Testicular Seminoma 

Updated: Sep 05, 2019
Author: Michael B Williams, MD, MS; Chief Editor: Bradley Fields Schwartz, DO, FACS 

Overview

Practice Essentials

Testicular seminoma (see the image below) is a pathologic diagnosis in which only seminomatous elements are observed upon histopathologic review after a radical orchiectomy and in which the serum alpha-fetoprotein (AFP) level is within the reference range. Testicular cancer, although rare, is the most common malignancy in men aged 20-34 years; 95% of malignant tumors arising in the testes are germ cell tumors (GCTs), and seminomas are the most type of testicular GCTs.[1]  The risk of testis cancer is 10-40 times higher in patients with a history of cryptorchidism; 10% of patients with GCTs have a history of cryptorchidism.[2]

This is a classic testicular seminoma, high-power This is a classic testicular seminoma, high-power view, from a 37-year-old man with a painless mass in his right testis. Levels of serum beta-human chorionic gonadotropin and alpha-fetoprotein were within the reference range, and the metastatic workup findings were negative. Histopathology showed a pure seminoma. Metastatic workup showed no nodal or distant spread, T1N0M0 stage I. After orchiectomy, the patient underwent adjuvant external beam radiotherapy to the para-aortic nodes. At a 3-year follow-up study, the patient is disease free and has a greater than 95% chance of remaining disease free. See related image for a scrotal sonogram of this patient. Note here that tumor cells are uniform, have abundant clear cytoplasm, a large centrally located nucleus, and a variable mitotic pattern.

Signs and symptoms

The typical presentation in testicular seminoma is as follows:

  • A male aged 15-35 years presents with a painless testicular lump that has been noticeable for several days to months
  • Patients commonly have abnormal findings on semen analysis at presentation, and they may be subfertile [3]
  • Patients may present with a hydrocele, and scrotal ultrasonography may identify a nonpalpable testis tumor

Uncommon presentations include the following:

  • Testicular pain, possibly with an acute onset; may be associated with a hydrocele
  • A metastatic testis tumor may manifest as large retroperitoneal and/or chest lesions, while the primary tumor is nonpalpable

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies for testicular seminoma are as follows:

  • An elevated AFP level rules out pure seminoma, despite possible contrary histopathologic orchiectomy findings
  • Lactate dehydrogenase (LDH) is a less-specific marker for GCTs, but levels can correlate with overall tumor burden
  • Beta–human chorionic gonadotropin (beta-hCG) levels are elevated inn 5-10% of patients with seminomas; elevation may correlate with metastatic disease but not with overall survival
  • Placenta-like alkaline phosphatase levels can be elevated in patients with seminoma, especially as the tumor burden increases; however, those levels may also increase with smoking

Scrotal ultrasonography

  • Consider this study in any male with a palpable testicular mass that is suspicious or questionable.
  • Other indications may include acute scrotal pain (especially when associated with a hydrocele), nonspecific scrotal pain, or swelling.
  • If an asymptomatic hydrocele obscures physical examination of the testicle, this study may be appropriate prior to surgical intervention.
  • This study may also be appropriate for males who are at the peak age range for testicular cancer (ie, 15-35 years).
  • Scrotal ultrasonography commonly shows a homogeneous hypoechoic intratesticular mass.
  • Larger lesions may be more inhomogeneous.
  • Calcifications and cystic areas are less common in seminomas than in nonseminomatous tumors.

Other imaging studies

  • Abdominal and pelvic CT scanning: Can be used to identify metastatic disease to the retroperitoneal lymph nodes, but it results in understaging in approximately 15-20% of patients thought to be at stage I[4]

  • Chest CT scanning: Indicated only when abnormal findings are observed on a chest radiograph

  • Fluoro-2-deoxy-D-glucose (FDG) PET scanning: May be useful in restaging assessments of residual masses following chemotherapy

Histologic findings

Seminomas can have 3 histologic variants, as follows[5] :

  • Classic seminoma (the most common histologic type)
  • Anaplastic seminoma (5-15% of patients)
  • Spermatocytic seminoma (a rare variant that occurs in older adults)

See Workup for more detail.

Management

In testicular seminoma, orchiectomy provides both diagnosis and therapy. Orchiectomy alone cures most stage I seminomas. To prevent relapse, the following are standard options in stage I disease[1] :

  • Surveillance
  • Single-agent carboplatin
  • Radiotherapy 

Preferred treatments for more advanced stages are as follows6:

  • Stage IIA - Radiotherapy or chemotherapy with etoposide and cisplatin (EP) or bleomycin, etoposide, and cisplatin (BEP) 
  • Stage IIB - Chemotherapy with EP or BEP (preferred) or radiotherapy
  • Stage IIC, III (good risk) - Chemotherapy with EP or BEP 
  • Stage IIC, III (high risk) - Chemotherapy with EP or etoposide, mesna, ifosfamide and cisplatin (VIP)

After treatment, patients require lifelong follow-up. Surveillance includes the following, with the frequency determined by disease stage and duration of follow-up:

  • History and physical examination
  • Serum tumor markers (beta-hCG, LDH, AFP)
  • Chest radiography
  • CT scan of the abdomen, with or without CT scan of the pelvis

See Treatment and Medication for more detail.

For patient education information, see Men's Health, as well as Testicular Cancer and Testicular Self-Exam.

Background

The study of testicular germ cell tumors (GCTs) is a unique area of urologic oncology, as treatment algorithms have benefited from numerous randomized prospective clinical trials (unlike prostate cancer) and because metastatic disease is highly responsive to multimodal treatment (unlike renal cell carcinoma). Seminoma is a histologic subtype of GCTs, which are discussed separately as nonseminomas in Germ Cell Tumors.

The interest in GCTs is disproportional to its incidence because of its fascinating pathologic subtypes, success of multimodal therapy (even for metastatic disease), and almost universal incidence in otherwise healthy males aged 15-35 years. Testicular GCTs have various pathologic subtypes, including seminoma, embryonal, yolk sac, teratoma, and choriocarcinoma. The most important clinical distinction is between seminoma and nonseminoma, two broad categories with different treatment algorithms: (1) Seminoma as a classification refers to pure seminoma upon histopathologic review, and (2) the presence of any nonseminomatous elements (even if seminoma is prevalent) changes the classification to nonseminoma.

Pathophysiology

Testicular seminoma is a pathologic diagnosis in which only seminomatous elements are observed upon histopathologic review after a radical orchiectomy and in which serum alpha-fetoprotein (AFP) is within the reference range. Any elevation of AFP levels or nonseminomatous elements in the testis specimen mandates diagnosis of nonseminomatous GCT (NSGCT) and an appropriate treatment change.

GCTs have the following subtypes and frequencies: seminoma (40%), embryonal (25%), teratocarcinoma (25%), teratoma (5%), and choriocarcinoma (pure; 1%). Seminomas can be further subdivided into one of three categories based on histology: classic, anaplastic, and spermatocytic (see Histologic Findings).[5]

Germ cell carcinoma in situ (CIS) is a premalignant condition with a natural history of progression to seminoma or embryonal cancer. Patients with infertility, intersex disorders, cryptorchidism, prior contralateral GCTs, or atrophic testes more commonly have CIS. Histologically, it demonstrates intratubular atypical germ cells within seminiferous tubules. Most patients with seminomas (except spermatocytic seminoma) and NSGCTs have CIS or severe atypia associated with the primary tumor.[6] In patients with GCTs, 5% of those with contralateral testes harbor CIS.[7]

Testicular microcalcifications observed on scrotal sonograms were long held to be implicated in the development of testicular carcinoma. However, an analysis of 83 patients with asymptomatic microcalcifications observed for 5 years demonstrated only one with testicular carcinoma development over the interim. This represented an odds ratio for the study population of 317 (95% CI, 36-2756), with over 98% of men with asymptomatic microcalcifications having a benign course. A recommendation of continued monthly self-examination without further intervention was given for management of this indolent finding.[8]

Etiology

Risk of testis cancer is 10 to 40 times higher in patients with a history of cryptorchidism; 10% of patients with germ cell tumors (GCTs) have a history of cryptorchidism.[2]  Risk is greater for the abdominal versus inguinal location of undescended testis. An abdominal testis is more likely to be seminoma, while a testis surgically brought to the scrotum by orchiopexy is more likely to be a nonseminomatous SGCT. Orchiopexy allows for earlier detection by physical examination but does not alter the risk of GCT.

Other risk factors include trauma, mumps, and maternal estrogen exposure. Hemminki and colleagues demonstrated a familial risk for testicular cancer, with a 4-fold increased risk in a male with a father who had a GCT and a 9-fold increased risk if a brother was affected.[9]

Environmental exposures including organochlorines, polychlorinated biphenyls, polyvinyl chlorides, phthalates, marijuana, and tobacco have been shown to increase the incidence of testicular cancer.[10]  

Genetic changes in the form of amplifications and deletions are observed mainly in the 12p11.2-p12.1 chromosomal regions.[11]  A gain of 12p sequences is associated with invasive growth of both seminomas and NSGCTs. In contrast, spermatocytic seminoma shows a gain of chromosome 9, while most infantile yolk sac tumors and teratomas show no chromosomal changes.

Somatic mutations of the KIT gene occur in approximately 5% of all testicular GCTs. Of these, Coffey and colleagues (2008) demonstrated that only seminomas contain activating mutations of the KIT gene.[12]

Epidemiology

United States

Testicular cancer is relatively uncommon and accounts for < 1% of all male tumors. Approximately 9560 new cases of testicular cancer will be diagnosed in 2019, but only 410 men will die of the disease. Although relatively rare, the incidence of testicular germ cell neoplasms has been rising for the past 20 years.[13]  In the United States, testicular seminoma is the most common subtype of testicular cancer, accounting for 55% of cases.[10]

International

The incidence of testis cancer has increased from the early 1960s to the mid 1980s. Nonwhite populations have a lower incidence than white populations. The highest rates of testis cancer are in Denmark (11.5 cases per 100,000 persons per year), Norway (9 cases per 100,000 persons per year), and Switzerland (11 cases per 100,000 persons per year). Rates vary across Europe.[14]

A review by Bray and colleagues (2006) of 41 cancer registries in 14 countries found the seminoma rates to be highest in Denmark and Switzerland (9 cases per 100,000 persons per year) and the lowest rates in Japan, Israel, and Finland (1-3 cases per 100,000 persons per year).[15]  

Race- and Age-related Demographics

Established data sets have consistently demonstrated a higher incidence of GCTs in whites than in African Americans—as high as a 5:1 ratio. A 2005 analysis by McGlynn et al of 9 registries of the Surveillance, Epidemiology, and End Results (SEER) database from 1973-2001 found an increasing incidence among African Americans starting in the 1990s. The increased incidence was 100% for GCTs overall—124% for seminoma and 64% for nonseminoma. The reasons for this increase are unclear, and the authors' review of the data suggests environmental or nonperinatal factors (occupation, physical activity, diet) rather than early screening as the predominant cause.[16]

Testicular GCTs represent the most common malignancy in men aged 20-34 years.[1]

Prognosis

Mortality rates from testicular seminiomas increased until the 1970s but have since declined greatly as a result of advances in treatment. Currently, all stages have at least a 90% cure rate.[17]  

In a review of testicular GCT patients diagnosed in Norway from 1953-2012, Kvammen et al found that although relative survival has improved in recent decades, it generally continues to decline with increasing follow-up time, particularly beyond 15-30 years, regardless of disease extent at diagnosis. Relative survival was lower in patients diagnosed before 1980 or after age 40. These authors proposed that the likely main cause is treatment-induced late effects, with the continued use of adjuvant radiotherapy in seminomas until the year 2000 as the suspected culprit.[18]

Cure rates by stage are as follows:

  • Stage I: 98%-100%
  • Stage II (B1/B2 nonbulky): 98%-100%
  • Stage II (B3 bulky) and stage III: 90% complete response to chemotherapy and 86% durable response rate to chemotherapy.

Treatment-related disease in long-term survivors

Patients with testicular cancer are at an increased risk of secondary cancers because of their young age at diagnosis, high cure rate, and exposure to radiation, chemotherapy, or both. In a study of a cohort of 14 population-based tumor registries in Europe and North America totaling 40,576 patients, Travis et al reported that survivors of testicular cancer are at a significantly increased risk of solid tumors for at least 35 years after treatment.[19]

Tumors included malignant mesothelioma and those of the lung, colon, bladder, pancreas, and stomach. The relative risk increases were the same for seminoma and nonseminoma, and with treatment with radiation, chemotherapy, or both. For patients diagnosed with seminoma at age 35 years, the cumulative risk 40 years later was 36%, compared with 23% for the general population.[19]

Zagars et al reported on long-term follow-up involving 477 men with low-stage seminoma treated with orchiectomy and adjuvant radiation at a single institution. They compared long-term cancer-specific survival with cardiac-specific survival and performed a risk analysis in relation to standard US data for males. No differences were seen in the first 15 years, but, after 15 years, the relative risk of secondary cancer deaths was increased.[20]

In summary, these two long-term follow-up studies demonstrate that, although many men with seminoma are cured, they require counseling and long-term follow-up to minimize the risk of excess mortality from secondary cancers.

Increased risk for cardiac disease has also been observed in seminoma survivors.[19, 1]  However, a population-based study in 9193 patients with stage I testicular seminoma by Beard et al found no increase in deaths from cardiovascular disease after radiotherapy. Deaths from second malignant neoplasms were elevated, but at a rate considerably lower than reported in historical series.[21]

 

Presentation

History

Testicular seminoma is most often diagnosed when a male aged 15-35 years presents with a painless testicular lump that has been noticeable for several days to months. Delay in diagnosis is common because of patients' failure to perform self-examinations or to seek medical attention after noticing a testicular mass, or a physician's delay while treating the patient for presumed epididymo-orchitis or testicular trauma.

Patients commonly have abnormal findings on semen analysis at presentation, and they may be subfertile.[3]

Overall, in approximately 75% of patients, the seminomas are localized (stage I) at diagnosis. However, 15% have metastatic disease to the regional lymph nodes, and 5-10% have involvement of juxtaregional nodes or visceral metastases.

Uncommon presentations include the following:

  • Testicular pain, possibly with an acute onset, especially when an associated hydrocele prevents adequate physical examination.

  • A testis tumor may become metastatic and may manifest as large retroperitoneal and/or chest lesions, while the primary tumor is nonpalpable. Scrotal ultrasonography may locate the primary tumor. Histopathology of the primary testis often shows a focus of tumor surrounded by fibrous scar, termed burned-out testis cancer.

  • In 1996, Miller and associates reported on a series of patients with previously nonpalpable testes that were explored and incorrectly diagnosed as vanished testes. A subsequent seminoma was diagnosed intra-abdominally.[2]

 

DDx

 

Workup

Approach Considerations

In a patient with a suspicious testicular mass, the workup includes both laboratory tests and imaging studies. Scrotal ultrasonography may reveal features suggestive of seminoma, but the diagnosis of seminoma is established by pathologic examination of the testicle after surgical removal. Orchiectomy is thus both diagnostic and therapeutic (see Treatment). The histologic results are supported by laboratory testing, which helps differentiate seminomas from nonseminomatous germ cell tumors (NGCTs). In addition, a chest x-ray is indicated, to exclude metastases.

Once seminoma has been diagnosed, further evaluation includes the following[1] :

  • Abdominal/pelvic computed tomography (CT) scan
  • Chest CT, if abdominal CT is positive or chest x-ray shows abnormalities
  • Repeat laboratory studies, since staging is based on post-orchiectomy values
  • Brain magnetic resonance imaging (MRI) , if clinically indicated
  • Bone scan, if clinically indicated

Laboratory Studies

Laboratory studies in patients with a suspicious testicular mass include the following[1] :

  • Alpha-fetoprotein (AFP)
  • Lactate dehydrogenase (LDH)
  • Beta human chorionic gonadotropin (beta-hCG)
  • Serum chemistry profile

Yolk sac elements secrete AFP; an elevated AFP level rules out pure seminoma, despite possible contrary histopathologic orchiectomy findings. LDH is a less-specific marker for germ cell tumors (GCTs), but levels can correlate with overall tumor burden.

Beta-hCG is a glycoprotein with the same alpha unit as thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone. It has a 24- to 36-hour half-life and is secreted by syncytiotrophoblast cells within GCTs. Beta-hCG levels are elevated in 5%-10% of patients with seminomas. Elevation may correlate with metastatic disease but not with overall survival.

Richie suggested that if beta-hCG levels do not normalize after orchiectomy, the treatment approach should be that for nonseminomatous GCT (NSGCT), citing a study in which one third of patients who died of metastatic seminoma were found to have nonseminomatous elements at autopsy.[11] With the 10% incidence of pure seminomas producing beta-hCG, NSGCT chemotherapy regimens may better serve these patients.

Measurement of placentalike alkaline phosphatase may be considered, as levels can be elevated in patients with seminoma, especially as the tumor burden increases. However, levels may also increase with smoking.

Imaging Studies

Consider scrotal ultrasonography in any male with a suspicious or questionable testicular mass that is palpable upon physical examination. Scrotal ultrasonography commonly shows a homogeneous hypoechoic intratesticular mass. Larger lesions may be more inhomogeneous (see the image below).[22] Calcifications and cystic areas are less common in seminomas than in nonseminomatous tumors.

Testicular seminoma. This scrotal ultrasound of a Testicular seminoma. This scrotal ultrasound of a 37-year-old man with a painless mass in his right testis shows a right testis with hypoechoic solid masses compared to the homogeneous, more hyperechoic, healthy left testis. Levels of serum beta-human chorionic gonadotropin and alpha-fetoprotein were within the reference range, and the metastatic workup findings were negative. Histopathology showed a pure seminoma. Metastatic workup showed no nodal or distant spread, T1N0M0 stage I. After orchiectomy, the patient underwent adjuvant external beam radiotherapy to the para-aortic nodes. At a 3-year follow-up study, the patient is disease free and has a greater than 95% chance of remaining disease free.

Other indications for scrotal ultrasonography may include acute scrotal pain (especially when associated with a hydrocele), nonspecific scrotal pain, swelling, or the presence of a mass. If an asymptomatic hydrocele obscures physical examination of the testicle, this study may be appropriate prior to surgical intervention. It may also be appropriate for males who are at the peak age range for testicular cancer (ie, 15-35 y).

Computed tomography

Abdominal and pelvic CT scanning, with intravenous and oral contrast, can be used to identify metastatic disease to the retroperitoneal lymph nodes; however, CT scanning results in understaging in approximately 15%-20% of patients thought to be at stage I.[4]

The CT below depicts retroperitoneal involvement from testicular seminoma.

Testicular seminoma. A 57-year-old man presents wi Testicular seminoma. A 57-year-old man presents with abdominal pain of slow onset. CT scanning shows a large 25-cm retroperitoneal lesion encompassing the aorta and renal vasculature and displacing the right kidney laterally. The patient had a history of cryptorchidism repaired at age 8 years. Testes were normal and descended; however, ultrasonography showed a small 5-mm lesion on the right testis, which proved to be pure seminoma at orchiectomy. The beta-human chorionic gonadotropin level was 70 mIU/mL (reference range, &lt; 5 mIU/mL), and the alpha-fetoprotein level was within the reference range; no metastatic lesions were observed above the diaphragm, indicating stage IIb (bulky), T1N3M0. The patient was referred for 4 cycles of cisplatin-based chemotherapy.

Chest CT scanning is indicated only when abnormal findings are observed on a chest radiograph.

Positron emission tomography

Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been evaluated for its utility in staging and restaging of seminomatous and nonseminomatous tumors.[23, 24, 25] In primary staging, FDG-PET has been found to have no benefit over CT scanning alone. However, in restaging assessments of residual masses, FDG-PET was noted to improve the ability to detect a fibrotic residual mass compared to that of residual teratoma postchemotherapy.

Hinz et al (2008) prospectively evaluated 20 patients with a residual mass following chemotherapy for seminoma greater than stage IIa prior to surgical resection. Although all patients with viable tumor were identified, FDG-PET findings were falsely positive in 9 of the 20 patients. They concluded that FDG-PET should be as an adjunctive tool for patient counseling.[26]

Histologic Findings

Seminomas can have three histologic variants: classic, anaplastic, and spermatocytic.[5]

Classic seminoma has a uniform population of large cells that form sheets and nests separated by delicate connective tissue. Leukocytic infiltration (20%), multinucleated cells, syncytiotrophoblasts (7%-35%), and microcalcifications (60%) may be present. Upon gross examination, the tumor has a uniform yellow color and bulges from the cut surface. Classic seminoma is the most common histologic type (see images below).

Testicular seminoma. This is a classic seminoma at Testicular seminoma. This is a classic seminoma at low power. Uniform tumor cells are observed with mild inflammatory response (lymphocytes). Other seminoma findings not seen could include a fibrovascular stroma, syncytiotrophoblastic cells, and multinucleated histiocytes.
This is a classic testicular seminoma, high-power This is a classic testicular seminoma, high-power view, from a 37-year-old man with a painless mass in his right testis. Levels of serum beta-human chorionic gonadotropin and alpha-fetoprotein were within the reference range, and the metastatic workup findings were negative. Histopathology showed a pure seminoma. Metastatic workup showed no nodal or distant spread, T1N0M0 stage I. After orchiectomy, the patient underwent adjuvant external beam radiotherapy to the para-aortic nodes. At a 3-year follow-up study, the patient is disease free and has a greater than 95% chance of remaining disease free. See related image for a scrotal sonogram of this patient. Note here that tumor cells are uniform, have abundant clear cytoplasm, a large centrally located nucleus, and a variable mitotic pattern.

Anaplastic seminoma is observed in 5%-15% of patients with seminomas. Histopathology is as described for classic seminoma but with increased mitotic figures. Patients tend to present at more advanced stages than those with classic seminoma, but stage prognosis is similar.

Spermatocytic seminoma is a rare variant that occurs in older adults. Histopathology shows tumor cells arranged in solid sheets, containing poorly developed inconspicuous septae without leukocytic infiltrate. No glycogen is present. Small, medium, and large cell types are observed. Orchiectomy alone is sufficient treatment; metastases are rare.

Staging

American Joint Committee on Cancer and the International Union Against Cancer: Testicular Cancer Staging System[27]

Table 1. Primary Tumor (T) (Open Table in a new window)

pTx

Primary tumor cannot be assessed

p0

No evidence of primary tumor

pTis

Germ cell neoplasia in situ

pT1

Tumor limited to the testis without lymphovascular invasion

pT1a

Tumor smaller than 3 cm

pT1b

Tumor 3 cm or larger

pT2

Tumor limited to the testis and epididymis with lymphovascular invasion OR

Tumor invading hilar soft tissue or epididymis or

penetrating viceral mesothelial layer covering the external surface of tunica albuginea

with or without lymphovascular invasion

pT3

Tumor invades the spermatic cord with or without lymphovascular invasion

pT4

Tumor invades the scrotum with or without lymphovascular invasion

Table 2A. Regional Lymph Nodes (N): Clinical (Open Table in a new window)

Nx

Nodes not assessed

N0

No regional lymph node metastasis

N1

Lymph node mass or multiple lymph node masses ≤ 2 cm in greatest dimension

N2

Lymph node mass or multiple lymph node masses >2 cm but ≤ 5 cm in greatest dimension

N3

Lymph node mass >5 cm in greatest dimension

Table 2B. Regional Lymph Nodes (N): Pathologic (Open Table in a new window)

pN0

No evidence of tumor in lymph nodes

pN1

Lymph node mass ≤ 2 cm in greatest dimension

≤ 5 nodes positive

pN2

Lymph node mass >2 cm but < 5 cm in greatest dimension

>5 nodes positive

Evidence of extranodal extension of tumor

pN3

Lymph node mass >5 cm in greatest dimension

Table 3. Distant Metastases (M) (Open Table in a new window)

M0

No evidence of distant metastases

M1a

Nonregional nodal or pulmonary metastases

M2b

Nonpulmonary visceral metastases

Table 4. Serum Tumor Markers (S) (Open Table in a new window)

S

LDH

hCG† (mIU/mL)

AFP (ng/mL)

Sx

Not assessed

Not assessed

Not assessed

S0

≤ N

and

Normal

and

Normal

S1

< 1.5 x N

and

< 5,000

and

< 1,000

S2

1.5-10 x N

or

5,000-50,000

or

1,000-10,000

S3

>10 x N

or

>50,000

or

>10,000

N = upper limit of normal for the LDH assay

†HCG = human chorionic gonadotropin

Table 5. Stage Grouping (Open Table in a new window)

Stage grouping

T

N

M

S

Stage 0

pTis

N0

M0

S0

Stage I

T1-T4

N0

M0

Sx

Stage IA

T1

N0

M0

S0

Stage IB

T2-4

N0

M0

S0

Stage IS

Any T

N0

M0

S1-S3

Stage II

Any T

N1-3

M0

Sx

Stage IIA

Any T

N1

M0

S0-S1

Stage IIB

Any T

N2

M0

S0-S1

Stage IIC

Any T

N3

M0

S0-S1

Stage III

Any T

Any N

M1

Sx

Stage IIIA

Any T

Any N

M1a

S0-S1

Stage IIIB

Any T

Any N

M0-M1a

S2

Stage IIIC

Any T

Any N

M0-M1a

S3

Any T

Any N

M1b

Any S

Additional staging systems are well discussed by Prow.[17] See also Seminoma Testicular Cancer Staging.

 

Treatment

Approach Considerations

In testicular seminoma, orchiectomy provides both diagnosis and therapy (see Surgical Care). Orchiectomy alone cures most stage I seminomas. To prevent relapse, the National Comprehensive Cancer Network (NCCN) recommends the following as standard options in stage I disease[1] :

  • Surveillance (preferred option for pT1-pT3 tumors)
  • Single-agent carboplatin (one or two cycles)
  • Radiotherapy (20 Gy, preferred or 25.5 Gy)

The NCCN cautions that stage IS pure seminoma is very uncommon. Because persistent elevation of serum tumor markers usually indicates metastatic disease, the NCCN recommends performing abdominal/pelvic computed tomography (CT) to determine the extent of disease.[1]

Preferred treatments for more advanced stages are as follows:

  • Stage IIA - Radiotherapy or chemotherapy with bleomycin, etoposide, and cisplatin (BEP) or etoposide and cisplatin (EP) 
  • Stage IIB - Chemotherapy (preferred) with BEP or EP or radiotherapy in select non-bulky (≤3 cm) cases
  • Stage IIC, III (good risk) - Chemotherapy with BEP (category 1) or EP (category 1)
  • Stage IIC, III (high risk) - Chemotherapy with BEP (category 1) or etoposide, mesna, ifosfamide and cisplatin (VIP)

Retroperitoneal lymph node dissection (RPLND) is being studied as a first-line option for treatment of stage II A/B testicular seminoma in order to reduce long-term toxicity and secondary malignancies. In a retrospective study, 10-year survival for patients who underwent primary RPLND for testicular seminoma was 97.4% for men with stage l disease and 92.1% for those with stage llA/B disease.[28]

An ongoing study, the Surgery in Early Metastatic Seminoma (SEMS) trial, will assess recurrence-free survival at 2 years in patients who undergo RPLND as first-line treatment for testicular seminoma with low-volume (≤2 cm) retroperitoneal disease. The trial will also assess the percent of those patients who can avoid external beam radiotherapy or systemic chemotherapy.

Sperm banking should be discussed in patients of reproductive age. The discussion should take place before the patient undergoes any procedure that may compromise fertility, including orchiectomy. If the patient desires sperm banking, it may be performed before or after surgery, but must be performed before radiation therapy or chemotherapy.[1] Even before orchiectomy, however, many men with testicular GCTs have reduced sperm count and sperm motility, as well as increased abnormal sperm morphology.[29]

Chemotherapy

Chemotherapy for stage IA and IB testicular germinoma is with single-agent carboplatin. The dosage is area under the curve (AUC)=7 for one or two cycles.[1]

For stage II or III disease, the recommended chemotherapy regimen is etoposide plus cisplatin (EP) for four cycles, or bleomycin, etoposide, and cisplatin (BEP) for three cycles. Radiotherapy is preferred for primary therapy in stage IIA, while chemotherapy is preferred in stage IIB and in both good-risk and intermediate-risk stage IIC and III disease. For stage IIA, the presence of multiple positive lymph nodes is an indication for BEP.[1]

 

 

Radiotherapy

Current radiotherapy for testicular germinoma uses smaller fields and lower doses than in the past. Radiotherapy should started once the orchiectomy wound has fully healed, and should be given five times per week.[1]

Short-term adverse effects of radiotherapy include fatigue, nausea, and vomiting. Antiemetic medication significantly improves nausea and should be given at least 2 hours before each radiation treatment.[1]

For stage I disease, a total dose of 20 Gy is delivered in 10 fractions of external beam radiotherapy.[30] Targets include the para-aortic and ipsilateral pelvic nodes or the para-aortic nodes alone. Radiotherapy is not preferred for stage I disease, as long-term follow-up studies indicate an increase in late toxicities.

For stage IIA disease, radiotherapy is preferred for primary therapy. The total dose is 30 Gy and the field includes the para-aortic and ipsilateral iliac lymph nodes. For stage IIB disease, chemotherapy is preferred, but radiotherapy may be indicated in select cases of non-bulky disease. The total dose is 36 Gy and the field includes the para-aortic and ipsilateral iliac lymph nodes.[1]

 

 

Surgical Care

Relevant anatomy

Seminoma arises from abnormal germ cells in the seminiferous tubules. The TNM staging system (see Staging) stages the tumor based on its local, regional, and distant invasion.[11]

Testicular lymphatics relate to the embryonic origin of the testis. The male gonad initially forms near the kidney and descends through the inguinal canal to the scrotal sac. The right gonadal vein derives from the inferior cava, while the left gonadal vein derives from the left renal vein. Additional blood supply derives from the artery of the vas and the cremasteric arteries.

Testicular lymphatics follow the vessels of the spermatic cord through the inguinal canal and into the retroperitoneum. Testicular cancer spreads predominantly and initially through lymphatic routes. On the right, the cancer landing zone is between the aorta and the inferior vena cava; on the left, it is on top of and lateral to the aorta. Within the retroperitoneum, there can be a crossover from the lymphatics draining the right toward those of the left.

Scrotal skin lymphatics are different from testicular lymphatics and drain into the inguinal nodes. Perform all orchiectomies for solid masses through an inguinal route to avoid tumor spillage into the inguinal drainage basin. If a patient undergoes scrotal exploration, subsequent therapy may necessitate hemiscrotectomy and radiation treatment of the inguinal nodes.

In patients who have undergone prior herniorrhaphy, orchiopexy, or other alteration in lymphatic drainage, extend their radiation field to include the contralateral inguinal region with contralateral testis shielding.

Radical inguinal orchiectomy

Preoperative details include the following:

  • Draw serum tumor markers preoperatively because values fall rapidly after orchiectomy; other staging tests can be performed preoperatively or postoperatively.

  • Because of the rapid doubling time of a potential choriocarcinoma, schedule surgery for testis tumors rapidly to avoid upstaging.

  • Most patients with seminoma are young and healthy and require only routine preoperative preparation.

  • Discuss semen donation for subsequent fertility if the function of the contralateral testis is in question; however, many patients have poor semen quality that improves after orchiectomy.

  • Cosmetic testicular prostheses are currently available from Coloplast (formerly Mentor). The saline-filled testicular prosthesis has been FDA-approved since 2002 and can be implanted in an outpatient setting if desired by the patient.

  • If a patient presents with symptomatic metastatic lesions from a testis tumor, proceed with platinum-based chemotherapy and delay radical orchiectomy. Radical orchiectomy is not a morbid procedure, but it may delay initiation of chemotherapy.

  • Differentiation of seminoma versus nonseminomatous germ cell tumor (NSGCT) for advanced disease is not important at the outset of treatment because both groups receive the same regimen.

  • Although chemotherapy may result in disappearance of the testicular mass, orchiectomy is always indicated.

Intraoperative details are as follows:

  • Spinal, general, or (uncommonly) local anesthesia may be used

  • Shave the inguinal area, and prep in a standard fashion.

  • Create an inguinal incision to allow exposure of the external and internal iliac canal.

  • Open the external iliac fascia, exposing the spermatic cord and internal iliac canal. Control the spermatic cord with a Penrose drain in a tourniquet fashion to stop retroperitoneal lymphatic and venous drainage of tumor cells.

  • Then, deliver the testis from the scrotum and ligate separately the vas deferens and spermatic arteries.

  • Leave a long nonabsorbable tie on the patient side of the spermatic cord. This is to facilitate identification if retroperitoneal lymph node dissection (RPLND) becomes necessary and the patient requires dissection of the remaining spermatic cord structures from the abdominal exposure.

  • Reapproximate the external oblique fascia and close the skin in standard fashion.

Postoperative care

Radical orchiectomy is usually performed on an outpatient or 23-hour admission basis, often accompanied by the staging workup. Conduct a follow-up study by staging and referring the patient for appropriate adjuvant therapies.

This surgery is comparable to an inguinal herniorrhaphy, and the patient can expect limited physical activity for a brief period after surgery. A short course of pain management medication may be indicated postoperatively.

Complications are rare but may include wound infection, inguinal skin numbness due to injury to the genitofemoral nerve, hematoma, and standard anesthetic risks.

 

Consultations

For low-stage disease, a radiation oncologist should be consulted for external beam radiotherapy; for advanced disease consultation with a medical oncologist for platinum-based chemotherapy is beneficial.

Prevention

Males should begin monthly testicular self-examinations starting at puberty. Any abnormalities found should be reported to their physician.

After diagnosis of testicular GCT, the patient and treating physician should come to a mutual understanding regarding strict adherence to follow-up regimens to monitor for tumor recurrence.

Long-Term Monitoring

Follow-up care for testicular seminoma depends on the pathology, as outlined in Treatment. National Comprehensive Cancer Network (NCCN) follkow-up schedules take into account that relapse in stage I seminoma occurs at a median of 14 months, with the great majority occurring within 3 years.[1]

Recommendations for surveillance in patients with stage I seminoma include regular history and physical examination (H&P), with testicular ultrasound for equivocal exam, along with abdominal computed tomography (CT) scans, with or without pelvic CT, and chest x-rays; serum tumor markers are optional. Chest x-rays should be performed as clinically indicated with chest CT considered in symptomatic patients.[1]

For patients who have undergone orchiectomy only, the schedule is as follows:

  • Year 1: H&P every 3-6 mo, CT at 3, 6, and 12 mo
  • Years 2 and 3: H&P and CT every 6-12 mo
  • Years 4 and 5: H&P annually, C every 12-24 mo

For patients who have received adjuvant chemotherapy or radiation,  the schedule is as follows:

  • Years 1 and 2: H&P every 6-12 mo, CT annually
  • Year 3: H&P and CT annually
  • Years 4 and 5: H&P annually

For patients with stage IIA and non-bulky IIB seminoma who have gone through chemotherapy or radiotherapy, with no residual mass or residual mess < 3 cm and normal serum tumor marker levels, surveillance consists of H&P, with testicular ultrasound for equivocal exam, abdominal CT scans with or without pelvic scans. Chest x-rays are used for routine follow-up, but chest CT is preferred if thoracic symptoms are present. Serum tumor markers are optional. The schedule is as follows:

  • Year 1: H&P every 3 mo, CT at 3, 6, and 12 mo, chest x-ray every 6 mo
  • Year 2: H&P every 6 mo, CT annually, chest x-ray every 6 mo
  • Year 3: H&P every 6 mo, CT annually
  • Years 4 and 5: H&P every 6 mo, CT as clinically indicated

For patients with bulky stage IIB, IIC, and stage III seminoma who have gone through chemotherapy and have no residual mass, or residual mass ≤3 cm and normal serum marker levels, surveillance consists of H&P, with testicular ultrasound for equivocal exam, and serum tumor marker assays. Abdominal CT scans, with or without pelvic scans, are performed at 3-6 mo, then as clinically indicated, and positron emission tomography (PET) scans are performed as clinically indicated. Chest x-rays are used for routine follow-up, but chest CT is preferred if thoracic symptoms are present. The schedule for H&P and chest x-ray is as follows:

  • Year 1: H&P, markers, and chest x-ray every 2 mo
  • Year 2: H&P, markers, and chest x-ray every 3 mo
  • Years 3 and 4: H&P and markers every 6 mo, chest x-ray annually
  • Year 5: H&P, markers, and chest x-ray annually
 

Medication

Medication Summary

BEP is the most common chemotherapy regimen administered for GCTs. It is usually administered in 4 cycles. Additional agents involved in primary, high-risk, and salvage protocols may include ifosfamide and vinblastine.

Antineoplastic agents

Class Summary

These agents inhibit deregulated growth of cells.

Bleomycin (Blenoxane)

Composed of cytotoxic glycopeptide antibiotics, which appear to inhibit DNA synthesis with some evidence of RNA and protein synthesis inhibition to a lesser degree; used in the management of several neoplasms as a palliative measure.

Etoposide (VP-16)

Arrests cells in the G2 portion of the cell cycle and induces DNA strand breaks by interacting with DNA topoisomerase II and forming free radicals.

Cisplatin (Platinol, Platinol-AQ)

Inorganic metal complex thought to act analogously to alkylating agents; inhibits DNA synthesis and thus cell proliferation by causing DNA crosslinks and denaturation of double helix.

Ifosfamide (Ifex)

Related to nitrogen mustards and is a synthetic analog of cyclophosphamide; inhibits DNA and protein synthesis and thus cell proliferation by causing DNA cross-linking and denaturation of double helix.

Vinblastine (Alkaban-AQ, Velban)

Inhibits microtubule formation, which in turn, disrupts the formation of mitotic spindle, causing cell proliferation to arrest at metaphase.