Testicular Cancer

1. What are the Causes and Risk factors of Testicular Cancer?
2. What are the Symptoms of Testicular Cancer?
3. Classification
4. Diagnosis
     4.1 Staging
5. Methods of Treatment
     5.1 Surgery
          5.1.1 Orchiectomy
          5.1.2 Retroperitoneal Lymph Node Dissection (RPLND)
     5.2 Radiation therapy
     5.3 Chemotherapy
6. Drugs rating
7. Prognosis
     7.1 Surveillance
     7.2 Fertility
8. Follow-up
9. Discussion and questions

Testicular cancer is a disease in which cells become malignant (cancerous) in one or both testicles.

The testicles (also called testes or gonads) are a pair of male sex glands. They produce and store sperm and are the main source of testosterone (male hormones) in men. These hormones control the development of the reproductive organs and other male physical characteristics. The testicles are located under the penis in a sac-like pouch called the scrotum.

Based on the characteristics of the cells in the tumor, testicular cancers are classified as seminomas or nonseminomas. Other types of cancer that arise in the testicles are rare and are not described here. Seminomas may be one of three types: classic, choriocarcinoma, embryonal carcinoma, teratoma, and yolk sac tumors. Testicular tumors may contain both seminoma and nonseminoma cells.

Testicular cancer accounts for only 1 percent of all cancers in men in the United States. About 8,000 men are diagnosed with testicular cancer, and about 390 men die of this disease each year. Testicular cancer occurs most often in men between the ages of 20 and 39, and is the most common form of cancer in men between the ages of 15 and 34. It is most common in white men, especially those of Scandinavian descent. The testicular cancer rate has more than doubled among white men in the past 40 years, but has only recently begun to increase among black men. The reason for the racial differences in incidence is not known.

What are the Causes and Risk factors of Testicular Cancer?

The exact causes of testicular cancer are not known. However, studies have shown that several factors increase a man’s chance of developing this disease.

• Undescended testicle (cryptorchidism): Normally, the testicles descend from inside the abdomen into the scrotum before birth. The risk of testicular cancer is increased in males with a testicle that does not move down into the scrotum. This risk does not change even after surgery to move the testicle into the scrotum. The increased risk applies to both testicles.
• Congenital abnormalities: Men born with abnormalities of the testicles, penis, or kidneys, as well as those with inguinal hernia (hernia in the groin area, where the thigh meets the abdomen), may be at increased risk.
• History of testicular cancer: Men who have had testicular cancer are at increased risk of developing cancer in the other testicle.
• Family history of testicular cancer: The risk for testicular cancer is greater in men whose brother or father has had the disease.

What are the Symptoms of Testicular Cancer?

A testicular mass can often be palpated. The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening for testicular cancer in asymptomatic adolescent and adults, which means that men should not perform routine testicular self-exams. This practice was encouraged in the past, but current scientific evidence suggests that screening for testicular cancer does not lead to decreased morbidity and mortality, and there are real harms associated with screening for this disease.

Symptoms may include one or more of the following:

• a lump in one testis which may or may not be painful
• sharp pain or a dull ache in the lower abdomen or scrotum
• a feeling often described as “heaviness” in the strotum
• breast enlargement (gynecomastia) from hormonal effects of β-hCG
• low back pain (lumbago) tumor spread to the lymph nodes along the back
• shortness of breath (dyspnea), cough or coughing up blood (hemoptysis) from metastatic spread to the lungs
• a lump in the neck due to metastases to the lymph nodes

The nature of any palpated lump in the scrotum is evaluated by scrotal ultrasound, which can determine exact location, size, and some characteristics of the lump, such as cystic vs solid, uniform vs heterogeneous, sharply circumscribed or poorly defined. The extent of the disease is evaluated by CT scans, which are used to locate metastases. Blood tests are also used to identify and measure tumor markers that are specific to testicular cancer. AFP alpha1 feto protein, Beta-HCG, and LDH are the typical markers used to identify testicular cancer. The diagnosis is made by performing an inguinal orchiectomy, surgical excision of the entire testis along with attached structures epididymis and spermatic cord; the resected specimen is evaluated by a pathologist. A biopsy should not be performed, as it raises the risk of migrating cancer cells into the scrotum. The reason why inguinal orchiectomy is the preferred method is that the lymphatic system of the scrotum links to the lower extremities and that of the testicle links to the retroperitoneum. A transscrotal biopsy or orchiectomy will potentially leave cancer cells in the scrotum and create two vectors for cancer spread, while in an inguinal orchiectomy only the retroperitoneal route exists.

Classification

Although testicular cancer can be derived from any cell type found in the testicles, more than 95% of testicular cancers are germ cell tumors. Most of the remaining 5% are sex cord-gonadal stromal tumours derived from Leydig cells or Sertoli cells. Correct diagnosis is necessary to ensure the most effective and least harmful treatment. To some extent, this can be done via blood tests for tumor markers, but definitive diagnosis requires examination of the histology of a specimen by a pathologist.

Most pathologists use the World Health Organization Classification system for testicular tumours:

• Germ cell tumours
  • Precursor lesions
    • Intratubular germ cell neoplasia
    • Unclassified type (carcinoma in situ)
    • Specifed types
  • Tumours of one histologic type (pure forms)
    • Seminoma
    • Variant – Seminoma with syncytiotrophoblastic cells
    • Spermatocytic seminoma
    • Variant – spermatocytic seminoma with sarcoma
    • Embryonal carcinoma
    • Yolk sac tumour
    • Trophoblastic tumours
    • Choriocarcinoma
    • Variant – monophasic choriocarcinoma
    • Placental site trophoblastic tumour
    • Cystic trophoblastic tumour
    • Teratoma
    • Variant – Dermoid cyst
    • Variant – Epidermoid cyst
    • Variant – Monodermal teratoma (Carcinoid, Primitive neuroectodermal tumour (PNET), Nephroblastoma-like tumor, others.
    • Variant – Teratomic with somatic-type malignancy
  • Tumours of more than one histologic type (mixed forms)
    • Embryonal carcinoma and teratoma
    • Teratoma and seminoma
    • Choriocarcinoma and teratoma.embryonal carcinoma
  • Others
• Sex cord/Gonadal stromal tumours
  • Leydig cell tumour
  • Sertoli cell tumour
  • Lipid rich variant
  • Scleriosing variant
  • Large cell calcifying variant
  • Intratubular sertoli cell neoplasia in Peutz-Jeghers syndrome
  • Granulosa cell tumour
  • Adult type
  • Juvenile type
  • Thecoma Fibroma Group
  • Thecoma
  • Fibroma
  • Sex cord/gonadal stromal tunour – incompletely differentiated
  • Sex cord/gonadal stromal tumour – mixed types
• Mixed Germ Cell and Sex Cord/Gonadal Stromal Tumours
  • Gonadoblastoma
  • Germ cell-sex cord/gonadal stromal tumour, unclassified
• Miscellaneous tumours of the testis
  • Carcinoid
  • Tumours of ovarian epithelial types
  • Serous tumour of borderline malignancy
  • Serous carcinoma
  • Well differentiated endometrioid tumour
  • Mucinous cystadenoma
  • Mucinous cystadenocarcinoma
  • Brenner tumour
  • Nephroblastoma
  • Paraganglioma
• Haematopoietic tumours
• Tumours of collecting ducts and rete
  • Adenoma
  • Carcinoma
• Tumours of the paratesticular structures
  • Adenomatoid tumour
  • Malignant mesothelioma
  • Benign mesothelioma
  • Adenocarcinoma of the epididymis
  • Papillary cystadenoma of the epididymis
  • Melanotic neuroectodermal tumour
  • Desmoplastic small round cell tumour
• Mesenchymal tumours of the spermatic cord and testicular adnexae
  • Lipoma
  • Liposarcoma
  • Rhabdomyosarcoma
  • Aggressive angiomyxoma
  • Angiomyofibroblastoma-like tumour
  • Fibromatosis
  • Fibroma
  • Solitary fibrous tumour
  • Others
• Secondary tumours of the testis

Diagnosis

To help find the cause of symptoms, the doctor evaluates a man’s general health. The doctor also performs a physical exam and may order laboratory and diagnostic tests. These tests include:

• Blood tests that measure the levels of tumor markers. Tumor markers are substances often found in higher-than-normal amounts when cancer is present. Tumor markers such as alpha-fetoprotein (AFP), Beta-human chorionic gonadotropin (ЯHCG), and lactate dehydrogenase (LDH) may suggest the presence of a testicular tumor, even if it is too small to be detected by physical exams or imaging tests.
• Ultrasound, a test in which high-frequency sound waves are bounced off internal organs and tissues. Their echoes produce a picture called a sonogram. Ultrasound of the scrotum can show the presence and size of a mass in the testicle. It is also helpful in ruling out other conditions, such as swelling due to infection or a collection of fluid unrelated to cancer.
• Biopsy (microscopic examination of testicular tissue by a pathologist) to determine whether cancer is present. In nearly all cases of suspected cancer, the entire affected testicle is removed through an incision in the groin. This procedure is called radical inguinal orchiectomy. In rare cases (for example, when a man has only one testicle), the surgeon performs an inguinal biopsy, removing a sample of tissue from the testicle through an incision in the groin and proceeding with orchiectomy only if the pathologist finds cancer cells. (The surgeon does not cut through the scrotum to remove tissue. If the problem is cancer, this procedure could cause the disease to spread.)

If testicular cancer is found, more tests are needed to find out if the cancer has spread from the testicle to other parts of the body. Determining the stage (extent) of the disease helps the doctor to plan appropriate treatment.

Staging

After removal, a testicular tumor is staged by a pathologist according to the TNM Classification of Malignant Tumors as published in the AJCC Cancer Staging Manual. Testicular cancer is categorized as being in one of three stages (which have subclassifications). The size of the tumor in the testis is irrelevant to staging. In broad terms, testicular cancer is staged as follows:

• Stage 1: the cancer remains localized to the testis.
• Stage 2: the cancer involves the testis and metastasis to retroperitoneal and/or Paraaortic lymph nodes (lymph nodes below the diaphragm).
• Stage 3: the cancer involves the testis and metastasis beyond the retroperitoneal and Paraaortic lymph nodes. Stage 3 is further subdivided into non-bulky stage 3 and bulky stage 3.
• Stage 4: if there is liver and/or lung secondaries

Methods of Treatment

Although the incidence of testicular cancer has risen in recent years, more than 95 percent of cases can be cured. Treatment is more likely to be successful when testicular cancer is found early. In addition, treatment can often be less aggressive and may cause fewer side effects.

Most men with testicular cancer can be cured with surgery, radiation therapy, and/or chemotherapy. The side effects depend on the type of treatment and may be different for each person.

Seminomas and nonseminomas grow and spread differently and are treated differently. Nonseminomas tend to grow and spread more quickly; seminomas are more sensitive to radiation. If the tumor contains both seminoma and nonseminoma cells, it is treated as a nonseminoma. Treatment also depends on the stage of the cancer, the patient’s age and general health, and other factors. Treatment is often provided by a team of specialists, which may include a surgeon, a medical oncologist, and a radiation oncologist.

The three types of standard treatment are described below.

Surgery

Orchiectomy

While it may be possible, in some cases, to remove testicular cancer tumors from a testis while leaving the testis functional, this is almost never done, as the affected testicle usually contains pre-cancerous cells spread throughout the entire testicle. Thus removing the tumor alone without additional treatment greatly increases the risk that another cancer will form in that testicle . Since only one testis is typically required to maintain fertility, hormone production, and other male functions, the afflicted testis is almost always removed completely in a procedure called inguinal orchiectomy. (The testicle is almost never removed through the scrotum; an incision is made beneath the belt line in the inguinal area.) Most notably, since removing the tumor alone does not eliminate the precancerous cells that exist in the testis, it is usually better in the long run to remove the entire testis to prevent another tumor. A plausible exception could be in the case of the second testis later developing cancer as well. In the UK, the procedure is known as a Radical Orchidectomy.

Retroperitoneal Lymph Node Dissection (RPLND)

In the case of nonseminomas that appear to be stage I, surgery may be done on the retroperitoneal/Paraaortic lymph nodes (in a separate operation) to accurately determine whether the cancer is in stage I or stage II and to reduce the risk that malignant testicular cancer cells that may have metastasized to lymph nodes in the lower abdomen. This surgery is called Retroperitoneal Lymph Node Dissection (RPLND). However, this approach, while standard in many places, especially the United States, is out of favor due to costs and the high level of expertise required to perform the surgery. The urologist may take extra care in the case of males who have not fathered children, to preserve the nerves involved in ejaculation.

Many patients are instead choosing surveillance, where no further surgery is performed unless tests indicate that the cancer has returned. This approach maintains a high cure rate because of the growing accuracy of surveillance techniques.

Lymph node surgery may also be performed after chemotherapy to remove masses left behind, particularly in the cases of advanced initial cancer or large nonseminomas.

Radiation therapy

Radiation therapy (also called radiotherapy) uses high-energy rays to kill cancer cells and shrink tumors. It is a local therapy, meaning that it affects cancer cells only in the treated areas. External radiation (from a machine outside the body), aimed at the lymph nodes in the abdomen, is used to treat seminomas. It is usually given after surgery. Because nonseminomas are less sensitive to radiation, men with this type of cancer usually do not undergo radiation therapy.

Radiation therapy affects normal as well as cancerous cells. The side effects of radiation therapy depend mainly on the treatment dose. Common side effects include fatigue, skin changes at the site where the treatment is given, loss of appetite, nausea, and diarrhea. Radiation therapy interferes with sperm production, but many patients regain their fertility over a period of 1 to 2 years.

Chemotherapy

Chemotherapy is the use of anticancer drugs to kill cancer cells. When chemotherapy is given to testicular cancer patients, it is usually given as adjuvant therapy (after surgery) to destroy cancerous cells that may remain in the body. Chemotherapy may also be the initial treatment if the cancer is advanced; that is, if it has spread outside the testicle at the time of the diagnosis. Most anticancer drugs are given by injection into a vein.

Chemotherapy is a systemic therapy, meaning drugs travel through the bloodstream and affect normal as well as cancerous cells throughout the body. The side effects depend largely on the specific drugs and the doses. Common side effects include nausea, hair loss, fatigue, diarrhea, vomiting, fever, chills, coughing/shortness of breath, mouth sores, or skin rash. Other side effects include dizziness, numbness, loss of reflexes, or difficulty hearing. Some anticancer drugs also interfere with sperm production. Although the reduction in sperm count is permanent for some patients, many others recover their fertility.

Some men with advanced or recurrent testicular cancer may undergo treatment with very high doses of chemotherapy. These high doses of chemotherapy kill cancer cells, but they also destroy the bone marrow, which makes and stores blood cells. Such treatment can be given only if patients undergo a bone marrow transplant. In a transplant, bone marrow stem cells are removed from the patient before chemotherapy is administered. These cells are frozen temporarily and then thawed and returned to the patient through a needle (like a blood transfusion) after the high-dose chemotherapy has been administered.

Men with testicular cancer should discuss their concerns about sexual function and fertility with their doctor. It is important to know that men with testicular cancer often have fertility problems even before their cancer is treated. If a man has pre-existing fertility problems, or if he is to have treatment that might lead to infertility, he may want to ask the doctor about sperm banking (freezing sperm before treatment for use in the future). This procedure allows some men to have children even if the treatment causes loss of fertility.

Drugs rating:

Prognosis

In the New England Journal of Medicine, treatment of testicular cancer has been called one of the success stories of modern medicine, with sustained response to treatment in more than 90% of cases, regardless of stage. Because of advances in chemotherapy, cure rates now approach 85% overall, with better than 95% for localized disease and 80% for metastatic disease—the best response by any solid tumor.

Surveillance

For many patients with stage I cancer, adjuvant (preventative) therapy following surgery may not be appropriate and patients will undergo surveillance instead. The form this surveillance takes, e.g. the type and frequency of investigations and the length time it should continue, will depend on the type of cancer (non-seminoma or seminoma), but the aim is to avoid unnecessary treatments in the many patients who are cured by their surgery, and ensure that any relapses with metastases (secondary cancers) are detected early and cured. This approach ensures that chemotherapy and or radiotherapy is only given to the patients that need it. The number of patients ultimately cured is the same using surveillance as post-operative “adjuvant” treatments, but the patients have to be prepared to follow a prolonged series of visits and tests.

For both non-seminomas and seminomas, surveillance tests generally include physical examination, blood tests for tumour markers, chest x-rays and CT scanning. However, the requirements of a surveillance programme differ according to the type of disease since, for seminoma patients, relapses can occur later and blood tests are not as good at indicating relapse.

CT scans are performed on the abdomen (and sometimes the pelvis) and also the chest in some hospitals. Chest x-rays are increasingly preferred for the lungs as they give sufficient detail combined with a lower false-positive rate and significantly smaller radiation dose than CT.

The frequency of CT scans during surveillance should ensure that relapses are detected at an early stage whilst minimising the radiation exposure.

For patients treated for stage I non-seminoma, a randomised trial (Medical Research Council TE08) showed that, when combined with the standard surveillance tests described above, 2 CT scans at 3 and 12 months were as good as 5 over 2 years in detecting relapse at an early stage.

For patients treated for stage I seminoma who choose surveillance rather than undergoing adjuvant therapy, there have been no randomised trials to determine the optimum frequency of scans and visits, and the schedules vary very widely across the world, and within individual countries. In the UK there is an ongoing clinical trial called TRISST. This is assessing how often scans should take place and whether magnetic resonance imaging (MRI) can be used instead of CT scans. MRI is being investigated because it does not expose the patient to radiation and so, if it is shown to be as good at detecting relapses, it may be preferable to CT. It is possible that one or more centres in Canada may join the trial in the next year or so.

For more advanced stages of testicular cancer, and for those cases in which radiation therapy or chemotherapy was administered, the extent of monitoring (tests) after treatment will vary on the basis of the circumstances, but normally should be done for five years in uncomplicated cases and for longer in those with higher risks of relapse.

Fertility

A man with one remaining testis can lead a normal life, because the remaining testis takes up the burden of testosterone production and will generally have adequate fertility. However, it is worth the (minor) expense of measuring hormone levels before removal of a testicle, and sperm banking may be appropriate for younger men who still plan to have children.

Less than five percent of those who have testicular cancer will have it again in the remaining testis. A man who loses both testicles will normally have to take hormone supplements (in particular, testosterone, which is created in the testicles), and will be infertile, but can lead an otherwise normal life.

Follow-up

Regular follow-up exams are extremely important for men who have been treated for testicular cancer. Like all cancers, testicular cancer can recur (come back). Men who have had testicular cancer should see their doctor regularly and should report any unusual symptoms right away. Follow-up varies for different types and stages of testicular cancer. Generally, patients are checked frequently by their doctor and have regular blood tests to measure tumor marker levels. They also have regular x-rays and computed tomography, also called CT scans or CAT scans (detailed pictures of areas inside the body created by a computer linked to an x-ray machine). Men who have had testicular cancer have an increased likelihood of developing cancer in the remaining testicle. Patients treated with chemotherapy may have an increased risk of certain types of leukemia, as well as other types of cancer. Regular follow-up care ensures that changes in health are discussed and that problems are treated as soon as possible.