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testicular cancer

Testis Cancer Definition
The testicles are the male reproductive organs located in the scrotum, just beneath the penis.  The testicles have two main functions:

  • The testicles produce sperm for reproduction
  • The testicles 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% of the testicle, the most common type of testis cancer is a germ cell tumor (see Types of Testis Cancer to learn about the rarer testis tumors).

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 1 in 270.  Fortunately, the cure rate is excellent (>95% 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 1 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 US. 
Testis cancer is most common in men in their late 20’s and early 30’s with an average age at diagnosis of 33 years-old.  In fact, testis cancer is the most common malignancy among men 20-40 years old. However, testis cancer can occur at any age: it is the 2nd most common malignancy in young men 15-19 years-old (leukemia is #1) with approximately 6% of cases occurring in children and teens, and about 7% occur 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 men, and Asian-American men.  In fact, white men are 4-5 times more likely to have testis cancer than black men and 3-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.

Risk Factors
There are four well-established risk factors for testis cancer:

  • Cryptorchidism (an undescended testicle)
  • Family History
  • Personal History
  • Intratubular germ cell neoplasia (ITGCN)

The most common risk factor for testis cancer is a history of cryptorchidism, otherwise known as an undescended testicleNormally in the developing male fetus, the testicles form near the kidneys in the abdomen (belly).  About the eight month of pregnancy, the testicles descend, exit the body and settle in the scrotum.  About 3% of boys will 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 (4 to 6-fold increased risk of cancer), but the risk of cancer is also higher in the normal testicle (less than 2-fold 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 (2 to 3-fold 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 8 to 12-fold risk if a brother with testis cancer and a 2 to 4-fold risk if father with testis cancer.  In addition, the average age at diagnosis is 2-3 years younger than 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 2% of men with 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 20’s or earlier, men with seminoma and men with intratubular germ cell neoplasia (ITGCN) have a higher risk of developing a second testis cancer. 
Most testis cancer arise from the precursor lesion known as ITGCN (or carcinoma-in-situ, CIS).  ITGCN is present adjacent to testis cancer in 80-90% of patients.  For men in whom ITGCN is found for other reasons, the risk of subsequent testis cancer is 50% at 5 years and 70% at 7 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 (GCT).  There are two main types of GCT: Seminoma and Non-Seminomatous 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.
Seminoma
Tend to grow and spread more slowly than NSGCT, although some seminomas can grow very rapidly.  Subtypes of seminoma include:

  • classic seminoma – 95% 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 (see the section on Tumor Markers for more details).  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.
Non-Seminomatous Germ Cell Tumors (NSGCT)
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% of tumors, among the most rapidly growing and potentially aggressive tumor types.  Embryonal carcinoma can secrete HCG or alpha-fetoprotein (AFP).
  • Yolk Sac carcinoma – most common type of tumor in children, respond 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.

Stromal Tumors
Tumors can also develop from the supportive tissues around the germ cells in the testicle.  These tumors are rare, less than 5% 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 – the Sertoli cells support and nourish the developing sperm and are usually benign tumors.

testis cancer


Initial Diagnosis: Symptoms and Initial Evaluation

Initial Diagnosis: Symptoms and Initial Evaluation
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, non-palpable 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% of non-palpable, asymptomatic masses that are 2cm or smaller will be benign tumors.  Benign lesions may include testicular cysts, small infarcts, Leydig cell nodules, 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% 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, infertility can be the initial presentation in rare men. 
The initial evaluation of a possible testis cancer should involve:

  • Scrotal ultrasound
  • Testicular tumor markers
  • Advanced Imaging (optional)
  • Orchiectomy

Scrotal Ultrasound
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 intra-testicular mass and suspicion of testis cancer.
Testicular Tumor Markers (see Testis Cancer Tumor Markers for more details)
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. 
Advanced Imaging
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 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 suspicion of pulmonary disease on x-ray.  Routine imaging of the brain or bones (with MRI, PET or Bone Scan) is not recommended unless specific symptoms and are therefore not routinely performed in the initial evaluation of testis cancer.
Orchiectomy (see Treatment of Testis Cancer for details)
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.  Surgical options are discussed in more details under Treatment of Testis Cancer.

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 non-seminomatous germ cell tumors (NSGCT) and 85% 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:

  • AFP (alpha fetoprotein)
  • HCG (human chorionic gonadotropin)
  • LDH (lactate dehydrogenase)

ALPHA-FETOPROTEIN (AFP)
NORMAL RANGE <40 micrograms/L
HALF-LIFE 5-7 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 non-seminomatous 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 non-malignant 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 24-36 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% of seminomas) has the same prognosis as seminoma that does not produce HCG. 
The HCG molecule is cross-reactive with another protein, leutenizing 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.

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/Prognosis

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 sub-divided 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 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 (RPLND).
The National Comprehensive Cancer Network (NCCN) outlines the Staging System for Testis Cancer.  The NCCN Guidelines for Testis Cancer can be found here: http://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf

Prognosis of Testis Cancer
The cure rate for testis cancer is excellent, with approximately 95% of the 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%.  Men with regional spread (Stage II: cancer in the lymph nodes of the retroperitoneum) have a cure rate of about 95%.  Men with distant metastatic disease (Stage III) have a cure rate of about 75%.
Importantly, approximately 80% of testis cancers that recur or progress, will do so within the first year of diagnosis.  An additional 15-20% will recur within two years of the initial diagnosis.  Less than 5% of men will have a recurrence or progression of cancer after two years.

Treatment of Testis Cancer

Orchiectomy (Radical Orchiectomy, Testis Sparing Surgery)
While scrotal ultrasound and serum tumor markers (beta-human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase) are the first steps in the diagnosis of a testis cancer, the diagnosis is not confirmed until an orchiectomy (surgical removal of the testicle) is performed.  The standard-of-care for the removal and treatment of testis cancer is a radical, inguinal orchiectomy.  This is the most common operation performed for testis cancer worldwide. However, as our understanding of this disease and surgical technique has improved, testis-sparing surgery or partial orchiectomy has become an option for some patients.

RADICAL ORCHIECTOMY
Rationale
This surgery involves removing the testicle and spermatic cord where it exits the body to identify and likely treat the majority of cancers localized to the testis.  As a male fetus develops, the testes develop near the fetal kidneys.  As the fetus grows, the testicles separate from the kidneys and, at about the eighth month of pregnancy, the testicles exit the body wall to rest in the scrotum (this is why premature infants have a higher likelihood of having undescended testicles).  Therefore the blood supply, lymphatic drainage and nerves to the testicle originate near the kidney on that side.  Once these structures exit the body through the internal inguinal ring they fuse with muscles of the body wall to form the spermatic cord.  To correctly stage and prevent any cancer from spreading, the spermatic cord must be taken as high toward or inside the body as possible -- hence the incision in the groin rather than the scrotum.
For men whose cancer has spread from the testicle and who have metastatic testis cancer (elsewhere in the body) or in the lymph nodes of the retroperitoneum, radical orchiectomy is an important first step in the diagnosis and management of disease.  Knowing the type of cancer may help guide chemotherapy or radiation treatments.

Surgery
The surgery can be performed under general or local anesthetic.  An approximately 5-10cm incision is made in the groin, just above the pubic tubercle (pubic bone) near the inguinal ligament.  This incision facilitates access to both the testicle and the proximal inguinal canal.  The skin incision is relatively painless, so a larger incision should be made to facilitate delivery of a large testicular tumor or to help with access to the spermatic cord.  The incision is carried down to the external oblique fascia (the outermost layer of the body wall).  The external oblique creates a tunnel through which the spermatic cord travels -- a hernia can form when there is weakness in these layers of the body wall.  Once the external oblique fascia is identified, the cord can then be identified exiting the external spermatic ring.  The cord should be isolated and the external fascia will need to be opened to gain access to the internal ring and to take the spermatic cord where it exits the body.  This can be done in either order.  Care should be taken to separate and preserve the ilioinguinal nerve which travels along the spermatic cord.  Once the cord is isolated, an occlusive, but non-crushing clamp or elastic drain can be used to stop blood supply to and from the testicle.  This prevents any "shedding" of tumor cells when the testicle is manipulated.  The testicle can then be "delivered" from the scrotum.  To deliver the testicle the scrotum can be inverted until the testicle is visible, facilitating dissection of the testicle from its scrotal contents.

Once the testicle and spermatic cord are entirely free from the inguinal canal, the testicle can be removed.  The spermatic cord should be ligated in two packets - one containing the gonadal artery and one containing the vas deferens (sperm duct) and its associated artery.  A large, non-absorbable suture should also be tied to the distal spermatic cord to facilitate easy identification in the case that a retroperitoneal lymph node dissection needs to be performed in the future.  Care should be taken to close the external oblique fascia to the level of the external ring to prevent future hernia.

Complications
The biggest risk of a radical orchiectomy is hematoma (or bleeding into the scrotum).  It is very common for the scrotum to be bruised, swollen and tender for 2-4 weeks after surgery.  However, a large, purple-appearing scrotum can indicate a hematoma.  Hematoma can be prevented with a compressive dressing, tight-fitting undergarments and/or ice packs.
Ilioinguinal nerve injury can occur if the nerve is damaged during dissection of the spermatic cord.  This is more common in men who underwent prior inguinal surgery (usually for an undescended testicle or hernia repair) and can occur during dissection or be inadvertently trapped in the closure of the external oblique fascia.  The deficit is often decreased sensation to the medial thigh, scrotum or base of the penis.  It is often transient, but can take several weeks or months to improve.
Inguinal hernia can occur if the external oblique fascia is not closed properly or if the closure breaks down.  It is important to minimize strenuous activities for 2-4 weeks to prevent development of a hernia.
Testicular Prosthesis
Prostheses should be offered to all men undergoing orchiectomy.  Not all men want a prosthesis -- it is a personal decision.  The prosthesis should be measured in the operating room with the patient asleep.  The goal should be to match the remaining testicle in size taking into account a cancerous testicle can be larger or smaller than normal, and the scrotal skin will make a prosthesis look larger once implanted.

TESTIS-SPARING SURGERY (PARTIAL ORCHIECTOMY)
Rationale
While radical orchiectomy remains the standard-of-care for the diagnosis and treatment of testis cancer, there are a couple of circumstances where testis-sparing surgery is advocated.  The primary indications are in men with:

  • bilateral testis cancers (either synchronous, at the same time; or metachronous, that develop some time after the first testicle is removed)
    • the standard-of-care would be to remove both testicles under suspicion of cancer, however the implications regarding fertility and testosterone replacement are well-established
  • small, palpable testis masses and normal serum tumor markers
    • these men have a low, but significant risk of having a benign mass or non-germ cell cancer that does not require orchiectomy
    • if a testis cancer is confirmed, a radical orchiectomy is completed
  • small, non-palpable, ultrasound detected testis mass with normal tumor markers
    • approximately 80% likelihood of benign mass

Some urologists advocate for testis-sparing surgery even for men with germ cell tumors of the testicle.  While some evidence indicates that this can be done safely in some patients, it is not a proven or well-established technique.  Before undergoing testis-sparing surgery, an extensive consultation should occur with the patient and their family regarding expectations and possible outcomes in the operating room.

Surgery
The beginning portion of a testis-sparing surgery is identical to a radical orchiectomy.  Once the testicle is "delivered," the testis-sparing portion should begin.  The tunica vaginalis should be opened vertically to expose the testicle and intraoperative ultrasound should be used to identify the mass, rule-out other masses and create a surgical plan.  The testicle should be iced down for 10 minutes prior to placing a tourniquet or non-crushing clamp on the spermatic cord.  Once the testicle has been iced, a clamp or tourniquet should be placed on the cord.  The tunica albuginea (which houses the tubules of the testicle) should be opened horizontally above the mass.  The mass can often be "shelled" out of the surrounding tubules with a margin of 3-5mm.  Surgical loupes or a microscope can be used to facilitate dissection with a clean margin.  Bipolar forceps can be used to control any bleeding to prevent injury to the remaining tubules.  The mass should then immediately go to pathology for frozen analysis - an expert genitourinary pathologist should evaluate the mass when possible.
If the patient has a normal contralateral testicle and cancer is confirmed in the mass, a completion radical orchiectomy should be performed.
If the patient has (or had) cancer in the contralateral testicle, the pathologist should confirm negative margins before leaving the remainder of the testicle.  If any suspicion of residual cancer, the testicle should be removed.  Once again, the standard-of-care is bilateral orchiectomy and testosterone can easily be replaced.

Complications
The complications are the same for radical orchiectomy and testis-sparing surgery.  In addition, even if testis-sparing surgery is performed, surgery can result in infertility or hypogonadism if the internal blood supply to the testicle is harmed or if the tubules are disrupted.

Cryopreservation
Retroperitoneal Lymph Node Dissection
Minimally-Invasive RPLND
Post-chemotherapy RPLND

 

FACULTY


Phillip M. Pierorazio, M.D.
Assistant Professor of Urology and Oncology
Director, Division of Testis Cancer
Director of Social Media


Christian P. Pavlovich, M.D.
Associate Professor of Urology
Director, Urologic Oncology
Director, Urologic Oncology Fellowship


Mohamad E. Allaf, M.D.
Associate Professor of Urology, Oncology, and Biomedical Engineering
Director, Minimally Invasive and Robotic Surgery



Trinity J. Bivalacqua, M.D, Ph.D
Associate Professor of Urology, Surgery, and Oncology
Director of Urologic Oncology
Associate Program Director Urologic Oncology Fellowship


Pravin Rao, M.D.
Assistant Professor
Director of Reproductive Medicine and Surgery






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