Testicular Cancer

WHAT IS TESTICULAR CANCER?

Testicular cancer is a disease in which malignant (cancer) cells form in the tissues of one or both testicles.

The testicles are 2 egg-shaped glands located inside the scrotum (a sac of loose skin that lies directly below the penis). The testicles are held within the scrotum by the spermatic cord, which also contains the vas deferens and vessels and nerves of the testicles.

The testicles are the male sex glands and produce testosterone and sperm. Germ cells within the testicles produce immature sperm that travel through a network of tubules (tiny tubes) and larger tubes into the epididymis (a long coiled tube next to the testicles) where the sperm mature and are stored.

Almost all testicular cancers start in the germ cells. The two main types of testicular germ cell tumors are seminomas and nonseminomas. These 2 types grow and spread differently and are treated differently. Nonseminomas tend to grow and spread more quickly than seminomas. Seminomas are more sensitive to radiation. A testicular tumor that contains both seminoma and nonseminoma cells is treated as a nonseminoma.

Testicular cancer is the most common cancer in men 20 to 35 years old.

WHAT ARE THE RISK FACTORS OF TESTICULAR CANCER?

Health history can affect the risk of developing testicular cancer. Risk factors for testicular cancer include:

Having had an undescended testicle.
Having had abnormal development of the testicles.
Having a personal or family history of testicular cancer.
Having Klinefelter's syndrome.
Being white.


HOW TO DETECT TESTICULAR CANCER?

Possible signs of testicular cancer include swelling or discomfort in the scrotum.

A painless lump or swelling in either testicle.
A change in how the testicle feels.
A dull ache in the lower abdomen or the groin.
A sudden build-up of fluid in the scrotum.
Pain or discomfort in a testicle or in the scrotum.
Tests that examine the testicles and blood are used to detect (find) and diagnose testicular cancer.

The following tests and procedures may be used:

Physical exam and history: The testicles will be examined to check for lumps, swelling, or pain.
Ultrasound test will be used to check for abnormal sonogram of testicles.
Serum tumor marker test: The following 3 tumor markers are used to detect testicular cancer:
Alpha-fetoprotein (AFP).
Beta-human chorionic gonadotropin (β-hCG).
Lactate dehydrogenase (LDH).
Tumor marker levels are measured before radical inguinal orchiectomy and biopsy, to help diagnose testicular cancer.
Radical inguinal orchiectomy and biopsy: A procedure to remove the entire testicle through an incision in the groin. A tissue sample from the testicle is then viewed under a microscope to check for cancer cells. If cancer is found, the cell type (seminoma or nonseminoma) is determined in order to help plan treatment.
Testicular cancer is broadly divided into seminoma and nonseminoma types

Types are very important for treatment planning because seminomas are more sensitive to radiation therapy. For patients with seminoma (all stages combined), the cure rate exceeds 90%. For patients with low-stage disease, the cure rate approaches 100%.

Tumors which have a mixture of seminoma and nonseminoma components should be managed as nonseminoma. Nonseminoma includes embryonal carcinoma, teratoma, yolk sac carcinoma and choriocarcinoma, and various combinations of these cell types. Tumors that appear to have a seminoma histology but that have elevated serum levels of alpha fetoprotein (AFP) should be treated as nonseminomas. Elevation of the beta subunit of human chorionic gonadotropin (HCG) alone is found in approximately 10% of patients with pure seminoma.

Risk of metastases is lowest for teratoma and highest for choriocarcinoma, with the other cell types being intermediate.

Stage Information

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.

Primary tumor (T)

The extent of primary tumor is classified after radical orchiectomy, and for this reason, a pathologic stage is assigned.

pTX: Primary tumor cannot be assessed*
pT0: No evidence of primary tumor (e.g., histologic scar in testis)
pTis: Intratubular germ cell neoplasia (carcinoma in situ)
pT1: Tumor limited to the testis and epididymis without lymphatic/vascular invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis
pT2: Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
pT3: Tumor invades the spermatic cord with or without vascular/lymphatic invasion
pT4: Tumor invades the scrotum with or without vascular/lymphatic invasion
* [Note: Except for pTis and pT4, extent of primary tumor is classified by radical orchiectomy. TX may be used for other categories in the absence of radical orchiectomy.]

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis with a single lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
N2: Metastasis with a single lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension
N3: Metastasis with a lymph node mass more than 5 cm in greatest dimension
Distant metastasis (M)

MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
M1a: Non-regional nodal or pulmonary metastasis
M1b: Distant metastasis other than to non-regional lymph nodes and lungs
Serum tumor markers (S)

SX: Marker studies not available or not performed
S0: Marker study levels within normal limits
S1: LDH < 1.5 X N* AND
hCG (mIu/ml) < 5000 AND
AFP (ng/ml) < 1000
S2: LDH 1.5-10 X N* OR
hCG (mIu/ml) 5000-50,000 OR
AFP (ng/ml) 1000-10,000
S3: LDH > 10 X N* OR
hCG (mIu/ml) > 50,000 OR
AFP (ng/ml) > 10,000
* [Note: N indicates the upper limit of normal for the LDH assay.]

AJCC stage groupings

Stage 0

pTis, N0, M0, S0
Stage I

pT1-4, N0, M0, SX
Stage IA

pT1, N0, M0, S0
Stage IB

pT2, N0, M0, S0
pT3, N0, M0, S0
pT4, N0, M0, S0
Stage IS

Any pT/Tx, N0, M0, S1-3
Stage II

Any pT/Tx, N1-3, M0, SX
Stage IIA

Any pT/Tx, N1, M0, S0
Any pT/Tx, N1, M0, S1
Stage IIB

Any pT/Tx, N2, M0, S0
Any pT/Tx, N2, M0, S1
Stage IIC

Any pT/Tx, N3, M0, S0
Any pT/Tx, N3, M0, S1
Stage III

Any pT/Tx, any N, M1, SX
Stage IIIA

Any pT/Tx, any N, M1a, S0
Any pT/Tx, any N, M1a, S1
Stage IIIB

Any pT/Tx, N1-3, M0, S2
Any pT/Tx, any N, M1a, S2
Stage IIIC

Any pT/Tx, N1-3, M0, S3
Any pT/Tx, any N, M1a, S3
Any pT/Tx, any N, M1b, any S
Surgical stage

In addition to the clinical stage definitions, surgical stage may be designated based on the results of surgical removal and microscopic examination of tissue.

Stage I

Stage I testicular cancer is limited to the testis. Invasion of the scrotal wall by tumor or interruption of the scrotal wall by previous surgery does not change the stage but does increase the risk of spread to the inguinal lymph nodes, and this must be considered in treatment and follow-up. Invasion of the epididymis tunica albuginea and/or the spermatic cord also does not change the stage but does increase the risk of retroperitoneal nodal involvement and the risk of recurrence. This stage corresponds to AJCC stages I and II.

Stage II

Stage II testicular cancer involves the testis and the retroperitoneal or para-aortic lymph nodes usually in the region of the kidney. Retroperitoneal involvement should be further characterized by the number of nodes involved and the size of involved nodes. The risk of recurrence is increased if more than 5 nodes are involved, if the size of 1 or more involved nodes is larger than 2 centimeters, or if there is extranodal fat involvement. Bulky stage II disease describes patients with extensive retroperitoneal nodes (>5 centimeters) who require primary chemotherapy and who have a less favorable prognosis. This stage corresponds to AJCC stages III and IV (no distant metastasis).

Stage III

Stage III implies spread beyond the retroperitoneal nodes based on physical examination, x-rays, and/or blood tests. Stage III is subdivided into nonbulky stage III versus bulky stage III. In nonbulky stage III, metastases are limited to lymph nodes and lung with no mass larger than 2 centimeters in diameter. Bulky stage III includes extensive retroperitoneal nodal involvement, plus lung nodules or spread to other organs such as liver or brain. This stage corresponds to AJCC stage IV (distant metastasis).



HOW TO TREAT TESTICULAR CANCER?

Testicular cancer is broadly divided into seminoma and nonseminoma for treatment planning because seminomatous types of testicular cancer are more sensitive to radiation therapy. Nonseminomatous testicular tumors include yolk sac tumors.

Stage I Testicular Cancer

Stage I seminoma

Stage I seminoma has a cure rate of greater than 95%.

Radical inguinal orchiectomy-radiation therapy：Removal of the testicle via radical inguinal orchiectomy followed by radiation therapy. Prophylactic irradiation of the retroperitoneal nodes will be performed even with a negative lymphangiogram and/or computed tomographic (CT) scan because approximately 15% of patients will have occult nodal spread that can be cured with irradiation. Patients with tumors with vascular invasion seem at higher risk for nodal metastases.
Radical inguinal orchiectomywith no retroperitoneal node irradiation: Postorchiectomy surveillance should be performed with determination of serum markers, chest x-rays, and CT scans. Patients whose disease recurred will receive radiation therapy or chemotherapy. The overall cure rate is often indistinguishable from that achieved with adjuvant radiation therapy. The size of the primary tumors may be a prognostic factor, as the patients with tumors larger than 6 centimeters have a higher risk of relapse.
Stage I nonseminoma

Stage I nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, a surgical technique for sparing sympathetic ganglia and chains should be used. This technique is associated with postoperative fertility in most patients and appears to be as effective as non-nerve-sparing procedures in preventing retroperitoneal relapse.

Removal of the testicle through the groin followed (in adults) by retroperitoneal lymph node dissection. A nerve-sparing retroperitoneal lymphadenectomy (RPL) that preserves ejaculation in virtually every patient has been described in clinical stage I patients and appears to be as effective as the standard RPL dissection. Surgery should be followed by monthly determination of serum markers and chest x-rays for the first year and 1 to 2 month determinations the second year. In patients with pathologic stage I disease after RPL, the presence of lymphatic or venous invasion in the primary tumor appears to predict for relapse. Chemotherapy is employed immediately on first evidence of recurrence.
Radical inguinal orchiectomy with no retroperitoneal node dissection followed by regular (e.g., every 1-2 months) history, physical examination, determination of serum markers, and, during the first year, abdominal CT scan (surveillance). Intervals for abdominal CT scans have varied from every 2 months to scans at 3 and 12 months postorchiectomy, with apparently similar outcomes. Disease recurrence is rarely detected by chest x-ray alone, so chest x-ray may play little or no role in routine surveillance. Long-term follow-up is important, since relapses have been reported more than 5 years after the orchiectomy in patients who did not undergo a retroperitoneal dissection.
Stage II Testicular Cancer

Stage II seminoma

Stage II seminoma is divided into bulky and nonbulky disease for treatment planning and expression of prognosis. Bulky disease is generally defined as tumors greater than 5 centimeters on a computed tomographic (CT) scan.

For patients with nonbulky tumors

Radical inguinal orchiectomy followed by radiation to the retroperitoneal and ipsilateral pelvic lymph nodes. Evidence favors the omission of prophylactic radiation therapy to the mediastinum and neck. Radiation to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk.
For patients with bulky tumors

Radical inguinal orchiectomy followed by combination chemotherapy (with a cisplatin-based regimen), or by radiation to the abdominal and pelvic lymph nodes. Recurrence rate is higher after radiation for bulky stage II tumors than radiation for nonbulky tumors, leading some authors to recommend primary chemotherapy for patients with bulky disease (>/= 5-10 centimeters).

Stage II nonseminoma

Stage II nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, surgical techniques for sparing sympathetic ganglia and chains without compromising the total removal of all involved nodes are available, although this technique may not be feasible in many patients. In most patients, an orchiectomy is performed prior to starting chemotherapy.

Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes with or without fertility-preserving RPL followed by monthly checkups, which include physical examination, chest x-ray, and serum marker tests (alpha fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase). This option of surgery and careful follow-up, reserving chemotherapy for relapse, is particularly attractive for patients who have less than 6 positive nodes at retroperitoneal lymph node dissection, none of which are greater than 2 centimeters in diameter, and no extracapsular lymph node invasion.
Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes followed by chemotherapy and then monthly checkups. Two courses of cisplatin-based chemotherapy (either cisplatin, vinblastine, bleomycin (PVB) or vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin (VAB VI)) prevented a relapse in greater than 95% of patients.
Radical inguinal orchiectomy followed by chemotherapy with delayed surgery for removal of residual masses (if present) followed by monthly checkups. This option would be considered for patients in whom clinical examination, lymphangiogram, or CT scan show large enough retroperitoneal masses that there are concerns about resectability.
Chemotherapy regimens include:
BEP: bleomycin + etoposide + cisplatin for 3 courses. A modified regimen has been used in children.
EP: etoposide + cisplatin for 4 courses in good-prognosis patients.
A randomized study has shown that bleomycin is an essential component of the BEP regimen when only 3 courses are administered.
Other regimens that appear to produce similar survival outcomes but are in less common use include:
PVB: cisplatin + vinblastine + bleomycin.
VAB VI: vinblastine + dactinomycin + bleomycin + cyclophosphamide + cisplatin.
VPV: vinblastine + cisplatin + etoposide.
Stage III Testicular Cancer

Stage III seminoma

Stage III seminoma is usually curable.

Radical inguinal orchiectomy followed by multidrug chemotherapy. In seminoma patients, the residual masses after chemotherapy are often fibrotic, although persistent, discrete (large) masses (>/= 3 centimeters) that may contain residual seminoma that would require additional therapy. In some patients, fertility has been returned following the use of bleomycin, etoposide, and cisplatin (BEP).
Chemotherapy combinations include:
BEP: bleomycin + etoposide + cisplatin. A modified regimen has been used in children.
EP: etoposide + cisplatin for 4 courses in good-prognosis patients.
Other regimens that appear to produce similar survival outcomes but are in less common use include:
PVB: cisplatin + vinblastine + bleomycin.
VIP: etoposide + ifosfamide + cisplatin.
Stage III nonseminoma

Stage III nonseminoma is usually curable (70%) with standard chemotherapy. In some patients fertility has returned following the use of chemotherapy. The 30% of patients who are not cured with standard chemotherapy usually have widespread visceral metastases, high tumor markers, or mediastinal primary tumors at presentation. In most patients, an orchiectomy is performed prior to starting chemotherapy.

Chemotherapy

BEP: bleomycin + etoposide + cisplatin. A modified regimen has been used in children.
EP: etoposide + cisplatin for 4 courses in good-prognosis patients.
Other regimens that appear to produce similar survival outcomes but have been studied less extensively or are in less common use include:

PVB: cisplatin + vinblastine + bleomycin.
POMB/ACE: platinum + vincristine + methotrexate + bleomycin + dactinomycin + cyclophosphamide + etoposide.
VIP: etoposide + ifosfamide + cisplatin.
A randomized study comparing 4 courses of BEP to 4 courses of VIP showed similar overall survival and time-to-treatment failure for the 2 regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy. Hematologic toxic effects were substantially worse with the VIP regimen.

Recurrent Testicular Cancer

Salvage regimens consisting of ifosfamide, cisplatin, and either etoposide or vinblastine can induce long-term complete responses in about one-quarter of patients with disease that has persisted or recurred following other cisplatin-based regimens. Patients who have had an initial complete response to first-line chemotherapy and those without extensive disease have the most favorable outcomes. This regimen is now the standard initial salvage regimen.
High-dose chemotherapy with autologous marrow transplantation has also been used with some success in the setting of refractory disease. Durable complete remissions may be achieved in 10% to 20% of patients with disease resistant to standard cisplatin-based regimens who are treated with high-dose carboplatin and etoposide with autologous bone marrow transplantation. The durable complete remission rate may exceed 50% if high-dose chemotherapy is used as salvage chemotherapy at the initial relapse of primary testicular cancer.
HOW TO DETECT THE PROGNOSIS OF TESTICULAR CARCINOMA?

The following factors affect prognosis (chance of recovery) of this cancer.

Stage of the cancer (whether it is in or near the testicle or has spread to other places in the body, and blood levels of AFP, β-hCG, and LDH).
Type of cancer.
Size of the tumor.
Number and size of retroperitoneal lymph nodes.
Testicular cancer is a highly treatable, often curable cancer. Some or all of the following factors may independently predict worse prognosis:

Presence of liver, bone, or brain metastases.
Very high serum markers.
Primary mediastinal nonseminoma.
Large number of lung metastases.
It is important to note that even patients with widespread metastases at presentation, including those with brain metastases, may still be curable and should be treated with this intent.

An important aspect of the follow-up of testicular cancer is the use of serum markers. Serum markers include AFP, HCG (measurement of the beta subunit reduces luteinizing hormone (LH) cross-reactivity), and lactate dehydrogenase (LDH). They may detect a tumor which is too small to be detected on physical examination or x-rays. Patients typically receive follow-up monthly for the first year and every other month for the second year after diagnosis and treatment. While the majority of tumor recurrences appear within 2 years, late relapse has been reported and lifelong marker, radiologic, and physical examination is recommended.

Patients who have been cured of testicular cancer have approximately a 2% to 5% cumulative risk of developing a cancer in the opposite testicle over the 25 years after initial diagnosis.

Good Prognosis

Nonseminoma:

Testis/retroperitoneal primary AND
No non-pulmonary visceral metastases AND
Good markers - all of:
AFP < 1000 ng/ml AND
hCG < 5000 iu/l (1000 ng/ml) AND
LDH < 1.5 x upper limit of normal
56% of nonseminomas
5-year progression-free survival (PFS) 89%; 5-year survival 92%
Seminoma:

Any primary site AND
No non-pulmonary visceral metastases AND
Normal AFP, any hCG, any LDH
90% of seminomas
5-year PFS 82%; 5-year survival 86%
Intermediate Prognosis

Nonseminoma:

Testis/retroperitoneal primary AND
No non-pulmonary visceral metastases AND
Intermediate markers - any of:
AFP >/= 1000 and hCG >/= 5000 iu/l and LDH >/= 1.5 x N* and 28% of nonseminomas
5-year PFS 75%; 5-year survival 80%
[Note: N indicates the upper limit of normal for the LDH assay.]
Seminoma:

Any primary site AND
Non-pulmonary visceral metastases AND
Normal AFP, any hCG, any LDH
10% of seminomas
5-year PFS 67%; 5-year survival 72%
Poor Prognosis

Nonseminoma:

Mediastinal primary OR
Non-pulmonary visceral metastases OR
For markers - any of:
AFP > 10,000 ng/ml OR
hCG > 50,000 iu/l (10,000 ng/ml) OR
LDH > 10 x upper limit of normal
16% of nonseminomas
5-year PFS 41%; 5-year survival 48%
Seminoma:

No patients classified as poor prognosis.