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Testis Cancer Definition
The testicles are the male reproductive organs located in the scrotum, just beneath the penis. The testicles have two main functions:
They produce sperm for reproduction.
They make testosterone, the main male hormone responsible for male sexual characteristics.
Testis cancer develops when one or more of the cells in the testicle grow out of control. Normally, hundreds of thousands of cells live, grow and die in an orderly fashion within the testicle. When one of these cells becomes abnormal and grows uncontrolled, it becomes a cancer.
The most common cell type in the testicle is called a germ cell. Normally, the sperm develop from these germ cells. As germ cells make up approximately 90 percent of the testicle, the most common type of testis cancer is a germ cell tumor.
Testis Cancer Statistics
It is estimated that 8,000 to 10,000 men will develop testis cancer each year. The chance of developing testis cancer is about one in 270. Fortunately, the cure rate is excellent (greater than 95 percent for all men with testis cancer). Only about 400 men will die from testis cancer each year (the chance of death from testis cancer is better than one in 5,000). Because of the excellent cure rate, about 20,000 are surviving with cancer and 200,000 have been cured at any given time in the United States.
Testis cancer is most common in men in their late 20s and early 30s, with an average age of diagnosis of 33 years old. In fact, testis cancer is the most common malignancy among men 20 to 40 years old. However, testis cancer can occur at any age: It is the second most common malignancy in young men 15 to 19 years old (leukemia is No. 1), with approximately 6 percent of cases occurring in children and teens, and about 7 percent occurring in men over the age of 55.
In the United States, testis cancer is most common in white (Caucasian) men and less common in black (African-American), Hispanic and Latino and Asian-American men. In fact, white men are four to five times more likely to have testis cancer than black men and three times more likely than Asian-American men. Worldwide, the risk of developing testis cancer is highest in the United States and Europe and lowest among men living in Africa or Asia.
There are four well-established risk factors for testis cancer:
The most common risk factor for testis cancer is a history of cryptorchidism, otherwise known as an undescended testicle. Normally in the developing male fetus, the testicles form near the kidneys in the abdomen (belly). About the eighth month of pregnancy, the testicles descend, exit the body and settle in the scrotum. About 3 percent of boys have one or both testicles that fail to make it into the scrotum. Testicles can settle in the abdomen or in the inguinal canal or groin (where the testicle exits the body wall and enters the scrotum). Most of the time, an undescended testicle will move down and settle into the scrotum within the first year of life. Sometimes surgery is required to bring down and fix the testicle to the scrotum — this surgery is called an orchiopexy.
Boys with a history of cryptorchidism have an increased risk of testis cancer. The risk of cancer is not directly related to the fact that the testicle does not descend, but it is believed that the abnormality in descent likely indicates an abnormality in the testicle that makes cancer more likely. This belief is based on the following observations: The cancer usually develops in the undescended testicle (four- to sixfold increased risk of cancer), but the risk of cancer is also higher in the normal testicle (less than twofold increased risk). In addition, generally the higher the testicle, the higher the risk of testis cancer — intra-abdominal testis have a much higher risk of cancer than those in the inguinal canal. Early surgery (orchiopexy) reduces the risk of testis cancer (two- to threefold risk if the surgery is performed prior to puberty) but does not erase the chance for that boy to develop cancer later in life.
A family history of testicular cancer is another common risk factor, with an eight- to 12-fold risk if a man has a brother with testis cancer and a two- to fourfold risk if his father has testis cancer. In addition, the average age at diagnosis is two to three years younger than the general population if a first-degree relative has testicular cancer. However, it should be remembered that testis cancer is rare and it is therefore rare for this disease to run in families.
Men with a personal history of testicular cancer have the highest risk of developing another cancer. Fortunately, only two percent of men will develop cancer in both testicles, but that risk is 12-fold higher than men without testis cancer. In addition, men who develop testis cancer in their 20s or earlier, men with seminoma and men with ITGCN have a higher risk of developing a second testis cancer.
Most testis cancer arises from the precursor lesion known as ITGCN (or carcinoma in situ, CIS). ITGCN is present adjacent to testis cancer in 80 percent to 90 percent of patients. For men in whom ITGCN is found for other reasons, the risk of subsequent testis cancer is 50 percent at five years and 70 percent at seven years. Therefore, ITGCN is the last well-known risk factor for testis cancer.
Other potential but not established risk factors for testis cancer include: HIV infection, body type (tall men may be more likely to develop testis cancer) and a history of trauma to the testicles.
Types of Testis Cancer
As stated above, the most common type of testis cancer is a germ cell tumor. There are two main types of GCT: seminoma and nonseminomatous germ cell tumors (NSGCT). Both seminoma and NSGCT occur at about the same rate, and men can have seminoma, NSGCT or a combination of both. There are several differences between seminomas and NSGCT, but the initial distinction is based on how the tumor looks under the microscope.
Seminomas tend to grow and spread more slowly than NSGCT, although some seminomas can grow very rapidly. Subtypes of seminoma include:
Classic seminoma: 95 percent of seminomas are classic
Spermatocytic seminoma: tend to occur in older men and has an excellent prognosis
Seminomas can secrete human chorionic gonadotropin (HCG) but do not secrete other tumor markers. If seminoma spreads from the testicle, it is most often and best treated with chemotherapy and/or radiation. Surgery can be performed in some cases.
Nonseminomatous Germ Cell Tumors
NSGCT are very variable in appearance and prognosis. There are four main types of NSGCT that can appear alone, but most often appear as a “mixed” NSGCT, with more than one type present:
Embryonal carcinoma: present in about 40 percent of tumors and among the most rapidly growing and potentially aggressive tumor types. Embryonal carcinoma can secrete HCG or alpha fetoprotein (AFP).
Yolk sac carcinoma: the most common type of tumor in children; responds well to chemotherapy in children and adults. Yolk sac tumors almost always secrete AFP.
Choriocarcinoma: very rare and very aggressive form of testis cancer. Can secrete HCG.
Teratoma: most often appear as a mixed NSGCT; usually grow locally but can appear in retroperitoneal lymph nodes. Teratoma is chemotherapy- and radiation-resistant and best treated with surgical removal.
Tumors can also develop from the supportive tissues around the germ cells in the testicle. These tumors are rare, making up less than 5 percent of testis cancers, and have an excellent prognosis if surgically resected. There are two types of stromal tumors:
Leydig cell tumors: Leydig cells make the male hormone testosterone and are most often cured with surgery.
Sertoli cell tumors: Sertoli cells support and nourish the developing sperm and are usually benign tumors.
Initial Presentation and Symptoms
Most testis cancers present as a mass confined to the testicle. Therefore, the most common presentation is a painless testicular mass. Most of these masses are palpable and of significant size (a few to several centimeters). Small, nonpalpable lesions without pain and in the absence of distant disease have a higher likelihood of being a benign tumors. In a number of studies, upwards of 80 percent of nonpalpable, asymptomatic masses that are 2 cm or smaller will be benign tumors. Benign lesions may include testicular cysts, small infarcts or small Leydig cell or Sertoli cell tumors.
Serious, acute pain is associated with rapidly growing tumors and associated hemorrhage or infarction (if the tumor outgrows its blood supply). Most patients with pain complain of dull scrotal discomfort or heaviness. Rarely trauma can lead to a diagnosis, mostly because it brings a mass or pain to the patient's awareness.
For the upwards of 30 percent of men who present with metastatic cancer, symptoms of metastases can be the presenting complaint. Bulky retroperitoneal lymphadenopathy can lead to abdominal mass; abdominal, flank or back pain due to direct invasion or obstruction of muscles, blood vessels or the ureters; lower extremity swelling if the IVC is compressed or gastrointestinal symptoms if the intestines are involved. Pulmonary metastases can present as chest pain, shortness of breath and cough.
As testis cancers can lead to diminished spermatogenesis, and infertility can be the initial presentation in rare men.
The initial evaluation of a possible testis cancer should involve:
Scrotal ultrasound often demonstrates an intratesticular, hypoechoic (dark) mass. Testis cancers are often vascular (or hypervascular), although the absence of blood flow does not rule out a testis cancer. Even in patients with suspicion of metastatic cancer, a scrotal ultrasound should be used to identify an active primary tumor or a "burned out" testicular mass, which is typically a small, impalpable scar or calcification. Radical orchiectomy should strongly be considered for any intratesticular mass and suspicion of testis cancer.
Testicular Tumor Markers
Testicular cancer is one of the few cancers associated with tumor markers. These markers are well established to help in the diagnosis, prognosis, treatment and monitoring of testis cancer.
Additional imaging can be performed before or after the diagnosis of cancer is confirmed, based on the strength of suspicion for cancer. Abdominal and pelvic computed tomography (CT) scan can be performed before or after orchiectomy to evaluate the retroperitoneum. Once cancer is confirmed, an initial chest X-ray should be performed to rule out involvement in the lungs. Chest CT is only warranted if there is a suspicion of pulmonary disease on X-ray. Routine imaging of the brain or bones — with magnetic resonance imaging (MRI), positron emission tomography (PET) or bone scan — is not recommended unless specific symptoms are present and are therefore not routinely performed in the initial evaluation of testis cancer.
Biopsy (or removal of just a portion of the tumor) is not recommended for testis cancers, as this can spread the cancer. Therefore, surgical removal of the testicle is diagnostic (confirming the clinical suspicion provided by physical examination, ultrasound and tumor markers) and therapeutic in most cases.
Testis Cancer Tumor Markers
Testicular cancer is one of the few cancers associated with tumor markers . It is not clear why testicular cancers release these markers. Most testis cancers that secrete tumor markers are nonseminomatous germ cell tumors (NSGCT), and 85 percent of NSGCT will secrete at least one tumor marker. These cancers often develop from the germ cells in the testis that have the potential to transform into a variety of cell types. It is hypothesized that as these germ cells turn into cancer cells, they turn on genes and secrete proteins usually only released during fetal development.
Despite the lack of understanding as to the cause of elevated tumor markers, these markers are well established to help in the diagnosis, prognosis, treatment and monitoring of testis cancer. However, many patients and their families are confused about where tumor markers come from, what an elevation in a level means and how markers should change over time. There are three important tumor markers for testicular cancer:
Normal range: <40 micrograms/L
Half life: 5 to 7 days
AFP is a protein secreted by the fetal yolk sac, liver and gastrointestinal tract and appears in high levels in the blood of the fetus. AFP can be secreted by NSGCT that contain embryonal carcinoma, yolk sac tumor or teratoma. By definition, seminoma or choriocarcinoma do not secrete AFP. Therefore any patient with an elevated AFP must have a nonseminomatous component of testis cancer.
AFP can be elevated in patients with a number of other malignancies, including with hepatocellular (liver) carcinoma, cancer of the stomach, pancreas, biliary tract and lung. In addition, AFP elevation is associated with a number of nonmalignant diseases, including diseases of the liver and the rare diseases ataxic telangiectasia and hereditary tyrosinemia.
Human Chorionic Gonadotropin (HCG)
Normal range: <5 IU/L
Half life: 24 to 36 hours
HCG is a glycoprotein produced by the placenta to maintain the corpus luteum during pregnancy. HCG can be elevated in a number of other malignancies, including cancers of the liver, lung, pancreas and stomach. In germ cell tumors of the testis, including both seminomas and NSGCT, cancerous cells can transform into syncytiotrophoblasts (a normal component of the placenta) and secrete HCG. Levels greater than 5,000 IU are usually indicative of NSGCT, and in NSGCT, higher levels of HCG are associated with a worse prognosis. However, HCG-producing seminoma (approximately 15 percent of seminomas) has the same prognosis as seminoma that does not produce HCG.
The HCG molecule is cross-reactive with another protein, luteinizing hormone (LH). Hypogonadal men can have elevated LH levels and subsequently falsely elevated HCG levels — administration of exogenous testosterone can help distinguish HCG elevation from hypogonadism from HCG from testis cancer. In addition, marijuana smoking has been associated with an elevated HCG level.
Testicular Lactate Dehydrogenase (LDH)
Normal range: 1.5–3.2 microkat/L
Half life: 24 hours
LDH is a cellular enzyme found in every tissue in the body. Highest concentrations of LDH in normal tissue are found in muscle (including skeletal, cardiac and smooth muscle), liver and brain. LDH is expressed on chromosome 12p, which is often amplified in testis cancer cells. LDH is less specific for testis cancer than HCG or AFP. However, elevated LDH levels are correlated to high tumor burden in seminoma and recurrence in NSGCT.
Staging of Testis Cancer
The staging of testis cancer refers to how far the cancer has spread. Staging is determined with information from the orchiectomy, tumor markers and imaging studies.
As the testicles form and develop near the kidneys in a fetus, the blood supply, lymphatic drainage and nerves to the testicle originate near the kidney on that side. Therefore, testis cancer has a very predictable pattern of spread. The first place these cancers typically spread is to the lymph nodes around the kidneys, an area called the retroperitoneum. In addition, because testis cancer can secrete tumor markers, blood tests can also determine the spread of disease (patients with very high tumor markers are presumed to have distant metastatic disease).
If the cancer is confined to the testicle it is known as localized cancer. These cancers are also termed stage I cancers. Stage I cancers can be further subdivided into stage IA, IB and IS disease. Stage IA refers to cancers limited to the testicle, without lymphovascular invasion (LVI). LVI is indicative of the aggressiveness of a cancer and the likelihood of spread beyond the testicle. Men with LVI have stage IB cancer. Men with stage IS cancer have their tumor confined to the testicle, but elevated tumor markers after orchiectomy.
If the cancer has spread to the retroperitoneal lymph nodes, it is known as regional spread. Men with regional spread have stage II disease. If cancer has spread beyond the lymph nodes, it is termed distant metastatic disease. Common sites of metastatic spread include the chest, lungs, brain and lymph nodes of the chest or neck. These men have stage III disease.
Clinical stage refers to how far it appears the cancer has spread based on imaging (like a CT scan). Pathological stage refers to how far cancer has actually spread and is confirmed when tumors are surgically removed, usually after retroperitoneal lymph node dissection.
Prognosis of Testis Cancer
The cure rate for testis cancer is excellent, with approximately 95 percent of men cured. Cure rates depend on the stage of cancer. Men with localized cancer (stage I: cancer confined to the testicle) have a cure rate of about 99 percent. Men with regional spread (stage II: cancer in the lymph nodes of the retroperitoneum) have a cure rate of about 95 percent. Men with distant metastatic disease (stage III) have a cure rate of about 75 percent.
Importantly, approximately 80 percent of testis cancers that recur or progress will do so within the first year of diagnosis. An additional 15 percent to 20 percent will recur within two years of initial diagnosis. Less than 5 percent of men will have a recurrence or progression of cancer after two years.
The best way to preserve fertility is by sperm banking prior to beginning cancer treatment. Even if you are not ready to start a family, sperm can be stored for many years. Labs needed prior to sperm cryopreservation: HIV, hepatitis B, hepatitis C, rapid plasma reagin (RPR).
Please call the Assisted Reproductive Technologies (ART) Laboratory at 410-583-2714 for more information and to schedule an appointment.
There are several agencies that provide financial assistance for qualifying patients. Please inquire with your practitioner at Johns Hopkins for guidance.