Soft Tissue Sarcomas
Introduction:
l Rare: only 8300 new cases annually in
l 3900 die annually from STS
l Mesodermal origin
Location and Type:
Etiology:
l h/o Radiation therapy increases grade of tumors and risk for metastasis
l Chemical exposure
l Thorotrast, vinyl chloride, arsenic for hepatic angiosarcoma
l Genetic syndromes
l Neurofibromatosis – nerve sheath tumors
l Familial gastrointestinal stromal tumor syndrome – KIT mutation
l Skin hyperpigmentation, uticaria, cutaneous mast cell dx
Classification:
l Soft tissue and bone
l viscera (gastrointestinal, genitourinary, and gynecologic organs)
l nonvisceral soft tissues (muscle, tendon, adipose, pleura, and connective tissue)
l By differentiation (usually with IHC staining)
l adipocytic tumors
l fibroblastic/myofibroblastic tumors
l fibrohistiocytic tumors
l smooth muscle tumors
l pericytic (perivascular) tumors
l primitive neuroectodermal tumors (PNETs)
l skeletal muscle tumors
l vascular tumors
l osseous tumors
l tumors of uncertain differentiation
Biopsy:
l Most present as painless mass leading to delayed diagnosis as lipoma or hematoma
l Core needle biopsy guided by palpation or by image guidance if not palpable
l Few cases of tumor seeding with closed biopsy so some recommend tattooing site for later excision with specimen
l Excisional biopsy for superficial small lesions if needle biopsy non-diagnostic
l Incision biopsy
l Longitudinal incision without tissue flaps with meticulous hemostasis to prevent tumor seeding in hematomas
l Send biopsy fresh and orientated
Tumor seeding after biopsy
Imaging:
l MRI
l For extremity masses
l Gives good delineation between muscle, tumor and blood vessels
l CT for abdominal and retroperitoneal
l PET
l May help determine high vs. low grade
l May be helpful in recurrences
Staging:
l AJCC/UICC Staging System for Soft Tissue Sarcomas
l T1: <5cm
– T1a: superficial to muscular fascia
– T1b: Deep to muscular fascia
l T2: >5cm
– T2a: superficial to muscular fascia
– T2b: Deep to muscular fascia
l N1: Regional nodal involvement
l Grading
– G1: Well-differentiated
– G2: Moderately differentiated
– G3: Poorly differentiated
– G4: Undifferentiated
|
Stage IA |
G1,2 |
T1a,b |
N0 |
M0 |
|
Stage IB |
G2,2 |
T2a,b |
N0 |
M0 |
|
Stage IIA |
G3,4 |
T1a,b |
N0 |
M0 |
|
Stage IIB |
G3,4 |
T2a |
N0 |
M0 |
|
Stage III |
G3,4 |
T2b |
N0 |
M0 |
|
Stage IV |
Any G |
Any T |
N1 |
M1 |
Survival:
Relative risk for recurrence and survival:
l Age >50 years 1.6
l Local recurrence at presentation 2.0
l Microscopically positive margin 1.8
l Size 5.0–10.0 cm 1.9
l Size >
l High-grade 4.3
l Deep location 2.5
l Local recurrence 1.5
Surgery:
l Limb-sparing vs amputation
l Comparison study with post-op radiation in limb sparing showed no difference in survival
l Amputation still may be indicated for neurovascular or bone involvement
Resection:
l Arbitrary
l Negative margins may be adequate for post-op radiation therapy
l Presence of positive margins increases local recurrence by 10-15%
l No need for lymph node dissection as only 2-3% have nodal metastasis
Adjuvant radiotherapy:
l Small, low grade tumors resected with
l Improves local control but not survival
l Whether improved local control leads to improved survival is controversial
Local recurrence with post-op brachytherapy:
Pre-op or post-op radiation?
l Some avoid pre-op use because of increased wound complications (although this is debatable)
l RCT looking at wound complication rate pre-op vs post-op radiation showed 35% vs 17%
l Risk confined to lower extremity
l Conclusions: pre-op may be better for upper extremity and head & neck because of equal wound complication risk and benefit of lower radiation doses to more vital tissues
Pre-op vs post-op radiotherapy:
Chemotherapy:
l Can improve local control, but not survival
l Doxorubicin and ibosfamide have response rates of 20%
l Use only in advanced disease
l Combination with radiation or neoadjuvant therapy are controversial
l Hypothermic isolated limb perfusion may be used for palliation
Treatment of Recurrence:
l 20-30% of STS patients will recur
l More common in retroperitoneal and head & neck high grade tumors because hard to get clear margins
l 38% for retroperitoneal
l 42% for head and neck
l 5-25% for extremity
l After re-resection recurrence is 32% for extremity and much higher for visceral
Metastatic disease:
l Lung most common site of mets, but visceral often go to liver
l Median survival from development of metastatic disease is 8-12 months
l Resection of pulmonary mets can give 5 year survival of 32% if all mets can be removed
l >3 mets is poor prognosticator
Case 1:
l 64 y/o male with increasing abdominal girth
Retroperitoneal Sarcomas:
l 15% of all sarcomas
l Liposarcoma 42% and leiomyosarcoma 26%
l CT scan can show cystic/solid/necrotic components and relation to surroundings
l CXR to r/o mets, chest CT if CXR abnormal
l Biopsy not necessary unless suspect a lymphoma or germ cell tumor or plan preop chemo or radiation
l En bloc resection is standard treatment
l bowel prep
l assess bilateral kidney function
l 50-80% need organ resection
l 78% of primary lesions can be completely resected
l
Survival after resection of primary retroperitoneal sarcoma:
Prognosis for retroperitoneal sarcomas:
l 5 year survival after complete resection of 54-65%
l Drops to 10-36% if incompletely resected
l Recurrence occurs in 46-59% of completely resected tumors
Radiation or chemotherapy for retroperitoneal sarcomas:
l Radiation
– GI and neurotoxicities limit delivery of sufficient doses
– May improve local control
– Recommended for use only in clinical trials given lack of data either way
l Chemotherapy
– Use for recurrent, unresectable or metastatic disease
Case 2:
49 y/o female with GERD undergoing EGD
GIST:
l Separate subtype of sarcoma defined by expression of c-Kit (CD117)
l Surgery: complete resection without local or regional lymphadenectomy
l Very resistant to traditional chemotherapy
l Gleevec (imantinib mesylate)
l c-Kit is constitutively active tyrosine kinase receptor
l Drug is tyrosine kinase inhibitor used in CML
l Initial studies showed 54% response rates
l Two RCTs currently looking at adjuvant treatment
GIST
Extremity sarcomas
MFH
Synovial sarcoma
Breast Sarcoma:
l 1% of all breast neoplasms
l Wide excision with negative margins
l No clear role for adjuvant radiotherapy
Sarcoma after mastectomy
Vascular sarcomas:
l Angiosarcoma, hemangiosarcoma, lymphangiosarcoma, hemangiopericytoma
l Key points:
l Hepatic angiosarcoma – thorotrast, vinyl chloride, arsenic
l Stewart Treve’s – lymphangiosarcoma in chronic lymphedema
l High risk for bleeding during excision
l No clear role for chemo or radiation
Bone Sarcomas
The second group of sarcoma is bone sarcomas or bone cancer. There are three types of bone sarcoma: osteosarcoma; Ewing’s sarcoma; and chondrosarcoma. Bone sarcomas very rare with approximately 2,890 new cases diagnosed in the United States each year, and approximately 1,410 deaths. The incidence is slightly higher in males than females and no race has a higher incidence than another, although, Ewings sarcoma is more among Americans of European descent. Bone sarcomas are very likely to be diagnosed in children; and due to the rarity and severity of bone cancer, a bone cancer specialist such as a pediatric oncologist or an orthopedic oncologist should be consulted in the treatment of the disease.
Bones consist of three types of tissue: compact tissue (the hard outer portion of the bone), cancellous tissue (spongy tissue inside the bone containing the bone marrow), and subchondral tissue (the smooth bone tissue of the joints). Cartilage surrounds the subchondral tissue to form a cushion around the joints.
Bone tumors can be benign (non-cancerous) or malignant (cancerous). Benign bone tumors are rarely life threatening and do not spread within the body; however, they can grow and compress healthy bone tissue. Cancer that develops in the bone is called primary bone cancer. It is differentiated by secondary bone cancer which spreads to the bone from another part of the body. Primary bone cancer is rare with approximately 2,500 new cases diagnosed each year in the United States (this figure includes bone cancer which is not sarcoma).
The most common type of primary bone cancer is osteosarcoma. Because it occurs in growing bones, it is most often found in children. Another type of primary bone cancer is chondrosarcoma which is found in the cartilage. This cancer occurs more often in adults. Ewing’s sarcoma can occur as either a bone sarcoma or a soft tissue sarcoma depending upon the original location in the tumor.
Scientists are uncertain what causes bone cancer however they have been able to identify some factors which may put a person at risk. Children and young adults who have had undergone radiation therapy or chemotherapy for other diseases are at increased risk for bone cancer. Additionally, adults with Paget’s disease which is a disease characterized by abnormal growth of new bone cells have an increased risk of osteosarcoma. There are also some hereditary conditions which can increase the risk of bone cancer.
Symptoms of bone cancer can vary depending on the size and location of the tumor. Pain is the most common symptom. Tumors arising in or around the joints often cause swelling and tenderness. Tumors can also weaken the bones thus causing fractures. Some other symptoms can be weight loss, fatigue and or anemia.
The first step in diagnosing primary bone cancer is a complete medical history and physical examination performed by a physician. The doctor may order a blood test to determine the level of an enzyme called alkaline phosphatase. Approximately 55% of patients with primary bone cancer will have elevated levels of alkaline phosphatase. However, it isn’t a completely reliable indicator for bone cancer since growing bones in children will cause the enzyme to be elevated.
X-rays are also used to locate a tumor. If an x-ray suggests a tumor is present than a doctor may require further testing such as a CT scan, Magnetic Resonance Imaging (MRI), or an angiogram. Finally, a biopsy must be performed to determine if cancer is present. A biopsy is a procedure used to remove sample tissue from the tumor. A surgeon, usually an orthopedic oncologist, performs the procedure using a needle or making an incision. During a needle biopsy the surgeon makes a small hole in the bone and removes sample tissue with a small instrument. During an incisional biopsy, the surgeon cuts into the tumor and removes sample tissue. A Pathologist (a doctor specializing in identifying disease) then studies the cells and tissues under a microscope to determine whether the tumor is cancerous.
The treatment of bone cancer depends on the size, location, type and stage of the cancer. Chemotherapy with surgery is often the primary treatment. While amputation of a limb is sometimes necessary, using chemotherapy either before or after surgery has allowed physicians to save the limb and improve survival in many cases. Radiation may be used in Ewing’s sarcoma is surgery is not feasible or in certain select cases of metastatic disease.
New and more effective treatments are being developed in clinical trials at many hospitals and cancer centers in the United States.
Ewing’s Sarcoma
Ewing’s sarcoma is actually several types of sarcomas known as the Ewings Family of Tumors. In the U.S., there are approximately 250 cases diagnosed a year, generally in children and young adults under the age of 30. It can be found in any bone, but is most common in the bones of the lower body such as the pelvis, tibia (shin), fibula (shin), and femur (thigh). Ewing’s sarcoma is often associated with a chromosomal translocation between genes EWS and FLI1 on chromosomes 22 and 11. Although Ewings is classified as a bone cancer, the type of cells it originates in is not completely known, which is why as mentioned above, occasionally Ewing’s sarcoma may occur in soft tissues, Peripheral Primitive Neuroectodermal Tumor (peripheral PNET) is a rare tumor that has the same translocation, and is now considered to be identical to Ewings. The Ewings Family of Tumors (EFT) includes Ewing’s sarcoma of bone, extraosseous Ewings, and peripheral PNET. It is not known what causes the tumor, although it is more likely to occur in people of European descent. It is an aggressive cancer and is treated with a combination of surgery, radiation, and chemotherapy, with a good outcome for many cases.
Chondrosarcoma
Chondrosarcoma is a cancer that develops from the cells that produce cartilage. A little less than one-third of bone sarcomas are chondrosarcomas. While the disease can affect people of any age, unlike most other forms of skeletal system cancer, it is more common among older people than among children. Also unlike the other bone cancers chondrosarcoma is more often found in the spine and pelvis than in legs or arms. Surgery is the most common treatment for chondrosarcoma, sometimes with radiation or chemotherapy as well.
Osteosarcoma (Osteogenic Sarcoma). Osteosarcoma is a malignant (cancerous) bone tumor that occurs predominantly in adolescents and young adults. It accounts for approximately 5% of the tumors in childhood. the bones most frequently involved are the large bones of the upper arm (humerus) and the leg (femur and tibia). In children and adolescents, 80% of these tumors arise from the bones around the knee. It is slightly more common in males than females. It is the most common primary malignant bone tumor with the exception of myeloma. Although osteosarcoma is a common malignant bone tumor, it is still rare with less than 1,000 new cases each year in the United States. Due to its rarity, it is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the management of this disease. This evaluation should be done prior to the initial biopsy, since an inappropriately performed biopsy may jeopardize a limb-sparing procedure.
Osteosarcoma occurs in adolescents at the time they are most rapidly growing in their most rapidly growing bones; therefore, it is suspected that rapid bone growth may play a role in the development of osteosarcoma. Additionally, some evidence suggests that chronic bone injury can increase the risk for osteosarcoma. When osteosarcoma occurs in adults over age 40 it is usually associated with a pre-existing condition such as Paget’s disease.
The initial symptoms include pain, often in and around the knee, especially in tumors on the tibia or femur. The pain typically worsens over time and is not related to the time of day. Swelling and tenderness typically occur late in the course of osteogenic sarcoma, followed by a large soft tissue mass appearing. A screening of serum alkaline phosphatase levels may be done. These levels are high in approximately 45-50% of patients with osteosarcoma; therefore it cannot be used alone to diagnose the disease.
Osteosarcoma must be diagnosed by biopsy. Because the disease commonly spreads (metastasizes) to other parts of the body, especially the lungs, chest x-rays, lung tomograms, CT scans of the chest , and an x-ray skeletal survey or bone scan may be done before treatment. This process is called staging. There are three groups used to describe the extent of the disease: Localized – the cancer cells have not spread beyond the bone or nearby tissue. Metastatic – the cancer cells have spread from the bone where the cancer began to other parts of the body (commonly the lungs, however it can spread to other bone). Recurrent – the cancer has come back after it has been treated. It may come back to the original site of the tumor or another part of the body.
Surgery is the primary method of treatment. This can be either an amputation or limb-sparing procedure. A limb-sparing procedure is when a surgeon removes the tumor and a block of surrounding tissues to ensure clean (cancer free) margins around the tumor. The surgeon then reconstructs the limb using prosthetic devices, bone grafts or other reconstructive techniques. These procedures are highly specialized and are usually performed by an orthopedic oncologist. In general 70-90% of osteosarcomas of the limb can be treated by a limb-sparing procedure and do not require amputation; therefore, before undergoing an amputation, it is recommended that the patient seek the advice of an orthopedic oncologist.
Surgery is usually followed by a course of chemotherapy using one or more anti-cancer drugs. Some clinical trials have shown that adjuvant chemotherapy ( chemotherapy given wheo clear evidence of cancer can be found i.e. after the tumor is removed) may be helpful in preventing the relapse or recurrence of the disease. Other trials suggest that there is no difference in outcome between pre-operative chemotherapy or adjuvant chemotherapy.
Parosteal osteosarcoma. Parosteal osteosarcoma is a low grade tumor that arises on the surface of the bone. It rarely penetrates the center of the bone and rarely becomes a highly malignant osteosarcoma. It accounts for approximately 4% of all osteosarcomas and is slightly more common in females than males. It is different than classic osteosarcoma in that it typically arises in adults between the ages of 20 and 40. It has a better prognosis than classic osteosarcoma with an overall survival rate of 75% to 85%. It has a very slow rate of metastases (spreading).
Parosteal osteosarcoma is most commonly found on the femur, behind the knee (72% of all cases). It usually presents itself with minimal pain and tenderness and in its typical location behind the knee there may be some restriction in movement of the knee joint.
Surgery with wide margins is the standard treatment for parosteal osteosarcoma, either by amputation or limb-sparing surgery. Because they are located at the end of the bone, are typically low grade, and lack local invasiveness, they are often amenable to limb-sparing procedures. Grade III parosteal lesions usually require chemotherapy because of the risk of metastases.
Periosteal osteosarcoma. Like parosteal osteosarcoma, periosteal osteosarcoma is an uncommon tumor arising on the surface of the bone, most commonly the tibia. It is a high grade tumor composed of malignant cartilage. It occurs in a younger age group and is even more common among females than males than parosteal osteosarcoma. Because periosteal osteosarcoma is more likely to metastasize than the parosteal, some oncologists treat this tumor more aggressively with combination therapy such as surgery and chemotherapy.
Multifocal Sclerosing osteosarcoma. Multifocal sclerosing osteosarcoma is an extremely rare form of osteosarcoma. It tends to occur in children less than 10 years old and represents less than 3% of all primary osteosarcomas. It is an aggressive tumor which presents as a single painful tumor, much like other types of osteosarcoma. However further tests looking for metastases reveal tumor in virtually all of the skeleton.
Since all the bones of the body are involved surgery is usually not an option, except to relieve pain. Aggressive chemotherapy can lead to a remission; however, multiple tumors eventually progress and mortality approaches 100%.
Osteosarcoma of the Jaw and Skull. Osteosarcoma of the craniofacial bones are relatively rare and represent less than 10% of all osteosarcomas. They typically occur in patients between the ages of 20 and 40 and have the same occurrence rate between males and females. The bones most commonly affected are the mandible (jaw bone) and the maxilla (cheek bone). Because they are located in the head and neck, they tend to be diagnosed earlier and can remain localized for longer periods of time; however, they are more difficult to remove surgically and therefore local recurrence is common.
Treatment of malignant osteosarcoma in the skull bones is similar of classic osteosarcoma. It should include preoperative chemotherapy. This is extremely important due to the limited margins available for surgical excision.
Osteosarcoma in Paget’s Disease. Paget’s disease affects approximately 3% of the population over the age of 60. It is characterized by abnormal growth of new bone cells leading to multiple bone deformities. Approximately 1% of patients with Paget’s disease develop primary bone sarcoma. The tumors usually arise in the pelvis, femur, or humerus. They typically are large and very destructive making surgery difficult. At the time of diagnosis, the cancer has often metastasized to the lungs. Amputation is sometimes necessary.
Patients with suspected osteosarcoma arising in Paget’s disease should receive a bone scan and x-ray of all identified tumors. Additionally, a CT scan of the chest should be done to rule out metastases to the lungs. Treatment is the same as fully malignant osteosarcoma arising in a younger population. Patients with preoperative chemotherapy, radical surgery of the tumor, followed by post-operative chemotherapy have the best prognosis. Tumors arising in the skull and spine are sometimes inoperable. In this instance patients are typically given chemotherapy and radiation therapy to control and shrink the tumor. Great care must be taken during chemotherapy treatments since many older patients have impaired kidney function.
Post-irradiation Osteosarcoma (Radiation Induced). Radiation Induced Osteosarcoma is a rare form of osteosarcoma which occurs in people who have undergone radiation therapy treatments for other diseases. The average length of time before these tumors appear is 10 years following radiation. The younger the patient is at the time of radiation, the higher the risk of osteosarcoma. Additionally, evidence suggest that patients who receive higher doses of radiation are at a higher risk of developing osteosarcoma than patients who receive lower doses of radiation.
Post-irradiation osteosarcomas are most commonly located in the spine, pelvis, hips and shoulders. People with retinoblastoma, a malignant tumor of the eye, are at a higher risk of developing post-irradiation osteosarcoma due to a defect in the RB gene.
Symptoms of postirradiation osteosarcoma are painful swelling in and around the area of radiation. A biopsy must be performed in order to diagnose the disease. Once the diagnosis is made, staging of the tumor is done using bone scan, CT scan or MRI. Additionally a CT scan of the lungs should be done to rule out metastases to the lungs.
The treatment of postirradaition sarcoma is similar to classic osteosarcoma. It usually included preoperative chemotherapy, surgery and followed by postoperative chemotherapy. Surgery can be difficult when tumors are in and around the spine and therefore preoperative chemotherapy to shrink the tumor is crucial. Due to this challenge, the prognosis for postirradiation osteosarcoma is worse than that for classic osteosarcoma.
CANCERS OF THE GENITOURINARY SYSTEM
KIDNEY CANCER
Signs and symptoms of kidney cancer
Unfortunately, early kidney cancers do not usually cause any signs or symptoms, but larger ones might. Some possible signs and symptoms of kidney cancer include: blood in the urine (hematuria); low back pain on one side (not caused by injury); mass (lump) on the side or lower back; Fatigue (tiredness); Weight loss not caused by dieting; Fever that is not caused by an infection and that doesn’t go away after a few weeks; Anemia (low red blood cell counts.
These symptoms may be caused by cancer, but more often they are caused by other, benign, diseases. For example, blood in the urine can be a sign of kidney, bladder, or prostate cancer, but most often it is caused by a bladder infection or a kidney stone. Still, if you have any of these symptoms, consult a doctor so that the cause can be evaluated and treated, if needed.
Medical history and physical exam.
If symptoms and/or the results of the physical exam suggest kidney cancer might be present, more tests will probably be done. These might include imaging tests and/or lab tests.
Lab tests. Lab tests cannot be used to diagnose kidney cancer, but they can sometimes give the first hint that there may be a kidney problem. They are also done to get a sense of a person’s overall health and to help tell if cancer may have spread to other areas. They also can help show if a person is healthy enough to have an operation.
Urinalysis. Urinalysis (urine testing) is sometimes part of a complete physical exam, but it may not be done as a part of more routine physicals. This test may be done if your doctor suspects a kidney problem.
Microscopic and chemical tests are done on a urine sample to look for 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. If the patient has an urothelial carcinoma (in the renal pelvis, the bladder, or other parts of the urinary tract), sometimes special microscopic examination of urine samples (called urine cytology) will show actual cancer cells in the urine.
Complete blood count. The complete blood count (CBC) is a test that measures the different cells in the blood, such as red blood cells, white blood cells, and platelets. This test result is often abnormal in people with renal cell cancer. Anemia (having too few red blood cells) is very common. Less often, a person may have too many red blood cells (called polycythemia) because the kidney cancer makes a hormone (erythropoietin) that causes the bone marrow to make more red blood cells. Blood counts are also important to make sure a person is healthy enough for surgery.
Blood chemistry tests
Blood chemistry tests are usually done in people who might have kidney cancer, because the cancer can affect the levels of certain chemicals in the blood. For example, high levels of liver enzymes are sometimes found. High blood calcium levels may indicate that cancer has spread to the bones, and may therefore prompt a doctor to order a bone scan. Blood chemistry tests also look at kidney function, which is especially important if certain imaging tests are planned.
Imaging tests
Imaging tests use x-rays, magnetic fields, or radioactive substances to create pictures of the inside of your body. Imaging tests are done for a number of reasons, including to help find out whether a suspicious area might be cancerous, to learn how far cancer may have spread, and to help determine if treatment has been effective.
Unlike most other cancers, doctors can often diagnose a kidney cancer fairly certainly without a biopsy (removal of a sample of the tumor to be looked at under a microscope). Often, imaging tests can give doctors a reasonable amount of certainty that a kidney mass is (or is not) cancerous. In some patients, however, a biopsy may be needed to be sure.
Computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, and ultrasound can be very helpful in diagnosing most kinds of kidney tumors, although patients rarely need all of these tests. Other tests described here, such as chest x-rays and bone scans, are more often used to help determine if the cancer has spread (metastasized) to other parts of the body.
Computed tomography (CT) scan
The computed tomography (CT or CAT) scan is an x-ray that produces detailed cross-sectional images of your body. Instead of taking one picture, like a regular x-ray, a CT scanner takes many pictures as it rotates around you while you lie on a table. A computer then combines these pictures into images of slices of the part of your body being studied.
scanner has been described as a large donut, with a narrow table in the middle opening. You will need to lie still on the table while the scan is being done. CT scans will take longer than regular x-rays and you might feel a bit confined by the ring while the pictures are being taken.
Before any pictures are taken, you may be asked to drink 1 to 2 pints of a liquid called oral contrast. This helps outline the intestine so that certain areas are not mistaken for tumors. You may also receive an IV (intravenous) line through which a different kind of contrast dye (IV contrast) is injected. This helps better outline structures in your body.
The injection may cause some flushing (a feeling of warmth, especially in the face). Some people are allergic and get hives. Rarely, more serious reactions like trouble breathing or low blood pressure can occur. Be sure to tell the doctor if you have ever had a reaction to any contrast material used for x-rays.
CT contrast can damage the kidneys. This happens more often in patients whose kidneys are not working well in the first place. Because of this, your kidney function will be checked with a blood test before you get IV contrast.
CT scanning is one of the most useful tests for finding and looking at a tumor inside your kidney. It is also useful in checking to see if a cancer has spread to organs and tissues beyond the kidney. The CT scan will provide precise information about the size, shape, and position of a tumor, and can help find enlarged lymph nodes that might contain cancer.
Magnetic resonance imaging (MRI) scan
Like CT scans, magnetic resonance imaging (MRI) scans provide detailed images of soft tissues in the body. But MRI scans use radio waves and strong magnets instead of x-rays. The energy from the radio waves is absorbed and then released in a pattern formed by the type of body tissue and by certain diseases. A computer translates the pattern into a very detailed image of parts of the body. A contrast material called gadolinium is often injected into a vein before the scan to better see details. This contrast material isn’t used in people on dialysis, because in those people it can rarely cause a severe side effect called nephrogenic systemic fibrosis.
MRI scans are a little more uncomfortable than CT scans. First, they take longer − often up to an hour. Second, you have to lie inside a narrow tube, which is confining and can upset people with claustrophobia (a fear of enclosed spaces). Special, open MRI machines can sometimes help with this if needed, but the drawback is that the pictures may not be as clear. MRI machines also make buzzing and clicking noises that many people find disturbing. Some centers provide headphones with music to block this noise out.
MRI scans are used less often than CT scans in people with kidney cancer. They may be done in cases where CT scans aren’t practical, such as if a person can’t have the CT contrast dye, such as when they have an allergy to it or they don’t have good kidney function. MRI scans may also be done if there’s a chance that the cancer has grown into major blood vessels in the abdomen (like the inferior vena cava), because they provide a better picture of blood vessels than CT scans. Finally, they may be used to look for possible spread of cancer to the brain or spinal cord if a person has symptoms that suggest this might be the case.
Ultrasound or ultrasonography
Ultrasound uses sound waves to create images of internal organs. For this test, a small, microphone-like instrument called a transducer is placed on the skiear the kidney after a gel is applied. The transducer gives off sound waves and picks up the echoes as they bounce off the tissues in the kidney. The echoes are converted by a computer into a black and white image that is displayed on a computer screen. This test is painless and does not expose you to radiation.
Ultrasound can help determine if a kidney mass is solid or filled with fluid. The echo patterns produced by most kidney tumors look different from those of normal kidney tissue. Different echo patterns also can distinguish some types of benign and malignant kidney tumors from one another. If a kidney biopsy is needed, this test can be used to guide a biopsy needle into the mass to obtain a sample.
Positron emission tomography (PET) scan
In a positron emission tomography (PET) scan, a form of radioactive sugar (known as fluorodeoxyglucose or FDG) is injected into the blood. The amount of radioactivity used is very low. Because cancers use glucose (sugar) at a higher rate thaormal tissues, the radioactivity will tend to concentrate in the cancer. A scanner can spot the radioactive deposits and can create a picture of areas of radioactivity in the body. The picture is not finely detailed like a CT or MRI scan, but it provides helpful information about your body.
This test can be helpful for spotting small collections of cancer cells and can be useful in seeing if the cancer has spread to lymph nodes near the kidney. PET scans can also be useful if your doctor thinks the cancer may have spread but doesn’t know where. PET scans can be used instead of several different x-rays because they scan your whole body.
Special machines can perform both a PET and CT scan at the same time (PET/CT scan). This lets the radiologist compare areas of higher radioactivity (suggesting an area of cancer) on the PET with the appearance of that area on the CT. Still, PET and PET/CT scans are not a standard part of the work-up for kidney cancers.
Intravenous pyelogram
An intravenous pyelogram (IVP) is an x-ray of the urinary system taken after a special dye is injected into a vein. The kidneys remove the dye from the bloodstream and it then concentrates in the ureters and bladder. An IVP can be useful in finding abnormalities of the renal pelvis and ureter, such as cancer, but this test is not often used when kidney cancer is suspected.
Angiography
This type of x-ray also uses a contrast dye, although not the same as the one used for an IVP. A catheter is usually threaded up a large artery in your leg into the artery leading to your kidney (renal artery). The dye is then injected into the artery to identify and map the blood vessels that supply a kidney tumor. This can help in planning surgery for some patients. Angiography can also help diagnose renal cancers since the blood vessels usually have a special appearance with this test. Angiography can be done as a part of the CT or MRI scan, instead of as a separate test. This means less contrast dye is used, which is helpful since the dye can damage kidney function further if it is given to people whose kidneys don’t work as well as they should.
Chest x-ray
If kidney cancer has been diagnosed (or is suspected), your chest may be x-rayed to see if cancer has metastasized (spread) to your lungs. Spread to the lungs is not very likely unless the cancer is far advanced. This x-ray can be done in any outpatient setting. If the results are normal, you probably don’t have cancer in your lungs. The lungs are a common site of kidney cancer metastasis. Still, if your doctor has reason to suspect lung metastasis (based on symptoms like shortness of breath or a cough), you may have a chest CT scan instead of a regular chest x-ray.
Bone scan
A bone scan can help show whether a cancer has metastasized (spread) to your bones. For this test, a small amount of low-level radioactive material is injected into a vein (intravenously, or IV). The substance settles in areas of damaged bone throughout the entire skeleton in a couple of hours. You then lie on a table for about 30 minutes while a special camera detects the radioactivity and creates a picture of your skeleton.
Areas of active bone changes appear as “hot spots” on your skeleton − that is, they attract the radioactivity. These areas might suggest the presence of cancer spread, but arthritis or other bone diseases can also cause the same pattern. To distinguish between these conditions, your cancer care team may use other imaging tests such as simple x-rays or MRI scans to get a better look at the areas that light up, or they may even take biopsy samples of the bone.
Bone scans are done mainly when there is reason to think the cancer may have spread to the bones (like when the patient is having bone pain or blood test results show an increased calcium level). PET scans can usually show the spread of cancer to bones as well, so if you’ve had a PET scan you might not need a bone scan.
Fine needle aspiration and needle core biopsy
Biopsies are not often used to diagnose kidney tumors. Imaging studies usually provide enough information for a surgeon to decide if an operation is needed. However, a biopsy is sometimes used to get a small sample of cells from an area that may be cancer when the results of imaging tests are not definite enough to warrant removing a kidney. Biopsy may also be done to confirm a cancer diagnosis if a person may not be treated with surgery, such as with small tumors that will be watched and not treated, or when other treatments are being considered (this is discussed in more detail in the section, “How is kidney cancer treated?”).
Fine needle aspiration (FNA) and needle core biopsy are 2 types of kidney biopsies that may be done. For these types of biopsies a needle is put through the skin to take a sample of cells (called percutaneous biopsy).
For either type of biopsy, the skin where the needle is to be inserted is first numbed with local anesthesia. The doctor directs the biopsy needle into the area while looking at your kidney with either ultrasound or CT scans. Unlike ultrasound, CT doesn’t provide a continuous picture, so the needle is inserted in the direction of the mass, a CT image is taken, and the direction of the needle is guided based on the image. This is repeated a few times until the needle is within the mass.
For FNA, a small sample of the target area is sucked (aspirated) through the needle into a syringe. The needle used for FNA biopsy is thinner than the ones used for routine blood tests. The needle used in core biopsies is larger than that used in FNA biopsy. It removes a small cylinder of tissue (about 1/16- to 1/8-inch in diameter and ½-inch long). Either type of sample is checked under the microscope to see if cancer cells are present.
In cases where the doctors think kidney cancer may have spread to other sites, they may take a sample of the metastatic site instead of the kidney.
Fuhrman grade
The Fuhrman grade is found by looking at kidney cancer cells (taken during a biopsy or during surgery) under a microscope. Many doctors use it to describe how aggressive the cancer is likely to be. The grade is based on how closely the cancer cells’ nuclei (part of a cell in which DNA is stored) look like those of normal kidney cells.
Renal cell cancers are usually graded on a scale of 1 through 4. Grade 1 renal cell cancers have cell nuclei that differ very little from normal kidney cell nuclei. These cancers usually grow and spread slowly and tend to have a good prognosis (outcome). At the other extreme, grade 4 renal cell cancer nuclei look quite different from normal kidney cell nuclei and have a worse prognosis.
Although the cell type and grade are sometimes helpful in predicting a prognosis (outlook), the cancer’s stage is by far the best predictor of survival. The stage describes the cancer’s size and how far it has spread beyond the kidney. Staging is explained in the section, “How is kidney cancer staged?“
Stage of kidney cancer
There are actually 2 types of staging for kidney cancer. The clinical stage is your doctor’s best estimate of the extent of your disease, based on the results of the physical exam, lab tests, and any imaging studies you have had. If you have surgery, your doctors can also determine the pathologic stage, which is based on the same factors as the clinical stage, plus what is found during surgery and examination of the removed tissue. This means that if you have surgery, the stage of your cancer might actually change afterward (if cancer were found to have spread further than was suspected, for example). Pathologic staging is likely to be more accurate than clinical staging, because it allows your doctor to get a firsthand impression of the extent of your disease.
AJCC (TNM) staging system
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 is that of the American Joint Committee on Cancer (AJCC), sometimes also known as the TNM system. The TNM system:
T categories for kidney cancer
TX: The primary tumor cannot be assessed (informatioot available).
T0: No evidence of a primary tumor.
T1: The tumor is only in the kidney and is 7 cm (a little less than 3 inches) or less across
· T1a: The tumor is 4 cm (about 1 1/2inches) across or smaller and is only in the kidney.
· T1b: The tumor is larger than 4 cm but not larger than 7 cm across and is only in the kidney.
T2: The tumor is larger than 7 cm across but is still only in the kidney.
· T2a: The tumor is more than 7 cm but not more than 10 cm (about 4 inches) across and is only in the kidney
· T2b: The tumor is more than 10 cm across and is only in the kidney
T3: The tumor is growing into a major vein or into tissue around the kidney, but it is not growing into the adrenal gland (on top of the kidney) or beyond Gerota’s fascia (the fibrous layer that surrounds the kidney and nearby fatty tissue).
· T3a: The tumor is growing into the main vein leading out of the kidney (renal vein) or into fatty tissue around the kidney
· T3b: The tumor is growing into the part of the large vein leading into the heart (vena cava) that is within the abdomen.
· T3c: The tumor has grown into the part of the vena cava that is within the chest or it is growing into the wall of that blood vessel (the vena cava).
T4: The tumor has spread beyond Gerota’s fascia (fibrous layer that surrounds the kidney and nearby fatty tissue). The tumor may have grown into the adrenal gland (on top of the kidney).
N categories for kidney cancer
NX: Regional (nearby) lymph nodes cannot be assessed (informatioot available).
N0: No spread to nearby lymph nodes.
N1: Tumor has spread to nearby lymph nodes.
M categories for kidney cancer
M0: There is no spread to distant lymph nodes or other organs.
M1: Distant metastasis is present; includes spread to distant lymph nodes and/or to other organs. Kidney cancer most often spreads to the lungs, bones, liver, or brain.
Stage grouping
Once the T, N, and M categories have been assigned, this information is combined to assign an overall stage of I, II, III, or IV. The stages identify cancers that have a similar prognosis and thus are treated in a similar way. Patients with lower stage numbers tend to have a better prognosis.
Stage I: T1, N0, M0
The tumor is 7 cm across or smaller and is only in the kidney (T1). There is no spread to lymph nodes (N0) or distant organs (M0).
Stage II: T2, N0, M0
The tumor is larger than 7 cm across but is still only in the kidney (T2). There is no spread to lymph nodes (N0) or distant organs (M0).
Stage III: Either of the following:
T3, N0, M0: The tumor is growing into a major vein (like the renal vein or the vena cava) or into tissue around the kidney, but it is not growing into the adrenal gland or beyond Gerota’s fascia (T3). There is no spread to lymph nodes (N0) or distant organs (M0).
T1 to T3, N1, M0: The main tumor can be any size and may be outside the kidney, but it has not spread beyond Gerota’s fascia. The cancer has spread to nearby lymph nodes (N1) but has not spread to distant lymph nodes or other organs (M0).
Stage IV: Either of the following:
T4, any N, M0: The main tumor is growing beyond Gerota’s fascia and may be growing into the adrenal gland on top of the kidney (T4). It may or may not have spread to nearby lymph nodes (any N). It has not spread to distant lymph nodes or other organs (M0).
Any T, Any N, M1: The main tumor can be any size and may have grown outside the kidney (any T). It may or may not have spread to nearby lymph nodes (any N). It has spread to distant lymph nodes and/or other organs (M1).
Other staging and prognostic systems
The TNM staging system is useful, but some doctors have pointed out that there are factors other than the extent of the cancer that should be considered when determining prognosis and treatment.
This is a more complex system that came out in 2001. It was meant to improve upon the AJCC staging that was then in place. Along with the stage of the cancer, it takes into account a person’s overall health and the Fuhrman grade of the tumor. These factors are combined to divide people into low-, intermediate-, and high-risk groups. In 2002, researchers at UCLA published a study evaluating their system, looking at survival rates of the low-, intermediate- and high-risk groups. For patients with localized kidney cancer (cancer not spread to distant organs) they found 5-year survival rates of 91% for low-risk groups, 80% for intermediate groups, and 55% for high-risk groups.
Survival predictors
Stage of disease is a predictor of survival. Researchers have linked certain factors with shorter survival times in people with kidney cancer that has spread outside the kidney. These include:
· High blood lactate dehydrogenase (LDH) level
· High blood calcium level
· Anemia (low red blood cell count)
· Cancer spread to 2 or more distant sites
· Less than a year from diagnosis to the need for systemic treatment (targeted therapy, immunotherapy, or chemotherapy)
· Poor performance status (a measure of how well a person can do normal daily activities)
People with none of the above factors are considered to have a good prognosis; 1 or 2 factors are considered intermediate prognosis, and 3 or more of these factors are considered to have a poor prognosis (outlook) and may be more or less likely to benefit from certain treatments.
Survival rates for kidney cancer by TNM stage
Survival rates are often used by doctors as a standard way of discussing a person’s prognosis (outlook). Some patients with cancer may want to know the survival statistics for people in similar situations, while others may not find the numbers helpful, or may eveot want to know them. If you decide that you don’t want to know them, stop reading here and skip to the next section.
The 5-year survival rate refers to the percentage of patients who live at least 5 years after their cancer is diagnosed. Of course, many people live much longer than 5 years (and many are cured). Also, some people die from causes other than their cancer.
In order to get 5-year survival rates, doctors have to look at people who were treated at least 5 years ago. Improvements in treatment since then may result in a more favorable outlook for people now being diagnosed with kidney cancer.
Survival rates are often based on previous outcomes of large numbers of people who had the disease, but they cannot predict what will happen in any particular person’s case. Many other factors may affect a person’s outlook, such as the grade of the cancer, the treatment received, and the patient’s age and overall health. Your doctor can tell you how the numbers below may apply to you, as he or she is familiar with your situation.
The numbers below come from the National Cancer Data Base and are based on patients first diagnosed in the years 2001 and 2002. These are observed survival rates. They include people diagnosed with kidney cancer who may have later died from other causes, such as heart disease. People with kidney cancer tend to be older and may have other serious health conditions. Therefore, the percentage of people surviving the cancer itself is likely to be higher.
|
Stage |
5-Year Survival Rate |
|
I |
81% |
|
II |
74% |
|
III |
53% |
|
IV |
8% |
How is kidney cancer treated?
This information represents the views of the doctors and nurses serving on the American Cancer Society’s Cancer Information Database Editorial Board. These views are based on their interpretation of studies published in medical journals, as well as their own professional experience.
The treatment information in this document is not official policy of the Society and is not intended as medical advice to replace the expertise and judgment of your cancer care team. It is intended to help you and your family make informed decisions, together with your doctor.
Your doctor may have reasons for suggesting a treatment plan different from these general treatment options. Don’t hesitate to ask him or her questions about your treatment options.
The first part of this section describes the various types of treatments used for kidney cancer. This is followed by a description of the most common approaches used for these cancers based on the stage of the cancer.
Making treatment decisions
After the cancer is found and staged, your cancer care team will discuss your treatment options with you. It is important to take time and think about your possible choices. In choosing a treatment plan, one of the most important factors is the stage of the cancer. Other factors to consider include your overall health, the likely side effects of the treatment, and the probability of curing the disease, extending life, or relieving symptoms.
If you have kidney cancer, your treatment options may include:
· Surgery
· Ablation and other local therapies
· Immunotherapy (biologic therapy)
These treatments might also be used together, depending on the factors mentioned. In considering your treatment options it is often a good idea to seek a second opinion, if possible. This may provide you with more information and help you feel more confident about the treatment plan you have chosen.
Surgery for kidney cancer
Surgery is the main treatment for most renal cell carcinomas. The chances of surviving a renal cell cancer without having surgery are small. Even patients whose disease has spread to other organs may benefit from surgery to take out the kidney tumor. Depending on the stage and location of the cancer and other factors, surgery may be used to remove either the cancer along with some of the surrounding kidney tissue, or the entire kidney. The adrenal gland (the small gland that sits on top of each kidney) and fatty tissue around the kidney may be removed as well.
Radical nephrectomy
In this operation, the surgeon removes your whole kidney, the attached adrenal gland, and the fatty tissue around the kidney. (Most people do just fine with only the one remaining kidney.)
The surgeon can make the incision in several places. The most common sites are the middle of the abdomen (belly), under the ribs on the same side as the cancer, or even in the back, just behind the cancerous kidney. Each approach has its advantages in treating cancers of different sizes and in different locations in the kidney. Although removing the adrenal gland is a part of a standard radical nephrectomy, the surgeon may be able to leave it behind in some cases where the cancer is in the lower part of the kidney and is far away from the adrenal gland.
If the tumor has grown from the kidney through the renal vein (the large vein leading away from the kidney) and into the inferior vena cava (a large vein that empties into the heart), the heart may need to be stopped for a short time in order to remove the tumor. The patient is put on cardiopulmonary bypass (a heart-lung machine) that circulates the blood while bypassing the heart. If you need this, a heart surgeon will work with your urologist during your operation.
Laparoscopic nephrectomy: This approach to radical nephrectomy has quickly become a preferred method for removing kidney tumors.
The operation is done through several small incisions instead of one large one. Special long instruments are inserted through the incisions, each of which is about 1/2-inch long, to perform the operation. One of the instruments, the laparoscope, is a long tube with a small video camera on the end. This allows the surgeon to see inside the abdomen. Usually, one of the incisions has to be made longer in order to remove the kidney (although it’s not as long as the incision for a standard nephrectomy).
This approach can be used to treat most renal tumors that cannot be treated with nephron-sparing surgery (see below). In experienced hands, the technique is as effective as open radical nephrectomy and usually means a shorter hospital stay, a faster recovery, and less pain after surgery. This may not be an option for large tumors (those larger than10 cm [4 inches]) and tumors that have grown into the renal vein or spread to lymph nodes around the kidney.
Partial nephrectomy (nephron-sparing surgery)
In this procedure, the surgeon removes only the part of the kidney containing cancer, leaving the rest of the organ behind. As with a radical nephrectomy, the surgeon can make the incision in several places, depending on factors like the location of the tumor.
At first, this approach was only used when there was a reasoot to remove the entire kidney. This included people with cancer in both kidneys, those who only had one kidney and developed cancer in that kidney, and people who already had reduced kidney function for some other reason. It was also used in people who were likely to develop cancer in the other kidney in the future, such as those with von Hippel-Lindau disease and other hereditary forms of kidney cancer.
This type of surgery is now the preferred treatment for patients with early stage kidney cancer. It is often done to remove single small tumors (those less than 4 cm across), and can be done in patients with larger tumors (up to 7 cm across). Studies have shown the long-term results to be about the same as those when the whole kidney is removed. The obvious benefit is that the patient keeps more of their kidney function. A partial nephrectomy may not be an option if the tumor is in the middle of the kidney or is very large, if there is more than one tumor in the same kidney, or if the cancer has spread to the lymph nodes or distant organs. Not all doctors are able to do this type of surgery. It should only be done by someone with a lot of experience doing this procedure.
Some doctors can even do this procedure laparoscopically or using a robot. But again, this is a difficult operation, and it should only be done by a surgeon with a great deal of experience in this procedure.
Regional lymphadenectomy (lymph node dissection)
This procedure removes nearby lymph nodes to see if they contain cancer. Some doctors do this along with the radical nephrectomy, although not all doctors agree that it is always necessary. Most doctors agree that the lymph nodes should be removed if they are enlarged based on imaging tests or how they look during the operation. Some doctors also remove these lymph nodes to check them for cancer spread even when they aren’t enlarged, in order to better stage the cancer. Before surgery, ask your doctor if he or she plans to remove the lymph nodes near the kidney.
Removal of an adrenal gland (adrenalectomy)
Although this is a standard part of a radical nephrectomy, the adrenal gland does not have to be removed in every case. If the cancer is in the lower part of the kidney (away from the adrenal gland) and imaging tests show the adrenal gland is not affected, it may not have to be removed. Again, similar to lymph node removal, this is decided on an individual basis and should be discussed with the doctor before surgery.
Removal of metastases
About 1 in 4 patients with renal cell carcinoma will already have metastatic spread of their cancer when they are diagnosed. The lungs, bones, brain and liver are the most common sites of spread. In some patients, surgery may still be helpful.
Attempts at curative surgery: In rare cases where there is only a single metastasis or if there are only a few that can be removed easily without causing serious side effects, surgery may lead to long-term survival in some people. The metastasis may be removed at the same time as a radical nephrectomy or at a later time if the cancer recurs (comes back).
Surgery to relieve symptoms (palliative surgery): When other treatments aren’t helpful, surgically removing the metastases can sometimes relieve pain and other symptoms, although this usually does not help patients live longer.
Also, removing the kidney containing the cancer can help patients live longer even when the cancer has already spread to distant sites. This is why a doctor may suggest a radical nephrectomy even if the patient’s cancer has spread beyond the kidney. Kidney removal can also be used to ease symptoms such as pain and bleeding.
Risks of surgery
Risks of surgery include:
· Bleeding during surgery or after surgery that may require blood transfusions
· Wound infection
· Damage to internal organs and blood vessels (such as the spleen, pancreas, aorta, vena cava, large or small bowel) during surgery
· Pneumothorax (unwanted air in the chest cavity)
· Incisional hernia (bulging of internal organs near the surgical incision due to problems with wound healing)
· Kidney failure (if the remaining kidney fails to function well)
Ablation and other local therapy for kidney cancer
Whenever possible, surgery is the main treatment for kidney cancers that can be removed. But for people who are too sick to have surgery, other approaches can sometimes be used to destroy kidney tumors. They might be helpful for some people, but there is much less data on how well they work over the long run than there is for surgery, and so they are not yet considered a standard treatment.
Cryotherapy (cryoablation)
This approach uses extreme cold to destroy the tumor. A hollow probe (needle) is inserted into the tumor either through the skin (percutaneously) or during laparoscopy (laparoscopy was discussed in the “Surgery for kidney cancer” section). Very cold gases are passed through the probe, creating an ice ball that destroys the tumor. To be sure the tumor is destroyed without too much damage to nearby tissues, the doctor carefully watches images of the tumor during the procedure (with ultrasound) or measures tissue temperature.
The type of anesthesia used for cryotherapy depends on how the procedure is being done. Possible side effects include bleeding and damage to the kidneys or other nearby organs.
Radiofrequency ablation
This technique uses high-energy radio waves to heat the tumor. A thin, needle-like probe is placed through the skin and advanced until the end is in the tumor. Placement of the probe is guided by ultrasound or CT scans. Once it is in place, an electric current is passed through the probe, which heats the tumor and destroys the cancer cells.
Radiofrequency ablation is usually done as an outpatient procedure, using local anesthesia (numbing medicine) where the probe is inserted. You may be given medicine to help you relax as well. Major complications are uncommon, but they can include bleeding and damage to the kidneys or other nearby organs.
Arterial embolization
This technique is used to block the artery that feeds the kidney with the tumor. A small catheter (tube) is placed in an artery in the inner thigh and is moved up until it reaches the artery going from the aorta to the kidney (renal artery). Material is then injected into the artery to block it, cutting off the kidney’s blood supply. This will cause the kidney (and the tumor in it) to die. Although this procedure is not used very often, it is sometimes done before nephrectomy to reduce bleeding during the operation or in patients who have persistent bleeding from the kidney tumor.
Radiation therapy for kidney cancer
Radiation therapy uses high-energy radiation to kill cancer cells. External beam therapy focuses radiation from outside the body on the cancer. It is like getting an x-ray, but the radiation is much more intense. The procedure itself is painless.
Kidney cancers are not very sensitive to radiation. Radiation therapy can be used to treat kidney cancer if a person’s general health is too poor for them to have surgery. For patients who can have surgery, using radiation therapy before or after removing the cancer is not routinely recommended because studies have not shown that this helps people live longer.
Radiation therapy is more often used to palliate, or ease, symptoms of kidney cancer such as pain, bleeding, or problems caused by cancer spread (especially to the bones or brain).
A special type of radiation therapy known as stereotactic radiosurgery can sometimes be used for single tumors that have spread to the brain. This procedure does not actually involve surgery. There are 2 main techniques for stereotactic radiosurgery, but they all use the same principle of pinpoint radiation. In one technique, several beams of high-dose radiation are focused on the tumor from different angles over a few minutes to hours. The second technique uses a movable linear accelerator that is controlled by a computer (a linear accelerator is a machine that produces x-ray beams). Instead of delivering many beams at once, the linear accelerator moves around to deliver radiation to the tumor from different angles. In either approach, the patient’s head is kept in the same position by placing it in a rigid frame. This type of treatment can also be used for areas of cancer spread outside of the brain. When it is used to treat cancer elsewhere, it is called stereotactic body radiotherapy.
Side effects of radiation therapy may include mild skin changes (similar to sunburn), hair loss, nausea, diarrhea, or tiredness. Often these go away after a short while. Radiation may also make side effects from some other treatments worse. Radiation therapy to the chest area can damage the lungs and lead to shortness of breath. Side effects of radiation to the brain usually become most serious 1 or 2 years after treatment and can include headaches and trouble thinking.
Chemotherapy for kidney cancer
Chemotherapy (chemo) uses anti-cancer drugs that are given into a vein or by mouth (in pill form). These drugs enter your bloodstream and reach all areas of the body, which makes this treatment potentially useful for cancer that has spread (metastasized) to organs beyond the kidney.
Unfortunately, kidney cancer cells are usually resistant to chemo, and so chemo is not a standard treatment for kidney cancer. Some chemo drugs, such as vinblastine, floxuridine, 5-fluorouracil (5-FU), capecitabine, and gemcitabine have been shown to help a small number of patients. Still, chemo is often only used for kidney cancer after targeted drugs and/or immunotherapy have already been tried.
Possible side effects of chemotherapy
Chemo drugs work by attacking cells that are dividing quickly, which is why they often work against cancer cells. But other cells in the body, such as those in the bone marrow, the lining of the mouth and intestines, and the hair follicles, also divide quickly. These cells are also likely to be affected by chemo, which can lead to certain side effects.
The side effects of chemo depend on the type of drugs, the amount taken, and the length of treatment. Possible side effects can include:
· Hair loss
· Mouth sores
· Loss of appetite
· Nausea and vomiting
· Low blood counts
Chemo can affect the blood cell producing bone marrow, leading to low blood counts. This can cause:
· Increased chance of infections (due to low white blood cell counts)
· Easy bruising or bleeding (due to low blood platelet counts)
· Fatigue (due to low red blood cell counts)
These side effects usually go away after treatment is finished. There are often ways to prevent or lessen them. For example, drugs can be given to help prevent or reduce nausea and vomiting. Specific chemo drugs may each cause specific side effects. Ask your health care team about the side effects your chemo drugs may cause.
Targeted therapies for kidney cancer
As researchers have learned more about the molecular and genetic changes in cells that cause cancer, they have been able to develop newer drugs that specifically target some of these changes. These targeted drugs work differently from standard chemotherapy drugs and have different side effects. Targeted drugs are proving to be especially important in diseases such as kidney cancer, where chemotherapy has not been shown to be very effective.
The term targeted therapy may not be the most accurate way to describe these newer drugs, as even traditional chemotherapy targets certain cellular functions. However, this is the term commonly used for newer agents that have a more focused mechanism of action
Several targeted drugs have been approved by the US Food and Drug Administration for use against advanced kidney cancer. These include drugs that stop angiogenesis (growth of the new blood vessels that nourish cancers) and drugs that target other important cell growth factors. These drugs are often used as the first line of treatment against advanced kidney cancers. While they may shrink or slow the growth of the cancer, it doesn’t seem that any of these drugs can actually cure kidney cancer.
Doctors are still learning the best ways to use these targeted drugs against advanced kidney cancers. As of now, they are most often used one at a time. If one doesn’t work, another may be tried. It’s not yet known if any one of these drugs is clearly better than the others, if combining them might be more helpful than giving them one at a time, or if one sequence is better than the other. Studies are being done to help answer these questions.
Sorafenib (Nexavar®)
This drug has been shown to slow the progression of the cancer in some patients with advanced disease. It acts by blocking both angiogenesis and growth-stimulating molecules in the cancer cell. Sorafenib does this by blocking several important cellular enzymes called tyrosine kinases that are important for cell growth and survival. It is taken as a pill. The most common side effects seen with this drug include fatigue, rash, diarrhea, increases in blood pressure, and redness, pain, swelling, or blisters on the palms of the hands or soles of the feet (hand-foot syndrome).
Sunitinib (Sutent®)
Sunitinib also blocks several tyrosine kinases, but not the same ones as sorafenib. This drug is a pill that has been shown to shrink or slow the progression of kidney cancer in many cases. It attacks both blood vessel growth and other targets that stimulate cancer cell growth. The most common side effects are nausea, diarrhea, changes in skin or hair color, mouth sores, weakness, and low white and red blood cell counts. Other possible effects include tiredness, high blood pressure, congestive heart failure, bleeding, hand-foot syndrome, and low thyroid hormone levels.
Temsirolimus (Torisel®)
Temsirolimus is given as an intravenous (IV) infusion. It works by blocking a cell protein known as mTOR, which normally promotes cell growth and division. This drug has been shown to be helpful against advanced kidney cancers that have a poorer prognosis because of certain factors. The most common side effects of this drug include skin rash, weakness, mouth sores, nausea, loss of appetite, fluid buildup in the face or legs, and increases in blood sugar and cholesterol levels. Rarely, more serious side effects have been reported.
Everolimus (Afinitor®)
This drug also blocks the mTOR protein. It is taken as a pill once a day. Everolimus is used to treat advanced kidney cancers after other drugs such as sorafenib or sunitinib have been tried. Common side effects of this drug include mouth sores, an increased risk of infections, nausea, loss of appetite, diarrhea, skin rash, feeling tired or weak, fluid buildup (usually in the legs), and increases in blood sugar and cholesterol levels. A less common but serious side effect is lung damage, which can cause shortness of breath or other problems.
Bevacizumab (Avastin®)
This is an IV drug that works by slowing the growth of new blood vessels. Recent studies have shown it may be helpful against kidney cancer, especially when used with interferon-alpha. Bevacizumab is usually tolerated well by patients, but it can cause serious side effects such as increases in blood pressure, bleeding or blood clotting problems, and wound healing problems.
Pazopanib (Votrient®)
Pazopanib is another drug that blocks several tyrosine kinases. These kinases are involved in cancer cell growth and the formation of new blood vessels. It is taken as a pill once a day. Common side effects include high blood pressure, nausea, diarrhea, headaches, low blood cell counts, and liver problems. In some patients this drug causes lab test results of liver function to become abnormal, but it also rarely leads to severe liver damage that can be life threatening. As with bevacizumab, problems with bleeding, clotting, and wound healing can occur, as well. It also rarely causes a problem with the heart rhythm or even a heart attack. If you are taking this drug, your doctor will monitor your heart with EKGs as well as check your blood tests to check for liver or other problems.
Axitinib (Inlyta®)
This drug also inhibits several tyrosine kinases, including some that are involved in the formation of new blood vessels. It is taken as a pill twice a day. Common side effects include high blood pressure, fatigue, nausea and vomiting, diarrhea, poor appetite and weight loss, voice changes, hand-foot syndrome, and constipation. In studies, high blood pressure requiring treatment was fairly common, but in a few patients it got so high that it was life-threatening. As with bevacizumab, there may be problems with bleeding, clotting, and wound healing. In some patients, lab test results of liver function can become abnormal. Axitinib may also cause the thyroid gland to become underactive, so your doctor will watch your blood levels of thyroid hormone while you are on this drug.
Biologic therapy (immunotherapy) for kidney cancer
The goal of biologic therapy is to boost the body’s immune system to fight off or destroy cancer cells more effectively. The main immunotherapy drugs used in kidney cancer are cytokines (proteins that activate the immune system). In the past, the cytokines used most often were interleukin-2 (IL-2) and interferon-alpha. Both cytokines cause these cancers to shrink to less than half their original size in about 10% to 20% of patients.
At one point, IL-2 was the most common first-line therapy for advanced kidney cancer, and it may still be helpful for some people. But because it can be hard to give and can cause serious side effects, many doctors now only use it for cancers that aren’t responding to targeted therapies.
Patients who respond to IL-2 tend to have lasting responses. IL-2 is the only therapy that appears to result in long-lasting responses, although only a small percentage of patients respond. A cancer has certain characteristics that may help predict if IL-2 will be helpful, and more studies are being done to see which characteristics are most helpful.
Interferon has less serious side effects than IL-2, and may be used by itself or used at a lower dose combined with the targeted drug bevacizumab (Avastin). Common side effects of interferon include flu-like symptoms (fever, chills, muscle aches), fatigue, and nausea.
Combining low doses of both cytokines was once thought to be as effective as high-dose IL-2, with fewer and less severe side effects, but more recent studies have not supported this idea. Most doctors think that high-dose IL-2 has a better chance of shrinking the cancer. High dose IL-2 is only given in certain centers, because it can be very toxic and special care is needed to recognize and treat side effects.
The possible side effects of high-dose IL-2, include:
· Extreme fatigue
· Low blood pressure
· Fluid buildup in the lungs
· Trouble breathing
· Kidney damage
· Heart attacks
· Intestinal bleeding
· Diarrhea or abdominal pain
· High fever and chills
· Rapid heart beat
· Mental changes
These side effects are often severe and, rarely, can be fatal. For this reason, cytokine therapy is not used in people who are in poor overall health to begin with. Only doctors experienced in the use of these cytokines should give this treatment.
Cytokines can also be used as part of some experimental immunotherapy techniques. One approach took special immune system cells called tumor-infiltrating lymphocytes (TILs) that can be found within kidney tumors. These cells were taken from the tumor after surgery. These immune cells were then exposed to cytokines in the lab and then given back to the patient. The hope was that they would attack the cancer cells with fewer side effects than just giving cytokines, but the outcomes were disappointing.
Treatment choices by stage for kidney cancer
The type of treatment(s) your doctor recommends will depend on the stage of the cancer and on your overall health. This section summarizes options usually considered for each stage of kidney cancer.
Stages I, II, or III
These cancers are usually removed with surgery when possible. Partial or radical nephrectomy may be done, with partial nephrectomy often the treatment of choice in tumors up to 7 cm (a little less than 3 inches in size). If the lymph nodes around the kidneys are enlarged, they may be removed as well. If the cancer has grown into nearby veins (as with some stage III cancers), the surgeon may need to cut open these veins to remove all of the cancer. This may require putting the patient on bypass (a heart-lung machine), so that the heart can be stopped for a short time to remove the cancer from the large vein leading to the heart.
Other than as part of a clinical trial, additional treatments (known as adjuvant therapy) are usually not given after surgery that has removed all of the cancer. So far, treatments such as targeted therapy, chemotherapy, radiation therapy, or immunotherapy have not been shown to help patients live longer if all of the cancer has been removed. There are, however, ongoing clinical trials that are looking at adjuvant treatment for kidney cancer. Ask your doctor for more information about adjuvant clinical trials.
If you cannot have kidney surgery because of other serious medical problems, you may benefit from other local treatments such as cryotherapy, radiofrequency ablation, radiation therapy, or arterial embolization. These treatments are generally only given when surgery can’t be done. Although they haven’t been directly compared to surgery in studies, most doctors consider these treatments to be less effective than surgery.
Active surveillance is another option for small tumors. For this, the tumor is watched (with CTs or ultrasounds) and only treated if it grows.
Stage IV
Stage IV kidney cancer means that the cancer has grown from the kidney to spread beyond Gerota’s fascia (fibrous layer that surrounds the kidney and nearby fatty tissue) and it may have grown into the adrenal gland (on top of the kidney). It can also mean that the cancer has spread outside the kidney to other organs.
Treatment of stage IV kidney cancer depends on how extensive the cancer is and on the person’s general health. In some cases, surgery may still be a part of treatment.
In rare cases where the main tumor appears to be removable and the cancer has only spread to one other area (such as to one or a few spots in the lungs), surgery to remove both the kidney and the metastasis may be an option if a person is in good enough health. Otherwise, treatment with one of the targeted therapies would probably be the first option.
If the main tumor is removable but the cancer has spread extensively elsewhere, removing the kidney may still be helpful. This would likely be followed by systemic therapy, which might consist of one of the targeted therapies or cytokine therapy (interleukin-2 or interferon). More often targeted therapy is used first. It’s not clear if any one of the targeted therapies or any particular sequence is better than another, although temsirolimus appears to be most useful in people with kidney cancers that have a poorer prognosis (outlook).
For cancers that can’t be removed surgically (because of the extent of the tumor or a person’s health), first-line treatment is likely to be one of the targeted therapies or cytokine therapy.
Because advanced kidney cancer is very hard to cure, clinical trials of new combinations of targeted therapies, immunotherapy, or other new treatments are also options.
For some patients, palliative treatments such as embolization or radiation therapy may be the best option. A special form of radiation therapy called stereotactic radiosurgery can be very effective in treating single brain metastases. Surgery or radiation therapy can also be used to help reduce pain or other symptoms of metastases in some other places, such as the bones.
Having your pain controlled can help you maintain your quality of life. It is important to realize that medicines to relieve pain do not interfere with your other treatments and that controlling pain will often help you be more active and continue your daily activities.
Recurrent cancer
Cancer is called recurrent when it come backs after treatment. Recurrence can be local (in or near the same place it started) or distant (spread to organs such as the lungs or bone). Treatment of kidney cancer that comes back (recurs) after initial treatment depends on where it recurs and what treatments have been used, as well as a person’s health and wishes for further treatment.
For cancers that recur after initial surgery, further surgery might be an option. Otherwise, treatment with targeted therapies or immunotherapy will probably be recommended. Clinical trials of new treatments are an option as well.
For cancers that progress (continue to grow or spread) during treatment with targeted therapy or cytokine therapy, another type of targeted therapy may be helpful, at least for a time. If these don’t work, chemotherapy may be tried, especially in people with non-clear cell types of kidney cancer. Clinical trials may be a good option in this situation for those who want to continue treatment.
Again, for some patients, palliative treatments such as embolization or radiation therapy may be the best option. Controlling symptoms such as pain is an important part of treatment at any stage of the disease.
What happens after treatment for kidney cancer?
For some people with kidney cancer, treatment may remove or destroy the cancer. Completing treatment can be both stressful and exciting. You may be relieved to finish treatment, but find it hard not to worry about cancer coming back. (When cancer comes back after treatment, it is called recurrence.) This is a very common concern in people who have had cancer.
It may take a while before your fears lessen. But it may help to know that many cancer survivors have learned to live with this uncertainty and are leading full lives. Our document, Living With Uncertainty: The Fear of Cancer Recurrence, gives more detailed information on this.
For other people, the cancer may never go away completely. These people may get regular treatments with chemotherapy, radiation therapy, or other therapies to try to help keep the cancer in check. Learning to live with cancer that does not go away can be difficult and very stressful. It has its own type of uncertainty. Our document, When Cancer Doesn’t Go Away, talks more about this.
Follow-up care
When treatment ends, your doctors will still want to watch you closely. It is very important to go to all of your follow-up appointments. During these visits, your doctors will ask questions about any problems you may have and may do exams and lab tests or x-rays and scans to look for signs of cancer or treatment side effects. Almost any cancer treatment can have side effects. Some can last for a few weeks to months, but others can last the rest of your life. This is the time for you to talk to your cancer care team about any changes or problems you notice and any questions or concerns you have
For people whose kidney cancer has been removed by surgery, doctor visits (which include physical exams and blood tests) are usually recommended about every 6 months for the first 2 years after treatment, then yearly for the next several years.
scan is usually recommended about 4 to 6 months after surgery and may be repeated later if there’s reason to suspect the cancer may have returned. (Treatment of recurrent cancer is described in the section, “Treatment choices by stage for kidney cancer.”) Patients who have a higher risk of their cancers coming back after surgery, such as cancer that had spread to lymph nodes, may be seen more often with CT scans repeated at least every 6 months for the first few years.
Each type of treatment for kidney cancer has side effects that may last for a few months. You may be able to hasten your recovery by being aware of the side effects before you start treatment. You might be able to take steps to reduce them and shorten the length of time they last. Don’t hesitate to tell your cancer care team about any symptoms or side effects that bother you so they can help you manage them.
It is important to keep your health insurance. Tests and doctor visits cost a lot, and even though no one wants to think of their cancer coming back, this could happen.
Should your cancer come back, our document, When Your Cancer Comes Back: Cancer Recurrence, can give you information on how to manage and cope with this phase of your treatment.
Seeing a new doctor
At some point after your cancer diagnosis and treatment, you may find yourself seeing a new doctor who does not know anything about your medical history. It is important that you be able to give your new doctor the details of your diagnosis and treatment. Make sure you have this information handy:
· A copy of your pathology report(s) from any biopsies or surgeries
· If you had surgery, a copy of your operative report
· If you had radiation, a copy of your treatment summary
· If you were hospitalized, a copy of the discharge summary that doctor prepare when patients are sent home from the hospital
· If you had chemotherapy (including biologic therapy or targeted therapy), a list of the drugs, drug doses, and when you took them
· Copies of your CTs, MRIs, or other imaging tests (these can often be placed on a DVD)
The doctor may want copies of this information for his records, but always keep copies for yourself.
What`s new in kidney cancer research and treatment?
There is always research going on in the area of kidney cancer. Scientists are looking for causes of and ways to prevent renal cell carcinoma. Doctors are working to improve treatments as part of a major effort to lower the number of people who die from this cancer. In addition to finding new medicines and looking at the best way to combine and sequence existing ones, a major area of research lies in finding better ways to select therapy for an individual. That is, finding factors about a person’s cancer that make it more likely to respond to a certain medicine. This is a major area of research in many cancers, as doctors want to be able to individualize therapy as much as possible to increase a person’s chance of benefiting from a therapy.
Research on the treatments for renal cell carcinoma is now being done at many medical centers, university hospitals, and other institutions across the nation. The American Cancer Society supports research into the detection, diagnosis, and treatment of kidney cancer.
Genetics
Scientists are studying several genes that may play a part in changing normal kidney cells into renal cell carcinoma.
For example, problems with the von Hippel-Lindau tumor suppressor gene are found in most clear cell kidney cancers. This allows other genes such as the hypoxia-inducible factor (HIF) gene to be activated when they shouldn’t be, which drives a cell toward being cancerous. Newer treatments focus on attacking this cellular pathway.
Researchers now also have a better idea of the gene changes responsible for some other forms of kidney cancer. Doctors are now trying to determine which treatments are most likely to be effective for certain types of kidney cancer. This information can also be used to develop new treatments.
New approaches to local treatment
High-intensity focused ultrasound is a fairly new technique that is now being studied for use in kidney cancer. It involves pointing very focused ultrasound beams from outside the body to destroy the tumor.
Ablation with cryotherapy or radiofrequency ablation is sometimes used to treat small kidney cancers. Research is now under way to determine how useful these techniques are in the long term and to refine them further.
Targeted therapies
Because chemotherapy drugs have not been very effective against advanced kidney cancer, targeted therapies are now usually the first-line option to treat kidney cancers that cannot be removed by surgery. At this time they are usually given separately. Clinical trials are now under way to try to determine if combining these drugs, either with each other or with other types of treatment, might be better than using them alone. Several new targeted therapies are now being tested as well, with cediranib and linifanib showing promise.
The potential roles of giving these drugs before and after surgery (called neoadjuvant and adjuvant therapy, respectively) are also being studied.
Immunotherapy
Kidney cancer is one of a handful of cancers that may respond to immunotherapy. Clinical trials of new immunotherapy methods are being tested. Basic research is now being directed toward a better understanding of the immune system, how to activate it, and how it reacts to cancer.
Researchers are studying the use of cytokines to stimulate immune system cells that have been removed from circulating blood. The cells are treated with cytokines and exposed to killed tumor cells to make cells called dendritic cells. These cells are injected into lymph nodes in the hope that this will stimulate the immune system to fight the cancer. Early results have been promising, but more studies are needed.
Vaccines
Several types of vaccines for boosting the body’s immune response to kidney cancer cells are being tested in clinical trials. Unlike vaccines against infections like measles or mumps, these vaccines are designed to help treat, not prevent, kidney cancer. One possible advantage of these types of treatments is that they seem to have very limited side effects.
There are several ways to create vaccines that might stimulate the immune system. In one approach, cancer cells (removed during surgery) are altered in the lab to make them more likely to cause an immune response and are then returned to the body. In another approach, a special virus is altered so it is no longer infectious, but it carries a gene for a protein often found on cancer cells. Once the virus is injected into the body, the hope is that the protein will cause the immune system to react against cancer cells anywhere in the body. Combining vaccines with targeted agents or other agents to help them work better is also being studied.
At this time, these vaccines are only available in clinical trials.
Bone marrow or peripheral blood stem cell transplant
In people with advanced kidney cancer, the person’s own immune system is not effectively controlling the cancer. Another approach to immunotherapy is to try to use someone else’s immune system to attack the cancer cells.
First, very primitive immune system cells (called stem cells) are collected from a compatible donor, either from their bone marrow or their blood. The person with cancer is then treated with chemotherapy drugs, either in lower doses (called a mini or non-myeloablative stem cell transplant) to suppress the immune system or in higher doses to cause more severe damage to the immune cells and other components of the bone marrow. They are then given the stem cells to try to build a new immune system that will be more likely to attack the cancer cells.
Some early studies of this technique have been promising, finding that it may help shrink kidney cancers in some people. But it can also cause major complications, and side effects can be severe. Until more is known about its safety and usefulness, it will probably only be available in clinical trials.
References:
American Cancer Society. Cancer Facts and Figures 2013.
American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed.
Choyke PL. Radiologic imaging of renal cell carcinoma: its role in diagnosis. In: Vogelzang NJ, Scardino PT, Shipley WU, Debruyne FMJ, Linehan WM, eds. Comprehensive Textbook of Genitourinary Oncology. 3rd ed.
Prepared by Prof. Igor Y. Galaychuk, MD – 2014
Clague J, Lin J, Cassidy A, et al. Family history and risk of renal cell carcinoma: results from a case-control study and systematic meta-analysis. Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):801-7.
Molecular Biology of Genitourinary Cancers
Kidney cancer, or renal carcinoma, affects over 28,000 Americans annually and is responsible for nearly 12,000 deaths in the United States each year. Renal carcinoma occurs most commonly in adults between the ages of 50 and 70 years of age, although it has been reported in children as young as 3 years of age. Renal carcinoma is responsible for approximately 3% of adult malignancies and it occurs with a male:female ratio of 1.5:1. Leather workers and workers exposed to asbestos have an increased incidence of renal carcinoma and there is a strong correlation between cigarette smoking and the development renal carcinoma. [ref: 4,5] Up to 85% of renal carcinomas are of the clear cell type; 5% to 15% of renal carcinomas are of papillary histologic variant. [ref: 6,7] There is an increased incidence of renal carcinoma in dialysis patients with acquired cystic disease, in which a 30 times higher rate than normal controls has been estimated. [ref: 8] A family history of this malignancy has been associated with an increased risk of development of renal carcinoma.
Like colon cancer, breast cancer, and retinoblastoma, renal carcinoma occurs in both a familial (hereditary) and a sporadic (nonhereditary) form. It has been estimated that up to 4% of renal carcinoma may have a hereditary basis. [ref: 1] There are at least three types of hereditary renal carcinoma: renal carcinoma associated with Von Hippel-Lindau (VHL) disease, hereditary papillary renal carcinoma (HPRC), and hereditary clear cell renal carcinoma (HCRC). VHL disease is a hereditary cancer syndrome with an autosomal dominant inheritance pattern in which affected individuals develop tumors in a number of organs, including the kidney. HPRC is a recently described form of inherited renal carcinoma in which affected individuals develop multifocal, bilateral, early onset papillary renal carcinoma. In the third, but less well-understood form of inherited renal carcinoma, HCRC, patients have a predisposition to develop bilateral, multifocal clear cell renal carcinoma.
Location for a Renal Carcinoma Gene.
The first studies to provide information with reference to a potential location for a renal carcinoma gene came from the work of Cohen and coworkers, [ref: 9] who in 1979 reported a kindred in which affected individuals developed early onset, bilateral, multifocal clear cell renal carcinoma. In this family, every member who developed kidney cancer had a germline abnormality detectable on karyotypic analysis, a balanced translocation from the short arm of chromosome 3 to the long arm of chromosome 8. Every patient who was found to have early onset kidney cancer in this kindred had this abnormality; no patient who did not have this translocation was found to have kidney cancer. [ref: 9]. Subsequently, Pathak and coworkers [ref: 10] identified another family with a chromosome 3 to chromosome 11 translocation and Kovaks and coworkers [ref: 11] reported a family with a chromosome 3 to chromosome 6 translocation; the common abnormality occurred on the short arm of chromosome 3 (Fig. 33.1-1).
Abnormalities in Sporadic Renal Carcinoma.
These findings led scientists to study nonhereditary renal carcinoma, to determine if there were changes on chromosome 3. When Zbar and associates [ref: 12] studied tumor tissue from 18 patients with sporadic, nonhereditary renal carcinoma, by restriction fragment polymorphism analysis, loss of heterozygosity (LOH) on the short arm of chromosome 3 was detected in tumor tissue from 11 of 11 evaluable patients. LOH was detected in tumor tissue from patients with both localized as well as advanced disease, suggesting the presence of a gene involved in the earliest development of this neoplasm. In order to more precisely define the prevalence of chromosome 3p LOH in sporadic renal carcinoma as well as the location of a candidate gene for renal carcinoma, Anglard and associates [ref: 13] analyzed DNA from normal and tumor tissue from 60 patients with various stages of renal carcinoma for losses of alleles at different chromosomal loci. LOH that was independent of tumor stage was detected at one or more of 10 loci tested on chromosome 3 in tumor tissue from nearly 90% of patients. [ref: 13] LOH was detected in clear cell renal carcinoma, but not in papillary renal carcinoma. These findings and those of others showed deletion of a segment of chromosome 3p to be a consistent finding in clear cell renal carcinoma. [ref: 14-18]. Although these findings pointed to the presence of a renal carcinoma gene on the short arm of chromosome 3, the chromosome 3p area of minimal deletion in the renal tumors was too large to search by conventional cloning strategies available at the time. This then led investigators to initiate studies of the familial form of renal carcinoma associated with VHL disease, with the supposition that the gene for VHL may be involved in the sporadic form of renal carcinoma.
Hereditary renal carcinoma: Von Hippel-Lindau disease.
VHL disease is a familial cancer syndrome in which affected individuals develop tumors in a number of organs, including kidney, cerebellum, spine, eyes, pancreas, adrenal glands, inner ear, and epididymis. Patients with VHL disease often develop early onset bilateral, multifocal renal carcinoma, and multiple renal cysts. Frequently, renal tumors are found growing inside the renal cysts. The renal carcinoma in VHL patients is uniformly clear cell renal carcinoma. It has been estimated that there may be up to 600 clear cell renal carcinomas and 1100 benign or atypical cysts per kidney in an affected VHL patient. [ref: 20]. These kidney cancers are malignant and have been reported to metastasize in up to 40% of untreated patients. The cerebellar and spinal hemangioblastomas are multifocal and marked by extreme vascularity. Although these central nervous system tumors are benign, they can cause significant morbidity. The retinal angiomas can be the first clinical manifestation of VHL. These benign, hypervascular retinal tumors can be detected as early as 1 year of age. An identified manifestation of VHL is a tumor that develops in the endolymphatic sac of the inner ear. These papillary tumors are low-grade malignancies that rarely metastasize but can invade locally. VHL patients can develop islet cell tumors of the pancreas and pancreatic cysts. The islet cell tumors are rarely functional, however, they can be malignant and can spread. Of VHL patients, 18% to 20% develop pheochromocytomas. These tumors can be bilateral or extraadrenal and can be malignant. The epididymal cystadenomas that VHL patients develop are frequently bilateral and are uniformly benign. [ref: 1,21].
Localization of the VHL Gene to Chromosome 3. In order to identify the VHL gene, studies were conducted to perform genetic linkage analysis on chromosome 3p.
VHL Gene Mutations: Clear Cell Renal Carcinoma. In order to determine the role of the VHL gene renal carcinoma, Gnarra and colleagues analyzed tumors and cell lines from 110 patients with sporadic, nonfamilial renal carcinoma for VHL mutations and LOH; LOH was detected in 98% of the samples and VHL gene mutations were observed in 57% of clear cell renal carcinomas analyzed. VHL gene mutations were not detected in tumor tissue from patients with papillary renal carcinoma or from lung cancer, breast cancer, ovarian cancer, cervical carcinoma, prostate cancer, colon cancer, or bladder cancer. The somatic VHL mutations differed from the germline mutations in that a higher percentage of somatic mutations clustered in exon 2 than was detected the germlines. VHL gene mutations were found in early as well as late stage clear cell renal carcinomas; and where multiple samples were tested from the same patient, the identical mutation was found. Shuin and associates [ref: 36] detected somatic mutations in 56% of primary renal carcinomas and an 84% LOH of the VHL gene. Whaley and coworkers [ref: 37] detected somatic VHL in renal carcinoma and no mutations in over 180 sporadic tumors of other types. VHL gene mutations have also been detected in tumor tissue from patients from the 3;8 translocation family described by Cohen and associates, [ref: 9,35,38] further supporting the conclusion that the VHL gene has an important and specific role in clear cell renal carcinoma.
Hereditary papillary renal carcinoma
Papillary renal carcinoma is a histologic variant of renal carcinoma that is distinct from clear cell renal carcinoma. While clear cell renal carcinoma is characterized by loss of heterozygosity on the short arm of chromosome 3 and mutation of the chromosome 3p VHL gene, neither chromosome 3 LOH nor VHL gene mutation are detected in tumor tissue from patients with papillary renal carcinoma. Zbar and associates [ref: 44] described a distinct form of hereditary renal carcinoma, HPRC. HPRC is an autosomal dominant form of inherited renal carcinoma that is characterized by the appearance of bilateral, multifocal papillary renal carcinoma. HPRC is distinct from VHL disease. HPRC does not link to chromosome 3; VHL gene mutations are not detected in either the germline or tumor tissue of HPRC patients. [ref: 44] Additional families with papillary renal carcinoma have been identified, and these findings support the inherited nature of the predisposition to develop papillary renal carcinoma and HPRC being a distinct type of inherited cancer. [ref: 45] Studies with additional families are in progress to identify the chromosomal location of the HPRC gene and to further characterize the clinical manifestations of this hereditary cancer syndrome.
These findings support the molecular genetic classification of renal carcinoma between clear cell and papillary renal carcinoma with clear cell renal carcinoma being characterized by VHL gene mutation. Once the HPRC gene is identified, the ability to detect HPRC as well as VHL gene mutations should provide both increased understanding of the molecular genetic basis of both forms of renal carcinoma plus may provide significant improvement in our ability to diagnosis and manage patients with renal carcinoma.
BLADDER CANCER
Approximately 90% of malignant tumors arising in the urinary bladder are of epithelial origin, the vast majority being transitional cell carcinomas. [ref: 46,47] Based on morphologic evaluation and natural history, urothelial neoplasms have been classified into two groups having distinct behavior and prognosis: low-grade tumors (always papillary and usually superficial), and high-grade tumors (either papillary or nonpapillary, and often invasive). [ref: 48] Clinically, superficial bladder tumors (stages Ta, Tis, and T1) account for 75% to 85% of neoplasms, while the remaining tumors (15% to 25%) are invasive (T2, T3, T4) or metastatic (Nplus, Mplus) lesions at the time of initial presentation. [ref: 49] Over 70% of patients affected with superficial tumors have one or more recurrences after initial treatment, and about one third of those patients progress and eventually succumb to the disease. [ref: 50,51] Because the modality of therapy primarily depends on the clinical staging and morphologic evaluation, the diagnosis carries significant consequences. However, it is well known that two morphologically similar tumors presenting in any assigned stage may behave in different fashions, a fact that seriously hampers the ability to accurately predict clinical outcome in a given case. For these reasons, biologic markers and new detection methods are being developed in an attempt to identify and monitor those patients presenting with superficial tumors who are likely to develop recurrent or progressive disease. Crucial concerns regarding patients presenting with muscle invasive carcinomas include their metastatic potential and response to neoadjuvant regimens. The implementation of objective predictive assays enhances our ability to assess tumor biologic activities and to design effective treatment regimens.
Cytogenetics and interphase cytogenetics of bladder tumors
Cytogenetic studies of bladder cancer cells by karyotyping have revealed a variety of chromosomal abnormalities. Nonrandom chromosomal changes consisting of monosomy of chromosome 9 [ref: 52,53] and interstitial deletions of chromosome 13 [ref: 52] were observed. Other common abnormalities reported included trisomy of chromosome 7, 11p and 3p deletions, and chromosome 1 alterations. [ref: 54-56] Nevertheless, most of these analyses were performed using small cohorts, lacking clinicopathologic correlations, and combining superficial and muscle-invasive lesions. In a study, Tyrkus and coworkers [ref: 57] karyotyped 17 carcinomas in situ of the urinary bladder and found no chromosome 9 alterations, but identified nonrandom chromosomal changes involving chromosomes 1, 5, 8, and 11.
Interphase cytogenetic studies have been conducted, mainly using centromeric probes, in a search for numeric alterations in bladder cancer. In addition, new telomeric and locus-specific probes are being utilized to identify genetic aberrations using nonisotopic detection methods. Hopman and coworkers reported chromosomal alterations at 1q12, [ref: 58] as well as numeric abnormalities of chromosomes 1, 7, 9, 11, and 18. [ref: 59] Waldman and associates [ref: 60] also reported numeric aberration of chromosomes 7, 9, and
Fluorescence in situ hybridization (FISH) has been utilized to assess erbB-2 (17q21) gene amplification and c-myc (8q24) copy number gains in bladder cancer. [ref: 61,62] Sauter and coworkers [ref: 61] reported amplification of erbB-2 in 10 of 141 bladder tumors using a dual-labeling hybridization assay. Gene amplification was associated with protein overexpression and was found only in tumors with aneusomy of chromosome 17, being more frequent in muscle invasive lesions. [ref: 61] A similar approach was used for the analysis of c-myc gene copy number on 87 bladder tumors. Obvious amplification was found in three cases, while 32 of the remaining 84 tumors showed a low-level c-myc copy number increase. There was no association between low-level copy number increase and protein overexpression. However, there was strong association between c-myc gains and tumor grade, stage and Ki-67 labeling index, consistent with a role of chromosome 8 alterations in bladder cancer progression. [ref: 62] FISH assays have been also utilized for analyses of specific gene losses. Physical p53 gene deletion (at 17p13) was examined by FISH in 151 bladder tumors. [ref: 63] 17p deletion was found to be highly correlated with tumor stage and grade (P < .01). FISH has been more recently utilized to assay bladder irrigation specimens. [ref: 64] Labeled probes to centromeric sequences for chromosomes 1, 7, 9, 11, 15, and 17 were used on samples from 76 patients monitored for recurrent bladder tumors. Significantly, 24% of patients with a history of bladder cancer but no clinical evidence of disease exhibited monosomy of chromosome 9. [ref: 64]
Molecular and immunopathologic analyses of bladder tumors
Oncogenes. The first mutation of the RAS family of oncogenes, a point mutation in codon 12 of the H-RAS gene (11p15.1), was identified in the bladder cancer cell line T24. [ref: 65] There has been controversy regarding the mutation frequency of RAS genes in bladder tumors. Before the advent of polymerase chain reaction (PCR)-mediated DNA amplification, it was estimated that the rate of point mutations in RAS oncogenes ranged from 10% to 16% of samples analyzed. [ref: 66-68] The predominant alteration identified was codon 12 substitutions of the H-RAS gene, with few cases presenting K-RAS mutations and no mutations detected affecting N-RAS. However, two reports by Czerniak and coworkers, [ref: 69,70] utilizing a PCR-based method, revealed that approximately 40% of bladder tumors harbor H-RAS codon 12 mutations. Several studies have confirmed this high frequency of H-RAS point mutations. Ooi and colleagues [ref: 71] studied a cohort of 124 patients affected with Ta or T1 transitional cell carcinomas. The codon
Overexpression and amplification of particular growth factor receptors have been reported in bladder cancer. Neal and coworkers [ref: 77] observed increased expression of epidermal growth factor receptors (EGF-Rs) in invasive versus superficial bladder tumors. This group of investigators also reported that overexpression of EGF-R was associated with high-grade, high-stage bladder cancer and an independent prognostic factor. [ref: 78] Messing and colleagues [ref: 79] noticed that EGF-R was expressed at detectable levels in the basal layer of the normal urothelium, whereas increased expression in basal and suprabasal layers was identified in transitional cell carcinomas. Rao and associates [ref: 80] also found increased expression of EGF-R in urothelial samples with dysplastic changes, postulating that overexpression of EGF-R may be an early event in bladder carcinogenesis. In a more recent study, Nguyen and colleagues [ref: 81] reported that overexpression of EGF-R was not an independent prognostic marker in patients with advanced bladder cancer.
Amplification of the c-erbB-2 gene was found in 1 of 14 bladder tumors in a study of Wood and coworkers. [ref: 82] This case also displayed overexpression when analyzed for mRNA and protein levels. In addition, five cases displayed high levels of mRNA with no signs of gene amplification, and only three of these five cases had protein overexpression. Sato and associates [ref: 83] observed c-erbB-2 protein (p185) overexpression in 23 of 88 bladder tumors analyzed and found a significant association with overexpression and poor clinical outcome to be an independent prognostic factor. Also, Underwood and associates [ref: 84] studied c-erbB-2 status in 236 bladder tumors. Of 89 patients with recurrent disease, 16 had evidence of c-erbB-2 amplification; however, gene amplification was not observed in the nonrecurrent tumors. There was a strong association with disease progression and c-erbB-2 amplification. Nevertheless, protein overexpression could not be linked to disease progression. C-erbB-2 amplification was of predictive value in multivariate analysis for overall bladder cancer death; however, stage and grade remained the most significant independent prognostic parameters. [ref: 84]
A cellular protooncogene product, the mdm2 or p90, has been shown to bind to p53 and to act as a negative regulator, inhibiting its transcriptional transactivation activity. [ref: 85] The MDM2 gene is located on the long arm of chromosome 12 (12q13-14) and it encodes a 90 kd nuclear protein (mdm2). [ref: 86] Lianes and colleagues [ref: 87] undertook a study to determine the frequency and clinical relevance of identifying MDM2 and TP53 alterations in patients affected with bladder neoplasms. These investigators analyzed a cohort of 87 patients, and observed that 26 of 87 cases had abnormally high levels of mdm2 proteins; however, only one case showed an MDM2 amplification. There was a striking association between mdm2 overexpression and low-stage and low-grade bladder tumors (P < .01). Based on these results, it was concluded that aberrant mdm2 phenotypes are frequent events in bladder cancer and may be involved in tumorigenesis or early tumor progression in urothelial neoplasms. In an independent study, Barbareschi and colleagues [ref: 88] reported mdm2 nuclear overexpression in 5 of 25 bladder tumors analyzed, but this survey lacked clinicopathologic correlations.
Tumor Suppressor Genes
Molecular genetic studies of bladder cancer have identified certain abnormalities of bonafide or candidate tumor suppressor genes that appear to be involved in the development and progression of such neoplasms. Confirming initial cytogenetic observations, LOH of the short arm of chromosome 11 and 9q allelic losses were reported as frequent events in bladder tumors. [ref: 89,90] It was also observed that 17p LOH was a common event [ref: 90,91] and that it was associated with high-grade bladder cancer. [ref: 91]
In an attempt to define the role of molecular abnormalities of tumor suppressor genes in the pathogenesis and progression of human bladder cancer, a combined molecular genetic and immunopathologic approach was undertaken by Presti and associates. [ref: 92] In a survey of 34 unselected patients, five suspected or established tumor suppressor gene regions (3p21-25, 11p15, 13q14, 17p11-13, and 18q21) were studied. An immunohistochemical (IHC) assay was also utilized for the analysis of the retinoblastoma gene product (pRB). This study demonstrated that tumor grade correlated with deletions of 3p (P =.004) and 17p (P = .063). Tumor stage was correlated with deletions of 3p (P = .010), 17p (P = .015), and altered pRB expression (P = .054).
Vascular invasion correlated only with deletions of 17p (P = .038). This study also revealed that deletions of 17p (TP53 locus) and 18q (DCC gene locus) occur only in invasive tumors, while deletions of 3p and 11p occur in both superficial and invasive tumors. [ref: 92] Dalbagni and associates [ref: 93] followed this study by the analysis of 60 paired bladder tumors and normal tissues using polymorphic DNA markers on 18 different chromosomal arms. Allelic deletions were correlated with clinicopathologic parameters. Distinct genotypic patterns were associated with early and late stages of bladder cancer. Correlation of genetic alterations with clinicopathologic data suggested the existence of two different genetic pathways for the evolution of superficial bladder tumors. Briefly, 9q deletions were found in 60% of the informative cases, confirming previous reports. All superficial papillary tumors confined to the mucosa (Ta neoplasms) and almost all tumors invading the lamina propria (T1 lesions) showed 9q alterations. Instead, only 10 of 23 muscle invasive tumors (T2-4 or T2+) had 9q deletions. A statistically significant difference was observed when comparing 9q LOH between T1 versus T2+ tumors (P =.021). Moreover, 9q deletions were the sole abnormality found in some of the bladder lesions studied, suggesting the presence of a candidate tumor suppressor gene on chromosome 9, the alteration of which may lead to the genesis of a subset of superficial bladder tumors. None of the Ta lesions showed 5q alterations; however, 3 of 10 T1 and 8 of 26
T2+ tumors presented with 5q LOH, indicating that 5q deletions may be involved in the transition from papillary superficial (Ta) to early invasive (T1) tumors. Allelic loss of 17p was detected in 21 of 47 informative cases. Deletions were not identified among Ta lesions, while 21 of 38 invasive tumors exhibited 17p LOH. These findings support the involvement of 17p in the progression of bladder cancer. Allelic deletion of 3p was not present in any of the informative Ta neoplasms; however, 18 of 33 invasive tumors had such alterations. There was a statistically significant association with the various pathologic parameters of poor outcome and 3p LOH. Allelic losses of 11p, 6q, and 18q were frequently detected in the corresponding informative bladder tumors analyzed. However, no statistically significant differences were observed between these abnormalities and clinicopathologic parameters of poor outcome, suggesting their involvement in late bladder cancer. Other bonafide and putative suppressor loci analyzed in the study discussed showed a lower rate of LOH, and lacked association with clinicopathologic parameters. [ref: 93]
In a subsequent allelotyping study, Habuchi and coworkers [ref: 94] investigated the role of allelic losses of seven chromosomal arms (1p, 3p, 9q, 10q, 11p, 13q, and 17p) in 49 urothelial cancers. They also found that 9q LOH was a common event in bladder tumors, and that invasive tumors showed higher frequencies of 17p and 13q losses when compared to noninvasive lesions. Deletions of the long arm of chromosome 13, including the retinoblastoma locus (RB) on 13q14, were independently reported by two groups. [ref: 95,96] In one of these studies,
The potential relevance of RB alterations in bladder cancer was disclosed in two independent studies. [ref: 97,98] Using a mouse monoclonal antibody (mAB) and IHC in frozen tissue sections of 48 primary bladder tumors, Cordon-Cardo and associates [ref: 97] found normal levels of pRB expression in 34 cases. However, a spectrum of altered patterns of expression, from undetectable pRB levels to heterogeneous expression of pRB, was observed in 14 patients. Of the 38 patients diagnosed with muscle invasive tumors, 13 were categorized as pRB altered, while only 1 of the 10 superficial carcinomas had the altered pRB phenotype. The survival was significantly decreased in pRB altered patients compared with those with normal pRB expression (P<.001). [ref: 97] Similarly, Logothetis and coworkers [ref: 98] found altered pRB expression in locally advanced bladder cancer. Forty-three patients were evaluated using the Rb-WL-1 polyclonal antiserum and IHC. These investigators reported altered pRB expression in 37% of the tumor specimens analyzed. There was a significant decrease in disease-free survival for patients with documented abnormal pRB levels. Taken together, these data suggested that altered pRB expression occurred in all grades and stages of bladder cancer, but was more commonly associated with muscle invasive tumors. Moreover, altered patterns of pRB may become an important prognostic variable in patients presenting with invasive bladder cancer. The clinical implications of detecting TP53 mutations and altered patterns of its encoded product (p53) in bladder tumors have been the focus of a series of investigations. [ref: 99-109] Early studies revealed that TP53 mutations were common events in bladder cancer and associated with tumor stage and grade. [ref: 99,100]
Dalbagni and associates [ref: 101] correlated alterations of chromosome 17 with p53 nuclear overexpression in a cohort of 60 bladder tumors. Deletion of 17p correlated with grade (P = .039) and stage (P = .004), while p53 nuclear overexpression correlated with grade (P = .027), stage (P = .008), vascular invasion (P = .021), and presence of nodal metastases (P = .007). There was a strong correlation between the p53 overexpression and TP53 deletions (P <.001). Following this study, Cordon-Cardo and colleagues [ref: 102] designed a study to evaluate the sensitivity and specificity of different laboratory assays directed to the identification of TP53 mutations (including IHC with mAB PAb1801, RFLP, PCR-SSCP, and sequencing). Using this approach, they also tested the hypothesis that p53 nuclear overexpression detected by IHC can reliably identify the presence of mutant TP53 products in bladder neoplasms. Nuclear immunoreactivities were observed in 26 of 42 bladder tumors analyzed. Abnormal shifts in mobility were noted in 14 of the 42 cases in distinct exons. There was a strong association between p53 nuclear overexpression and 17p LOH (P < .001), as well as p53 nuclear overexpression and detection of TP53 mutations by SSCP and sequencing (P < .001). By using receiver operating curve statistical analysis, the accuracy of detecting TP53 mutations by IHC was estimated to be 90.3%. In addition, this study defined an appropriate cutoff point for IHC 20% tumor cells displaying nuclear immunoreactivities (p53-positive phenotype).
The aim of a group of analyses that followed was to investigate the hypothesis that altered patterns of p53 expression correlated with tumor progression in patients with superficial bladder tumors. Detection of p53 nuclear overexpression was evaluated by IHC using mAB PAb1801 on deparaffinized tissue sections in tumors from 43 patients with T1 bladder cancer, [ref: 103] 54 patients with Ta neoplasms, [ref: 104] and 33 patients affected with pure Tis. [ref: 105] Nuclear p53 overexpression was correlated with clinicopathologic variables, and results were submitted to the Fisher exact test, as well as univariate and multivariate analyses. [ref: 103-105] The median follow-up for these cohorts of patients was 119, 110, and 124 months, respectively. Patients in each stage were stratified into two groups, utilizing the cutoff point identified through the receiver operating curve analysis previously conducted (20% nuclear-positive tumor cells). [ref: 102] A strong association was found between tumor progression and p53-positive phenotype in the three studies (P < .01). Moreover, nuclear overexpression of p53 was an independent variable associated with disease progression and death resulting from bladder cancer.
Two studies dealing with p53 nuclear overexpression conducted in unselected bladder cancer patients were reported. Lipponen [ref: 106] analyzed 212 bladder tumors, using IHC and 20%-positive nuclear staining as the cutoff value. However, the primary antibody used was a purified rabbit polyserum (NCL-CM1 — 1:150 dilution). The mean follow-up time was over 10 years. Nuclear overexpression of p53 was associated with tumor grade and disease progression. In univariate analysis, p53 overexpression predicted poor outcome in the entire cohort. However, in a multivariant survival analysis, overexpression of p53 had no independent prognostic value over clinical stage and mitotic index. Esrig and associates [ref: 107] determined the relation betweeuclear accumulation of p53 and tumor progression in a cohort of 243 patients treated by radical cystectomy utilizing IHC and antibody PAb1801. These investigators noticed that detection of nuclear p53 was significantly associated with an increased risk of recurrence (P < .001) and decreased overall survival (P < .001). Moreover, p53-positive phenotype was an independent predictor of recurrence and survival.
The neoadjuvant use of chemotherapy offers the advantages of bladder preservation and early treatment of micrometastases in patients diagnosed with invasive bladder cancer. However, despite the chemosensitivity of invasive urothelial neoplasms, complete pathologic response in the primary lesion occurs in only 20% to 30% of patients. In order to determine if aberrant p53 expression has independent significance for response, relapse, and survival in patients with muscle-invasive bladder cancer treated with neoadjuvant M-VAC chemotherapy, Sakis and associates [ref: 108] evaluated 90 patients who received this regimen with a median follow-up of 5.8 years. Forty-seven patients whose tumors had p53-positive phenotype had a significantly higher proportion of cancer deaths. Multivariate analysis revealed that p53 overexpression had independent significance for long-term survival (P < .001). [ref: 108]
As discussed earlier, loss of genetic material on chromosome 9 is an early abnormality detected in bladder tumors. [ref: 52,90,93,94,109] The existence of two altered loci, one in each of both chromosome 9 arms, was postulated. [ref: 110,111] A detailed analyses conducted by Orlow and coworkers [ref: 112] on 73 bladder tumors showed that two regions, one on 9p at the interferon cluster (9p21), and the other on 9q associated with the q34.1-2 bands, had the highest frequencies of allelic losses. The 9p21 region has been found to be mutated frequently in a wide variety of human tumor cell lines, and the search for a putative tumor suppressor gene in this region led to the characterization of the so-called multiple tumor suppressor 1 (MTS1) gene. [ref: 113] It was confirmed that the MTS1 gene was the previously identified p16/INK4A/CDKN2 (p16) gene. [ref: 114] In addition to p16, the p15/INK4B/MTS2 (p15) gene is found in tandem at 9p21. [ref: 115] These genes encode members of a new family of negative cell cycle regulators, products of which function as cyclin-dependent kinase inhibitory molecules. [ref: 114-116] The initial enthusiasm over the high frequency of mutations of these genes in cell lines was restrained by reports from a number of investigators who failed to observe appreciable frequencies in primary human tumor material. Nevertheless, several independent groups of investigators have shown that genetic alterations mainly of p16, as well as deletions of p15, are common events in certain human primary tumors, including bladder cancer. [ref: 117-122] Moreover, genetic alterations of p16 are independent of TP53 mutations, suggesting that p16 and p53 function in separate pathways of tumor suppression. [ref: 121] Orlow and colleagues [ref: 122] have reported an overall frequency of deletions and rearrangements for the p16 and p15 genes in bladder cancer of 19% and 18%, respectively. Moreover, this study revealed that p16 and p15 alterations were associated with low-stage, low-grade bladder tumors. It should be emphasized that only Ta and T1, but not Tis, lesions showed deletions of either p16 or p15. Because p16 alterations occur independently of p53 mutations, [ref: 121] and p53 mutations are frequent events in Tis bladder tumors, [ref: 105] data from that report further support the hypothesis that bladder carcinogenesis may develop through two distinct molecular pathways. [ref: 93,123] Taken together, the results suggest that p16 and p15 alterations confer selective growth advantage to urothelial tumor cells, but mutations in other genes are required to produce an overt malignant phenotype.
Note: the text was taken from “Cancer: Principles & Practice of Oncology, Fifth Edition; edited by Vincent T. DeVita, Jr. MD, Samuel Hellman, MD, Steven A.
Prepared by Prof. Igor Y. Galaychuk, MD
2014
