Testicular Seminoma

Etiology

The exact etiology 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 (TDS). TDS 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 cryptorchidism.[6][7]

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. In a United Kingdom study, it seemed to be associated with a homozygous allele of the GSTP1 locus and expansion of (CAG)n repeats.

Epidemiology

Testicular germ cell tumors (GCT) are the most common solid malignancies affecting young males (age 15 to 45). It is ten times more common in males of northern European ancestry and five times more common in all White-race males as compared to others. The overall prevalence of seminoma generally increases with age.[8]

Pathophysiology

Testicular seminoma originates in the germinal epithelium of the seminiferous tubules. The disease is thought to result from the proliferation of immature spermatogonia. Arrested gonocyte maturation with the persistence of embryonic features and correspondingly increased genomic instability is the most probable model for the pathogenesis of CIS. The transition from the precursor lesion to invasive cancer is associated with a gain of the short arm of chromosome 12, Isochromosome i(12p), likely involving KRAS2 and possibly NANOG (pseudogenes). The exact mechanism is unknown. However, there is also an increased frequency of isozymes of 7, 15, 19, and X in seminoma.

Histopathology

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 a better prognosis. The syncytiocytotrophoblastic subtype is associated with increased serum βhCG levels. A seminoma with a high mitotic index (>3 mitotic figures/HPF) is designated an anaplastic seminoma. The name implies a more aggressive tumor, but research fails to support that concern.  

Toxicokinetics

Exposure to various factors in adolescence and adulthood appears linked to the development of testicular cancer. Firefighters and aircraft maintenance personnel, and farmers exposed to organochloride pesticides appear to have an increased risk of developing testicular cancer. Case-control studies have revealed significant associations between seminoma and levels of cis-nonachlor, trans-nonachlor, oxychlordane, and total chlordane.

Ochratoxin A, a substance less well-studied, naturally occurs in the mold in grains, coffee, nuts, and spices that have recently been linked to testicular cancer.

History and Physical

Patients usually present with an asymptomatic testicular mass, which may be associated with infertility. Testicular pain from malignancy is relatively rare but still should be included in the differential diagnosis.

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.

Evaluation

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.[9][3][10][11]

Several laboratory values may be useful in following tumor burdens. These include AFP, B-HCG, and LDH. Alpha-fetoprotein (AFP) elevation indicates at least some nonseminomatous disease, and those patients are then treated as nonseminomas, germ cell patients. LDH may be used to follow the overall seminomatous tumor burden. Beta-human chorionic gonadotropin (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 typically the most useful diagnostic method for the follow-up of metastatic masses.

Treatment / Management

Several treatment options are available to these patients, 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.[12][13][14]

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 that 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.

Differential Diagnosis

• Other germ-cell tumors
• Testicular dermoid
• Trauma
• Metastatic disease

Surgical Oncology

NCI has a Phase III clinical trial named Retroperitoneal Lymph Node Dissection in Treating Patients with Testicular Seminoma with Lymphadenopathy or Stage I-IIB Testicular Seminoma.

Sloan Kettering has a Phase I/II Study of Topical SOROO7 in Patients with Skin Metastasis from Cancer.

Radiation Oncology

Testicular seminoma is a germ cell tumor, which is very sensitive to radiation therapy. Radiation therapy planning is based on the results of a contrast-enhanced CT of the chest, abdomen, and pelvis. The optimal IMRT dose has been decreased to 20 to 25 Gy in CS I and to 30 to 36 Gy in CS IIs. Because of low pelvic relapse rates reported in stage I tumors (less than 5%), the indication for pelvic irradiation is no longer. This omission increases post-treatment fertility rates and diminished gastrointestinal toxicity. The optimal RT dose generally recommended is between 25 and 30 Gy in 15 to 20 fractions. Because left-sided primaries tend to relapse around the insertion of the left testicular vein the, left para-aortic region must be included in the irradiated volume. Radiation therapy planning is based on the results of a contrast-enhanced CT of the chest, abdomen, and pelvis.  

Pertinent Studies and Ongoing Trials

Volumetric modulated arc therapy radiotherapy has been studied in which radiation is delivered continuously as the treatment gantry rotates around the patient. With this approach, there is a greater spread of low-dose radiation in healthy tissues.

Proton (PT) pencil scanning beam therapy provides unique depth dose characteristics of protons. There is a significant reduction of doses to adjacent critical structures proximal and distal to the target volume in comparison to more traditional treatments. This therapy allows escalation of doses delivered to the tumor and normal tissue, sparing reducing toxicity and improving quality of life. This is possible only if the proton machine employs the pencil scanning beam, which avoids the production of neutrons and reduces the dose delivered to the total body. Proton therapy is recommended in pediatric patients because of the tenfold decrease in radiation dose. 

Treatment Planning

The optimal IMRT dose decreased to 20 to 25 Gy in CS I and 30 to 36 Gy in CS IIs.

In one study from Mass General, photon beams were weighted to yield a maximum of 26 Gy(RBE) and a minimum of 25.5 Gy(RBE) in 1.5 Gy(RBE)/fraction to the CTV. A 5 mm compensator expansion was added for proton plans to emulate a PTV expansion in photon treatment planning. 

Toxicity and Adverse Effect Management

Proton pencil beam scanning allows more precise targeting of the tumor with a 10 fold decrease in total radion dose compared with IMRT.  

Medical Oncology

Bleomycin, etoposide, and cisplatin (BEP) or etoposide and cisplatin (EP) are the two most common chemotherapy regimens. Recent studies suggest that 3 cycles are as effective as 4, with fewer side effects. 

Staging

Staging: The TNM System

• T stands for tumor size.
• N indicates whether nearby lymph nodes are involved.
• M denotes whether cancer has metastasized (spread).

In the Numerical System

• Stage I describes cancer confined to the testicle.
• Stage II describes cancer with metastases in the pelvis and abdomen.
• Stage III refers to cancer with metastases in the chest.

Management (National Comprehensive Cancer Network - NCCN 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 CIS is growing or turning into invasive cancer. (The diagnosis is typically made via a biopsy.)  If 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 CIS is found in the testicle, and there are no signs of cancer spread. These cases are treated like stage I 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 I 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 thermosensitive, and this avoids radiation-related side effects when there is extensive disease.

Stage II A

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

Stage II B and C

• Chemotherapy with BEP or EP is preferred.
• Radiation therapy is acceptable if affected nodes are less than 3 cm.

Stage III

• Stage III is treated with BEP or EP chemotherapy.

Small tumors are often watched with CT scans to see if they grow. If they do, further treatment is needed. If the tumors are detected on a PET scan, surgery, or different chemotherapy is indicated.

Stage IV

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

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%."

Complications

• Surgery: For all patients, orchiectomy may be complicated by retrograde ejaculation; however, infertility is not seen in all patients. Sperm counts may increase after removal of the cancerous testicle.  
• Complications of radiation therapy and chemotherapy may include anemia, immune compromise, and hair loss.
• Incompletely treated, widespread metastasis may be complicated by extensive bleeding which may be fatal. Frequent sites of metastasis are the lungs, lymph nodes, liver, and bones.