-term dialysis patients develop increasing numbers of cysts in both kidneys.  Over time, an up to 50-fold increase in RCC has been found and these cancers tend to occur in significantly younger patients than the general population.20
Obesity – There is a greater risk for RCC as weight increases in both men and women.21
Genetics – There are several hereditary disorders associated with RCC, with the most prominent of them being von Hippel-Lindau disease.  These patients develop a multitude of tumors within different organ systems.22 RCC develops in half of patients and tends to occur at a younger age and in multiple locations. 
Others – High blood pressure, radiation exposure, and previous chemotherapy treatment have also been implicated as possible risk factors. 
Who should be screened for RCC? – Because the primary method of diagnosis of a renal mass involves radiologic imaging, the rather low incidence of RCC limits the cost-effectiveness of screening.  While blood or urine tests would be much cheaper, there is no reliable test in existence that adequately could screen the general population.  There are, however, certain populations that merit screening based on their significantly higher risk of RCC.  These include patients with genetic syndromes such as von Hippel-Lindau disease, tuberous sclerosis, and familial RCC.  In addition, relatively healthy patients on chronic dialysis for over three years could also be candidates for screening.23
 

SIGNS AND SYMPTOMS

            Historically, the classic presentation of renal cancer was one or more of the following symptoms: hematuria (blood in the urine), flank pain, and the presence of a mass felt by pressing the abdomen.  These symptoms generally indicated that the cancer was more advanced and signified a worse prognosis.  With the widespread use of modern imaging, more than half of renal cancers are now found incidentally without any symptoms present.24 Overall, this has led to a greater number of smaller, less invasive tumors being detected.   
Symptoms can be broken down into the following categories:

Symptoms due to an invading tumor:

This occurs when the cancer invades into surrounding structures.
1.      Hematuria – The tumor invades into the renal pelvis and urinary collecting system causing blood to mix with urine.
2.      Flank pain – This can occur from the tumor itself bleeding or from blood clots passing into the ureter and blocking flow of urine from the kidney to the bladder.
3.      Scrotal varicoceles and swelling of the feet and legs – Varicoceles are dilated blood vessels that can be seen in the left scrotum.  This is due to invasion of tumor into the main vein that drains blood from the left kidney, the renal vein, and subsequent blockage of the vein that transports blood from the left testicle and scrotum to the left renal vein.  Invasion of tumor into the main vein that transports blood back to the heart, the vena cava, can cause swelling of the feet and legs as well as damage to the liver.

Symptoms due to metastatic spread of the tumor:

Metastases are tumors that have spread to other locations in the body. 
1.      Bone pain – Pain from tumor that has spread to and invaded the bones.
2.      Symptoms due to spread of tumor to specific organs in the body – Renal cancers that metastasize commonly travel to the lungs, bones, liver, and brain.  An example would be persistent coughing or spitting up blood due to the spread of renal cancer to the lungs.

Symptoms due to paraneoplastic syndromes:

Paraneoplastic syndromes are general symptoms that can affect the whole body – not by direct tumor invasion, but by substances secreted by the tumor cells themselves or by the body’s immune response to the tumor.  There are many different paraneoplastic syndromes associated with RCC with some examples below.
1.      High calcium levels in the blood
2.      Fevers, chills, and night sweats
3.      Weight loss and loss of appetite
4.      Increased or decreased red blood cell counts
5.      Liver damage and failure also called Stauffer’s syndrome
6.      High blood pressure (hypertension)


DIAGNOSIS AND WORKUP

            The majority of renal masses are discovered incidentally by patients undergoing radiologic testing for other reasons.  As mentioned previously, there is no acceptable blood or urine screening test available.  While the presence of blood in the urine necessitates a radiologic workup, it is rare that a renal tumor is found.25 
            CT scan of the abdomen and pelvis, ultrasound of the kidneys, and Magnetic Resonance Imaging (MRI) of the abdomen and pelvis are all radiologic modalities used to diagnose a mass in the kidney (Figure 1,2).  Once a renal mass is identified, it is useful to study the extent of the primary tumor as well as investigate if metastases are present.  CT scan and MRI can measure size of the tumor while also assessing for the presence and extent of invasion into surrounding structures.  As is further described below, RCCs can grow directly into the renal vein that drains blood from the kidney.  This is termed a tumor thrombus and both CT scan and MRI can determine if this has occurred. 

 Figure 1 - MRI of the abdomen - White arrows highlight tumor arising from right kidney
Figure 2 - MRI of the abdomen - White arrows highlight tumor arising from right kidney. Red arrows highlight simple cyst arising from the left kidney.

            The patient should also be evaluated for metastatic spread of the RCC.  A chest x-ray or CT scan of the chest evaluates the lungs, one of the most common places for RCC to spread.  Liver blood tests are performed to assess for spread of RCC to the liver.  A bone scan evaluates spread of cancer to the bones and can be done if bone pain is present.
Should we biopsy a renal mass? – A great majority of renal masses prove to be RCC even those less than 2 cm.26 As a result, surgical treatment is recommended and a biopsy would be an unnecessary added step.  In addition, approximately 5% to 15% of renal biopsies do not detect cancer even when it is indeed present.27,28  Based on the negative biopsy result, these patients might not receive treatment for their cancer.  There are clinical scenarios where a biopsy can be helpful and will alter the treatment options.  Indications for renal biopsy include the presence of metastatic lesions or if the mass is suspected to be from infection and not from cancer.  A metastatic lesion can be from another cancer that has spread to the kidney or from a kidney cancer that has spread to other organs in the body.  In these cases, surgical removal would not be indicated.


RENAL CANCER STAGE AND PROGNOSIS

            Several factors determine prognosis in patients with renal cancer.  The level or extent of invasion, also known as the stage of the tumor, has consistently been found to have significant predictive value in terms of patient survival.  The American Joint Committee on Cancer (AJCC) uses the tumor, nodes, and metastasis (TNM) system in order to stage renal cancers.  This was most recently revised in 2002; the TNM classification is listed in Table 1 and the staging system based on the TNM classification is listed in Table 2.29  T1 and T2 tumors are limited to the kidney while T3 tumors have extended past the kidney into the surrounding fat, the adrenal gland, or the renal vein or vena cava.  Finally, T4 tumors extend beyond Gerota’s fascia and invade into surrounding structures.  While survival from cancer is high with T1 renal cancers, it predictably worsens as stage progresses to T4.  Estimated five-year survival rates are 87% to 97% for T1, 71% for T2, 37% to 53% for T3, and 20% for T4.30 
            As mentioned above, the subtype of renal cancer also plays a significant role.  For example, a chromophobe RCC has a better long-term prognosis than the more aggressive collecting duct RCC.  The grade of the tumor cells, a measure of their irregularity is another important factor in determining survival.  The more abnormal a cell appears when looked at under a microscope, the higher the grade and the lower the survival.  Finally, the presence of symptoms associated with the renal cancer also indicates higher risk and worse survival.
Table 1 – AJCC 2002 TNM Classification
 
  Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor less than 7cm in diameter, limited to the kidney
     T1a Tumor 4 cm or less in greatest dimension, limited to the kidney
     T1b Tumor less than 7 cm but more than 4 cm, limited to the kidney
T2 Tumor more than 7 cm in greatest dimension, limited to the kidney
T3 Tumor extends into major veins or invades the adrenal gland or perinephric tissues (tissues around the kidney), but not beyond Gerota’s fascia
     T3a Tumor directly invades the adrenal gland or perinephric tissues (tissues around the kidney), but not beyond Gerota’s fascia
     T3b Tumor extends into the renal vein or its muscle-containing branches, or vena cava below the diaphragm
     T3c Tumor extends into the vena cava above the diaphragm or invades the wall of the vena cava
T4 Tumor invades beyond Gerota’s fascia


Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastasis in a single regional lymph node
N2 Metastasies in more than one regional lymph node
 
  Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Modified from the AJCC Cancer Staging Manual, Sixth Ed. New York: Springer-Verlag. 2002
  


Table 2 – AJCC Staging Based on 2002 TNM Classification
 
Stage grouping      
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T1 N1 M0
  T2 N1 M0
  T3a N0 M0
  T3a N1 M0
  T3b N0 M0
  T3b N1 M0
  T3c N0 M0
  T3c N1 M0
Stage IV T4 N0 M0
  T4 N1 M0
  Any T N2 M0
  Any T Any N M1
                               From the AJCC Cancer Staging Manual, Sixth Ed. New York:  Springer-Verlag. 2002

TREATMENT OPTIONS


Surgical Treatment

            The mainstay of treatment for potentially curable renal cancers (stages I, II, and III) is surgical resection (removal of part or the entire kidney).  Radical nephrectomy refers to the removal of the entire kidney along with Gerota’s fascia and the fat contained within, while partial nephrectomy, also known as nephron sparing surgery, refers to removal of only the portion of the kidney containing the tumor. 
Open versus laparoscopic radical nephrectomy
            Traditionally, open radical nephrectomy was the approach used to remove renal tumors.  Indications for radical nephrectomy include the following: tumor size over 4 cm, invasion into structures surrounding the kidney, extension into the renal vein or vena cava, and location in the center of the kidney.  Laparoscopic nephrectomy is carried out through small incisions in the abdomen.  A telescope attached to a video camera provides visualization within the abdominal cavity while narrow instruments are used to perform the resection of the kidney.  The first laparoscopic nephrectomy was performed 15 years ago and it has now become the principal technique for radical nephrectomy.  Multiple studies have shown that laparoscopic nephrectomy has long-term success rates comparable to its open counterpart.31,32  In addition, there is reduced blood loss, shorter hospital stays, less post-operative pain, and shorter recovery times.  Open nephrectomy should still be reserved for patients with tumors invading into the renal vein or lymph nodes as well as those that have had previous abdominal surgery and scarring around the kidney. 
Open versus laparoscopic partial nephrectomy
            Partial nephrectomy allows for resection of the tumor while preserving the surrounding normal tissue.  Patients undergoing radical nephrectomy have a higher rate of chronic kidney disease development when compared to those undergoing partial nephrectomy.33  Indications for partial nephrectomy include patients with tumor and only one kidney, those with tumors in both kidneys, the presence of tumors less than 4 cm, and patients with reduced kidney function.  Partial nephrectomy can also be performed laparoscopically and has been shown to have equivalent short-term success when compared to open partial nephrectomy.34  Currently, it should be reserved for those with small tumors located in regions of the kidney that make them easier to remove.    
Ablative techniques
            Ablative techniques treat the tumor without surgically removing it.  These less invasive procedures permit preservation of the surrounding normal renal tissue without the additional risk of surgical excision.  Examples of ablation include cryosurgery which destroys tumor by freezing it and radiofrequency ablation which utilizes heat energy.  Although early results have been encouraging, there is no long-term data regarding these techniques and, therefore, they should currently be limited to patients too unhealthy to undergo traditional surgery.
Immunotherapy  
            This approach is reserved for patients with advanced and metastatic renal cancer not amenable to surgical treatment alone.  Interleukin-2 injection stimulates the body’s immune system and enhances its ability to fight the cancer.  Response rates to high dose IL-2 have been seen in 10% to 15% of patients with many remaining alive at five years.35  High dose IL-2 therapy does have significant side effects and is reserved for patients in relative good health who can tolerate them. 
            Immunotherapy can be combined with nephrectomy for improved survival in select patients.  Patients with good response to initial IL-2 treatment may undergo subsequent nephrectomy to remove residual tumor.  Likewise, nephrectomy followed by IL-2 can be performed in those that can tolerate initial surgery.
Tyrosine kinase inhibitors
            These relatively new therapies prevent renal tumors from growing new blood vessels.  Tumors secrete a substance called vascular endothelial growth factor (VEGF) that promotes new blood vessel growth, allowing the tumors to continue to spread.  By blocking this pathway, tyrosine kinase inhibitors (sorafenib and sunitinib) have been found to prolong life by several months in patients with metastatic renal cancer.
Chemotherapy and Radiation
            Renal tumors remain resistant to both chemotherapy and radiation and, therefore, neither has a role in the primary treatment of renal cancer.  Radiation applied to metastatic sites such as bones and the brain has been used to treat conditions such as bone pain and seizures.

SURVEILLANCE

            After treatment for localized renal cancer, lifelong surveillance is mandatory.  Renal cancer has been found to recur over a decade after presumed successful surgical resection.  While specific recommendations for long-term follow-up vary, general guidelines can be suggested.  Patients with tumors of low stage should undergo history and physical examination, chest x-ray, and laboratory studies such as liver function tests and creatinine every six to twelve months.  Many recommend that a CT scan of the abdomen and pelvis be performed at least once after treatment, usually at six months to two years after surgery.  Patients with higher stage disease should have this testing performed at more frequent intervals.

ADDITIONAL RESOURCES

National Cancer Institute – www.cancer.gov
American Urological Association – www.urologyhealth.org
American Cancer Society – www.cancer.org
National Kidney Foundation – www.kidney.org
National Institutes of Health – www.nih.gov
National Institute of Diabetes and Digestive and Kidney Diseases – www.niddk.nih.gov


REFERENCES

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