Seminoma

Seminoma is the most type of testicular germ cell tumor. Almost all testicular cancers start in the germ cells in the testicles. This is why testicular cancers are also called germ cell tumors. Germ cells in men produce sperm. The two main types of testicular germ cell tumors are seminomas and nonseminomas (also known as teratomas). Between 40 and 45 out of every 100 testicular cancers (40 to 45%) are pure seminomas and is one of the most treatable cancers with a survival rate of 98% to 99% in early-stage disease ¹.

Seminomas tend to grow and spread more slowly than non-seminomas. The 2 main sub-types of these tumors are classical (or typical) seminomas and spermatocytic seminomas.

1. Classical seminoma: More than 95% of seminomas are classical. These usually occur in men between 25 and 45.
2. Spermatocytic seminoma: This rare type of seminoma tends to occur in older men. The average age is about 65. Spermatocytic tumors tend to grow more slowly and are less likely to spread to other parts of the body than classical seminomas.

Some seminomas can increase blood levels of a protein called human chorionic gonadotropin (HCG). HCG can be checked with a simple blood test and is considered a tumor marker for certain types of testicular cancer. It can be used for diagnosis and to check how the patient is responding to treatment.

While the overall incidence of testicular germ cell tumors is low, at only 1% to 2% of all male malignancies; it remains the most common cancer in the 15 to 35 year age group ².

Most other testicular cancers are mixtures of these non-seminomas:

• Teratoma: Teratomas are germ cell tumors with areas that, under a microscope, look like each of the 3 layers of a developing embryo: the endoderm (innermost layer), mesoderm (middle layer), and ectoderm (outer layer). Pure teratomas of the testicles are rare and do not increase AFP (alpha-fetoprotein) or HCG (human chorionic gonadotropin) levels. Most often, teratomas are seen as parts of mixed germ cell tumors.
• Embryonal carcinoma: These cells are found in about 40% of testicular tumors, but pure embryonal carcinomas occur only 3% to 4% of the time. When seen under a microscope, these tumors can look like tissues of very early embryos. This type of non-seminoma tends to grow rapidly and spread outside the testicle.
• Choriocarcinoma: This is a very rare and fast-growing type of testicular cancer in adults. Pure choriocarcinoma is likely to spread rapidly to other parts of the body, including the lungs, bones, and brain. More often, choriocarcinoma cells are seen with other types of non-seminoma cells in a mixed germ cell tumor. These mixed tumors tend to have a somewhat better outlook than pure choriocarcinomas, although the presence of choriocarcinoma is always a worrisome finding.
• Yolk sac carcinoma: These tumors are so named because their cells look like the yolk sac of an early human embryo. Other names for this cancer include yolk sac tumor, endodermal sinus tumor, infantile embryonal carcinoma, or orchidoblastoma. This is the most common form of testicular cancer in children (especially in infants), but pure yolk sac carcinomas (tumors that do not have other types of non-seminoma cells in them) are rare in adults. When they occur in children, these tumors usually are treated successfully. But they’re of more concern when they occur in adults, especially if they are pure. Yolk sac carcinomas respond very well to chemotherapy , even if they have spread.

Non-seminoma types of germ cell tumors usually occur in men between their late teens and early 30s.

So you might have a mix of some teratoma cells and some embryonal carcinoma cells for example. It’s also possible to have pure teratomas. These types are all treated in the same way.

Some testicular tumors have both seminoma cells and non seminoma cells. Doctors usually treat these in the same way as non seminomas.

Testicular germ cell tumors are the most common solid malignancies affecting young males (age 15 to 45 years). It is ten times more common in males of northern European ancestry and five times more common in all whites compared to others. The overall prevalence of seminoma generally increases with age ³.

Seminoma causes

The exact cause of seminoma is unknown. The most current theory is that environmental endocrine disrupters exert estrogenic and/or antiandrogenic activities, contributing to the arrested development of the gonocyte. The disease probably develops as carcinoma in situ during a short phase of intrauterine growth. One widely accepted theoretical concept is Testicular Dysgenesis syndrome. Testicular Dysgenesis syndrome groups germ cell tumors, impaired spermatogenesis, cryptorchism, and hypospadias based on reports that they share some common risk factors, hypothesized to originate during fetal life. An increased incidence is reported during the past several decades. Roughly 10% of all patients with germ cell tumors had a personal history of undescended testicle (cryptorchidism) ⁴.

A patient with an undescended testicle has at least four times the risk for carcinoma compared to a normal testicle. This risk is increased regardless of the age at repair. Patients with Trisomy 21 are 50 times more likely to have testicular cancer. There is evidence of a recessive gene inheritance in familial testicular cancer. In a Japanese population, this association was linked to the HLA class II allele DRB1*0410, and in a United Kingdom study, it seemed to be associated with a homozygous allele of the GSTP1 locus and expansion of CAG repeats.

There are three main pathologic categories of testicular seminoma: classical, spermatocytic, and seminoma with syncytiocytotrophoblastic cells. Spermatocytic type is rare, occurs in older men, and appears to have better prognosis. The syncytiocytotrophoblastic subtype is associated with increased serum βhCG levels. A seminoma with high mitotic index (>3 mitotic figures/high powered field) is designated an anaplastic seminoma. The name implies a more aggressive tumor, but research fails to support that concern.

Seminoma symptoms

Patients usually present with an asymptomatic testicular mass which may be associated with infertility.

On physical exam, there is usually a unilateral, firm to hard palpable mass in the scrotum which is localized to the testis. This may be associated with a hydrocele that would preclude palpation, so testicular ultrasonography may be needed to identify the mass. Metastatic disease, although rare, can present initially with lymphadenopathy in the retroperitoneum and the anterior mediastinum. Even massive metastatic disease can be produced from a non-palpable testicular malignancy.

Typically, testicular ultrasonography shows an intratesticular mass that is relatively hypoechoic and homogeneous. As the mass increases in size, it may become less homogeneous due to hemorrhage and necrosis.

Testicular cancer is not usually painful. But the first symptom for some men is a sharp pain in the testicle or scrotum. This happens in about 1 in 5 men (20%).

Less common symptoms

If the cancer has spread to lymph glands

Sometimes testicular cancer cells can spread into lymph glands at the back of the tummy (abdomen). This can cause backache or a dull ache in the lower tummy. Your doctor may call these lymph glands the para aortic or retro peritoneal lymph glands.

Less often testicular cancer spreads into lymph glands lower down, such as the pelvic lymph glands.

If testicular cancer has spread to lymph glands in other parts of the body you might feel lumps there, such as around the collarbone or in the neck

If the cancer has spread to the lungs

Sometimes testicular cancer spreads to the lungs. It rarely spreads to other organs in the body. If it has spread to the lungs you may have a cough or feel breathless.

Testicular cancer can usually be cured, even if it has spread when it is diagnosed.

Symptoms due to hormones

Many testicular cancers make hormones that can be detected in blood tests. Occasionally, men with testicular cancer have tender or swollen breasts because of these hormones.

The cells can also spread to lymph nodes in the center of your chest between the lungs – in an area called the mediastinum. If this happens you could have:

• a cough
• difficulty breathing
• difficulty swallowing
• a swelling in your chest

Seminoma diagnosis

The initial evaluation is by testicular ultrasonography. A CT scan of the abdomen and pelvis is the initial staging modality, but it may fail to identify retroperitoneal nodes in 15% to 20%. A chest CT is usually recommended only when there is an abnormal chest x-ray first. PET scanning is not usually part of the initial workup but may be useful in tracking activity and growth in residual masses following definitive chemotherapy ⁵.

Several laboratory values may be useful in following tumor burdens. These include AFP (alpha-fetoprotein), beta-HCG (beta-human chorionic gonadotropin) and LDH (lactate dehydrogenase). Alpha-fetoprotein (AFP) elevation indicates at least some nonseminomatous disease and those patients are then treated as nonseminomas, germ cell patients. Lactate dehydrogenase (LDH) may be used to follow the overall seminomatous tumor burden. Beta-human chorionic gonadotropin (beta-hCG) is present in 5% to 10% of seminoma patients; these usually demonstrate the syncytial cytotrophoblastic subtype. Such elevations tend to be associated with metastatic disease, but the beta-HCG elevation by itself has no connection with overall survival.

As noted earlier, a plain chest film may reveal metastatic disease, and chest CT is only indicated to evaluate abnormalities on the plain abnormalities. Ultrasound is the typically the most useful diagnostic method for follow-up of metastatic masses.

Serum tumor markers and testis cancer: AFP, beta-hCG, and LDH

Alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and lactase dehydrogenase (LDH) play an important role as serum tumor markers in the staging and monitoring of germ cell tumors and should be measured prior to removing the involved testicle ⁶. For patients with nonseminomas, the degree of tumor-marker elevation after the cancerous testicular has been removed is one of the most significant predictors of prognosis ⁷. Serum tumor markers are also very useful for monitoring all stages of nonseminomas and for monitoring metastatic seminomas because elevated marker levels are often the earliest sign of relapse.

Alpha-fetoprotein (AFP)

Elevation of serum AFP is seen in 40% to 60% of men with nonseminomas. Seminomas do not produce AFP. Men who have an elevated serum AFP are to have a mixed germ cell tumor (i.e., nonseminomatous germ cell tumors) even if the pathology shows a pure seminoma, unless there is a more persuasive explanation for the elevated AFP, such as liver disease.

Beta-human chorionic gonadotropin (beta-hCG)

Elevation of the beta subunit of hCG is found in approximately 14% of the patients with stage 1 pure seminoma prior to orchiectomy and in about half of patients with metastatic seminoma ⁸. Approximately 40% to 60% of men with nonseminomas have an elevated serum beta-hCG.

Significant and unambiguously rising levels of AFP and/or hCG are an indication of relapsed germ cell tumor in most cases and are an indication for treatment even in the absence of radiological evidence of metastatic disease. Nonetheless, tumor-marker elevations do need to be interpreted with caution. For example, false-positive hCG levels can result from cross reactivity of the assay with luteinizing hormone, in which case an intramuscular injection of testosterone should result in normalization of hCG values. There are also clinical reports of marijuana use resulting in elevations of serum hCG and some experts recommend querying patients about drug use and retesting hCG levels after a period of abstinence from marijuana use. Similarly, AFP is chronically mildly elevated in some individuals for unclear reasons and can be substantially elevated by liver disease.

Lactase dehydrogenase (LDH)

Seminomas and nonseminomas alike may result in elevated lactate dehydrogenase (LDH) but such values are of less clear prognostic significance because LDH may be elevated in many different conditions unrelated to cancer. A study of the utility of LDH in 499 patients with testicular germ cell tumor undergoing surveillance after orchiectomy or after treatment of stage II or III disease reported that 7.7% of patient visits had elevations in LDH unrelated to cancer, whereas only 1.4% of visits had cancer-related increases in LDH ⁹. Of 15 relapses, LDH was elevated in six and was the first sign of relapse in one. Over 9% of the men had a persistent false-positive increase in LDH. The positive predictive value for an elevated LDH was 12.8%.

A second study reported that among 494 patients with stage 1 germ cell tumors who subsequently relapsed, 125 had an elevated LDH at the time of relapse. Of these 125, all had other evidence of relapse: 112 had a concurrent rise in AFP and/or hCG, one had CT evidence of relapse before the elevation in LDH, one had palpable disease on examination, and one complained of back pain that led to imaging that revealed retroperitoneal relapse ¹⁰. Measuring LDH appears to have little value during surveillance of germ cell tumors for relapse. On the other hand, for patients with metastatic nonseminomatous germ cell tumors, large studies of prognostic models have found the LDH level to be a significant independent predictor of survival on multivariate analysis ¹¹.

Seminoma testicular stages

After someone is diagnosed with testicular cancer, doctors will try to figure out if it has spread, and if so, how far. This process is called staging. The stage of a cancer describes how much cancer is in the body. It helps determine how serious the cancer is and how best to treat it. Doctors also use a cancer’s stage when talking about survival statistics.

The earliest stage of testicular cancer is stage 0 (also called germ cell neoplasia in situ, or GCNIS). The other stage groupings range from I (1) through III (3). There is no stage IV (4) testicular cancer. Some stages are split further to cover more details, using capital letters (A, B, etc.).

As a rule, the lower the number, the less the cancer has spread. A higher number, such as stage III, means cancer has spread more. And within a stage, an earlier letter means a lower stage. Although each person’s cancer experience is unique, cancers with similar stages tend to have a similar outlook and are often treated in much the same way.

The staging system most often used for testicular cancer is the American Joint Committee on Cancer (AJCC) TNM system, which is based on 4 key pieces of information:

• The size and extent of the main tumor (T): How large is the tumor? Has it grown into nearby structures or organs?
• The spread to nearby lymph nodes (N): Has the cancer spread to nearby lymph nodes ? How many, and how big are they?
• The spread (metastasis) to distant sites (M): Has the cancer spread to distant parts of the body? (The most common sites of spread are distant lymph nodes, the bones, the liver, and the lungs.)
• The serum (blood) levels of tumor markers (S): Are any tumor marker levels higher than normal? This includes lactate dehydrogenase (LDH), human chorionic gonadotropin (HCG), and alpha-fetoprotein (AFP).

Numbers or letters after T, N, M, and S provide more details about each of these factors. Higher numbers mean the cancer is more advanced. Once a person’s T, N, M, and S categories have been determined, this information is combined in a process called stage grouping to assign an overall stage.

The system described below is the most recent American Joint Committee on Cancer (AJCC) system, effective as of January 2018. It’s used for germ cell tumors (seminomas and non-seminomas) that occur after puberty, and for sex cord stromal tumors (Leydig cell tumors and Sertoli cell tumors).

Testicular cancer might be given a clinical T category (written as cT) based on the results of a physical exam, biopsy, and imaging tests (as described in Tests for Testicular Cancer). Once surgery is done, the pathologic T category (written as pT) is determined by examining tissue removed during the operation.

Testicular cancer staging can be complex, so ask your doctor to explain it to you in a way you understand.

Table 1. Testicular cancer stages

Footnote:

*The following additional category is not listed on the table above:

NX: Nearby lymph nodes cannot be assessed due to lack of information.

Seminoma treatment

There are several treatment options available for patients with seminoma, but surgery, a radical orchiectomy, is almost always the primary intervention. The surgical approach usually requires an incision in the groin with the removal of the entire testicle and most of the spermatic cord. This is called a radical inguinal orchiectomy and is both therapeutic and a part of the staging procedure. A scrotal incision approach should be avoided in any orchiectomy or surgical testicular exploration where malignancy is suspected ¹³.

Stage 1 disease may be offered single therapy with carboplatin and for more advanced disease Bleomycin, Etoposide, and Cisplatin (BEP) or Etoposide and Cisplatin (EP) may be used.

Most men do not have a significant decrease in testosterone or low testosterone symptoms of sexual dysfunction with the removal of a single testicle. The procedure is not usually a cause of infertility, and 25% of men with testicular malignancies are already infertile before getting a testicular cancer diagnosis.

Sperm counts may increase after removal of the cancerous testicle. Reconstructive surgery with a prosthetic testicle is an option which may be exercised with the primary operation delayed until active treatment is done or completely declined. Retroperitoneal lymph node dissection is more complex and invasive. It is used for staging and is usually open, but laparoscopic approaches are being developed. Complications include immediate problems, such as infection or bowel blockage, and loss of the ability to ejaculate. For these reasons, retroperitoneal lymph node dissections are rarely done for seminoma except possibly for growing, residual abdominal masses not responding to other treatments. Radiation or chemotherapy generally is indicated for the management of positive lymph nodes.

Management (National Comprehensive Cancer Network Guidelines)

Stage 0 Seminomas: Carcinoma in situ (CIS) where the levels of tumor markers like HCG and AFP are not elevated. Treatment may not be needed as long as there are no signs that the carcinoma in situ (CIS) is growing or turning into invasive cancer. The diagnosis is typically made via a biopsy. If carcinoma in situ (CIS) is treated, it is with an orchiectomy (to remove the testicle) or with testicular radiation.

If tumor marker levels are high, then the cancer is not stage 0, even when only carcinoma in situ (CIS) is found in the testicle, and there are no signs of cancer spread. These cases are treated like stage 1 cancers. CT scan of the abdomen and pelvis is required to verify the extent of the malignancy in such cases.

All of the following cancers are treated initially with initial radical orchiectomy. After surgery, there may be several treatment choices as follows:

Stage 1 Seminomas:

• Careful observation (surveillance over 10 years): Usually, recurrence is found in the first 2 years
• Single-agent chemotherapy with carboplatin
• Radiation therapy: Seminoma is quite radiosensitive, but the general trend is to go with chemotherapy in more advanced disease, as seminoma is also very chemosensitive and this avoids radiation-related side effects when there is extensive disease.

Stage 2 A Seminomas

• Radiation Therapy
• Chemotherapy with Bleomycin, Etoposide, and Cisplatin (BEP) or Etoposide and Cisplatin (EP).

Stage 2 B and C Seminomas

• Chemotherapy with Bleomycin, Etoposide, and Cisplatin (BEP) or Etoposide and Cisplatin (EP) is preferred
• Radiation therapy is acceptable if affected nodes are less than 3 cm.

Stage 3 Seminomas

Even though stage 3 cancers have spread by the time they are found, most of them can still be cured.

Both stage 3 seminomas and non-seminomas are treated with radical inguinal orchiectomy, followed by chemo. Depending on the risk group the cancer falls into, this might be with:

• EP (etoposide and cisplatin) for 4 cycles
• BEP (bleomycin, etoposide, and cisplatin) for 3 or 4 cycles
• VIP (etoposide, ifosfamide, and cisplatin) for 4 cycles

If there’s a high suspicion that the cancer might be a testicular choriocarcinoma, chemo may be started without a biopsy or surgery to remove the testicle.

If the cancer has spread to the brain, surgery (if there are only 1 or 2 tumors in the brain), radiation therapy aimed at the brain, or both may also be used. If the tumors in the brain are not bleeding or causing symptoms, some doctors may choose to start the chemo first.

Once chemo is complete, the doctor looks for any cancer that’s left. If scans and tumor marker levels are normal, no further treatment may be needed.

Sometimes a few tumors might be left after treatment. These are most often in the lung or in the retroperitoneal lymph nodes. Further treatment at this point depends on the type of cancer:

• A stage 3 seminoma that’s still there after chemo or doesn’t “light up” on a PET scan, will be watched with CT scans to see if it grows. If it does, more treatment is needed. If the tumors do light up on a PET scan, they could be cancer, and treatment is needed. Treatment may be surgery (such as a retroperitoneal lymph node dissection) or chemo (using a different combination of drugs).

If the cancer is resistant to chemo or has spread to many organs, the usual doses of chemo may not always be enough.The doctor might recommend high-dose chemo followed by a stem cell transplant. Enrolling in a clinical trial of a newer chemo regimen might be another good option.

Stage 4 refers to cancer that has spread to any other organ.

Surveillance

Surveillance for all seminoma stages may include interval CT.

The Testicular Cancer Resource Center recommended follow-up:

Princess Margaret Hospital Protocol

• Years 1-3: Tumor Markers done every 4 months (for the first 2 years only) Chest X-ray done every 8 months Physical exam and Abdominal CT scan done every 4 months
• Years 4-7: Tumor Markers optional Chest X-ray done once a year Physical exam and Abdominal CT scan done every 6 months
• Years 8-10: Tumor Markers optional Chest X-ray done once a year Physical exam and Abdominal CT scan done once a year

Nichols protocol

• Year 1: Tumor Markers and Chest X-ray done every 2 months Abdominal CT scan done every 3 months
• Year 2: Tumor Markers and Chest X-ray done every 2 months Abdominal CT scan done every 4 months
• Years 3-5: Tumor Markers and Chest X-ray done every 6 months Abdominal CT scan done every 6 months
• After Year 5: Tumor Markers and Chest X-ray done once a year

Seminoma prognosis

According to the Testicular Cancer Society: “The overall survival rate is greater than 95%. If diagnosed early, while the cancer is confined to the testicle, the survival rate is 99%. If the cancer has spread to regional lymph nodes the survival rate is 96% and even if there are distant metastases the survival rate is over 70%.”

Seminoma testicular cancer survival rate

Survival rates can give you an idea of what percentage of people with the same type and stage of cancer are still alive a certain amount of time (usually 5 years) after they were diagnosed. They can’t tell you how long you will live, but they may help give you a better understanding of how likely it is that your treatment will be successful.

Keep in mind that survival rates are estimates and are often based on previous outcomes of large numbers of people who had a specific cancer, but they can’t predict what will happen in any particular person’s case. These statistics can be confusing and may lead you to have more questions. Talk with your doctor about how these numbers may apply to you, as he or she is familiar with your situation.

A relative survival rate compares people with the same type and stage of cancer to those in the overall population. For example, if the 5-year relative survival rate for a specific stage of testicular cancer is 90%, it means that people who have that cancer are, on average, about 90% as likely as people who don’t have that cancer to live for at least 5 years after being diagnosed.

Table 2. 5-year relative survival rates for testicular cancer (Based on people diagnosed with cancer of the testicle between 2008 and 2014)

Footnote:

• These numbers apply only to the stage of the cancer when it is first diagnosed. They do not apply later on if the cancer grows, spreads, or comes back after treatment.
• These numbers don’t take everything into account. These survival rates are grouped based on how far the cancer has spread. But other factors, including your age and overall health, the type of testicular cancer, and how well the cancer responds to treatment can also affect your outlook. Ask your doctor to explain how these or other factors might be important for you.
• People now being diagnosed with testicular cancer may have a better outlook than these numbers show. Treatments improve over time, and these numbers are based on people who were diagnosed and treated at least five years earlier.

Abbreviation: SEER = Surveillance, Epidemiology, and End Results

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