Seminoma

Updated by Reid F. Thompson

BACKGROUND

Clinically, what are the 2 main subgroups of testicular germ cell tumors (GCTs)?

Seminomatous and nonseminomatous germ cell tumors (NSGCTs) are the 2 main subgroups of testicular GCTs. 60% are pure seminoma, 30% are NSGCTs, and 10% are mixed (pts with mixed histology are typically considered to have NSGCTs).

What is the estimated annual incidence and mortality from testicular cancer in the U.S.? Has the incidence been increasing or decreasing?

In the U.S., the annual testicular cancer incidence is ~8,000 and mortality is ~380. From 1973–1998, the incidence in testicular GCTs rose 44% in the U.S. (mostly seminoma).

What is the most common age group for testicular seminoma?

Testicular seminoma is most common in those 25–40 yrs of age.

In the U.S., what is the relative incidence of testicular tumors in white men vs. black men?

Testicular cancer is 5.4 times more common in white men than black men.

What is the best established risk factor for testicular cancer?

A Hx of cryptorchidism increases the risk of testicular cancer by ∼5 times. The higher the undescended testicle (inguinal canal vs. intra-abdominal), the higher the risk. Orchiopexy prior to puberty lowers this risk. 5%–20% of tumors in pts with a Hx of cryptorchidism develop in the contralat, normally descended testis. The risk is greatest in cases of bilat cryptorchidism.

In a pt with a prior Dx of testicular cancer, what is the cumulative incidence (at 25 yrs) of contralat testicular seminoma?

At 25 yrs following the primary Dx, the cumulative incidence of contralat testicular seminoma is 3.6%.

What is the most common chromosomal abnormality in testicular GCTs?

A 12p isochromosome (i.e., a chromosome with 2 copies of the short arm of chromosome 12) is the most common testicular GCT chromosomal abnormality.

Name the layers of tissue surrounding the testes from outer to inner.

Layers of tissue surrounding the testes (outer to inner):

1. Skin

2. Tunica dartos

3. External spermatic fascia

4. Cremaster muscle

5. Internal spermatic fascia

6. Parietal layer of tunica vaginalis

7. Visceral layer of tunica vaginalis

8. Tunica albuginea

Compare and contrast lymphatic drainage of the left vs. right testis.

Lymphatic drainage from testicular tumors goes directly to the para-aortic (P-A) nodes. The left testicular vein drains to the left renal vein, and nodal drainage is primarily to the P-A nodes, directly below the left renal hilum. The right testicular vein drains to the IVC; paracaval and interaortocaval nodes are most commonly involved. Lymphatic drainage from the right testes commonly crosses over to the left, but the reverse is rare.

What is the chance of pelvic/inguinal nodal involvement from testicular cancer? What increases this risk?

Pelvic/inguinal nodes are rarely (<3%) involved by testicular cancer. Risk of involvement increases with:

1. Prior scrotal or inguinal surgery

2. Tumor invasion of the tunica vaginalis or lower onethird of epididymis

3. Cryptorchidism

What is the DDx of a testicular mass?

The DDx of a testicular mass includes tumor, torsion, hydrocele, varicocele, spermatocele, and epididymitis.

What is the classic presentation of testicular cancer?

A painless testicular mass is the classic presentation of testicular cancer. However, up to 45% of pts will present with pain.

WORKUP/STAGING

What imaging modality is preferred for primary evaluation of a testicular mass?

Transscrotal US is preferred for primary evaluation of a testicular mass. Testicular tumors are typically hypoechoic.

What is the preferred primary surgical Tx for a unilat testicular tumor?

Transinguinal orchiectomy is the preferred surgical Tx for unilat testicular tumor.

What are 3 tumor markers that should be drawn before orchiectomy for testicular tumor?

Before orchiectomy for a testicular tumor, levels of β-HCG, AFP, and LDH should be drawn.

What are the half-lives of β-HCG and AFP?

The half-life for β-HCG is 22 hrs. The half-life for AFP is 5 days.

How commonly are β-HCG and AFP elevated in testicular seminoma vs. NSGCT? What are unrelated etiologies for elevated β-HCG and AFP?

β-HCG is elevated in 15% of seminomas. AFP is never elevated in seminoma. 1 or both markers will be elevated in 85% of NSGCTs. The use of marijuana can elevate β-HCG, and reagent cross-reaction with LH can cause falsely elevated results. Hepatocellular carcinoma, cirrhosis, and hepatitis can elevate AFP.

What imaging studies, labs, and evaluation should be ordered following transinguinal orchiectomy for seminoma?

Following transinguinal orchiectomy for seminoma, chest imaging (CXR), CT abdomen/pelvis, AFP, β-HCG, and LDH should be ordered. If the CT is positive, bone scan should be added. Pts should also have fertility evaluation and consider sperm banking.

Describe the AJCC 7^th edition (2011) TNM and S staging for testicular tumors.

T1: limited to testis and epididymis with no LVSI or tunica vaginalis involvement

T2: LVSI or involvement of tunica vaginalis

T3: involvement of spermatic cord

T4: scrotal invasion

N1: single or multiple regional nodes, all ≤2 cm in greatest dimension

N2: single or multiple regional nodes, any >2–5 cm in greatest dimension

N3: single or multiple regional nodes, any >5 cm in greatest dimension

M1 a: nonregional nodal or pulmonary Dz

M1b: nonpulmonary visceral mets

S0: normal LDH, β-HCG, and AFP

S1: LDH <1.5 times normal, β-HCG <5,000 mIU/mL, and AFP <1,000 ng/mL

S2: LDH 1.5–10 times normal, β-HCG 5,000–50,000, or AFP 1,000–10,000

S3: LDH >10 times normal, β-HCG >50,000, or AFP >10,000

Summarize the AJCC 7^th edition (2011) stage grouping for testicular tumors.

Stage I: no Dz beyond testis/scrotum (i.e., T1-4N0M0S1-3)

Stage II: regional nodal involvement and S0-S1 tumor markers (IIA = N1, IIB = N2, IIC = N3)

Stage III: S2-S3 tumor markers with N1-S3 Dz, or M1 Dz

What is the stage group distribution for testicular seminoma at presentation?

Most testicular seminoma pts present with stage I Dz (70%–80%), 15%–20% have stage II Dz, and 5% have stage III Dz.

In addition to AJCC staging, what is another common staging system for testicular seminoma?

In addition to AJCC staging, Royal Marsden staging is also used for testicular seminoma. This staging is largely similar to the AJCC stage grouping:

Stage I: confined to testis

Stage IIA: node <2 cm

Stage IIB: node 2–5 cm

Stage IIC: node 5–10 cm

Stage IID: node >10 cm

Stage III: nodes above/below diaphragm

Stage IV: extralymphatic mets

TREATMENT/PROGNOSIS

Following transinguinal orchiectomy, what is the optimal Tx for stage I seminoma, stages IIA–IIB seminoma, and stage IIC or greater seminoma?

Following transinguinal orchiectomy, pts with stage I seminoma may rcv surveillance, adj RT, or single-agent chemo. Pts with stages IIA–IIB Dz should rcv adj RT. Pts with stage IIC or greater Dz should be treated with multiagent chemo.

For pts undergoing surveillance for stage I seminoma, estimate the 10-yr relapse rate and 10-yr CSS rate.

For pts undergoing surveillance for stage I seminoma, the 10-yr relapse rate is 15%–20% but nearly all relapses can be salvaged. 10-yr CSS is ~99.6%. (Mortensen MS et al., ASCO 2013 abstract)

For pts undergoing surveillance for stage I seminoma, where do most relapses occur?

85% of relapses are in the P-A nodes. Observation should therefore include regular CT assessment of the abdomen and pelvis.

What pathologic factors are associated with increased risk of relapse following transinguinal orchiectomy for stage I seminoma?

Pathologic factors associated with risk of relapse following transinguinal orchiectomy include:

1. tumor size >4 cm

2. LVSI

3. β-HCG >200 IU/L

4. Rete testis invasion

(Warde P et al., JCO 2002; Mortensen MS et al., ASCO 2013 abstract)

Following P-A relapse in pts observed following transinguinal orchiectomy for stage I seminoma, what are the appropriate Tx options?

Following P-A relapse in pts observed following transinguinal orchiectomy for stage I seminoma, retroperitoneal RT (for nodes <5 cm) or multiagent chemo are reasonable Tx options.

For pts treated with P-A RT following transinguinal orchiectomy for stage I seminoma, what is the relapse rate? Where do relapses occur?

For pts treated with P-A RT following transinguinal orchiectomy for stage I seminoma, relapse occurs in 0.5%–5% of pts. Most relapses occur within 2 yrs. In-field relapses are extremely rare; most relapses are mediastinal, lung, left supraclavicular, or (if risk factors are present) inguinal. Surveillance should include regular CXR.

What data support the option of adj chemo for stage I seminoma following transinguinal orchiectomy?

MRC-UK randomized 1,447 stage I seminoma pts between adj RT (2 Gy/fx to 20 or 30 Gy) and 1 cycle of carboplatin. There was no difference in 3-yr relapse rates (3.4% for RT vs. 4.6% for carboplatin). (Oliver R et al., Lancet 2005)

In a stage I seminoma pt, what factors would favor active treatment over surveillance?

In a stage I seminoma pt, concern over pt adherence with follow-up may favor active treatment.

Why is P-A RT not part of the definitive management of pts with stage IIC seminoma?

P-A RT is not part of the definitive management of pts with stage IIC seminoma due to high rates of distant failure (mediastinal, lung, supraclavicular, or bone). Thus, chemo is needed. In 1 series, 5-yr RFS among IIC pts treated with orchiectomy and RT alone was only 44%. (Chung PW et al., Eur Urol 2004)

What is the appropriate Tx for pts with stages I–IIB seminoma following relapse after adj P-A RT?

Pts with stages I–IIB seminoma who relapse following adj P-A RT should be treated with salvage chemo.

How should seminoma pts with stage IIC or greater be treated?

4 cycles of cisplatin/etoposide (+/- bleomycin) are appropriate for seminoma pts with stage IIC or greater.

What is the appropriate RT field for stage I seminoma pts?

Stage I seminoma pts (if receiving adj RT) should have the P-A nodes treated. MRC-UK TE 10 randomized 478 pts to P-A RT +/– pelvic RT and found equivalent RFS (96%). (Fossa SD et al., JCO 1999) 4 pelvic failures occurred in the P-A group (vs. none in the P-A + pelvic group).

For adj stage I seminoma, what are the borders for a P-A field?

Borders for a P-A field (for adj stage I seminoma):

Superior: T10-11 has been the historical standard, however, cranial reduction to T11-12 reduces kidney, stomach, and small bowel dose without compromise in RFS. (Bruns F et al., Acta Oncol 2005)

Inferior: L4-L5

Lateral: 2 cm on vertebral bodies. If left-sided primary, give 1-cm border on left renal hilum and sacroiliac joint. CT-based planning using vascular and nodal anatomy may help avoid marginal misses. (Martin JM et al., Radiother Oncol 2005)

What is the appropriate field for a stages IIA–IIB seminoma pt?

A stages IIA–IIB seminoma pt should have a “dogleg” or “hockey stick” field treated (including P-A and ipsi pelvic nodes). The sup border is at T10-11, and the inf border is at the obturator foramen. Per MRC-UK TE 10:

Superior: T10-11

Inferior: mid obturator foramen

Ipsilateral: renal hilum down as far as disc between 5^th lumbar and 1^st sacral vertebrae (L5-S1), then diagonally to lat edge of acetabulum, then vertically downward to mid obturator level

Contralateral: inclusion of processus transversus in P-A area down to L5-S1, then diagonally in parallel with ipsi border, then vertically to median border of obturator foramen

What is a reasonable dose and fractionation schedule for stage I seminoma?

For stage I seminoma, common prescription doses include:

Stage IA. 25 Gy in 1.25 Gy/fx

Stage IB. 25.5 Gy in 1.5 Gy/fx

Stage IC. 20 Gy in 2 Gy/fx

The MRC-UK TE 18 trial compared 2 Gy/fx to 20 Gy vs. 30 Gy and found equivalent relapse rates at 5 yrs. (Jones WG et al., JCO 2005)

What is a reasonable dose and fractionation schedule for stages IIA–IIB seminoma?

For stage IIA–IIB seminoma, the “dogleg” field may be treated with a similar dose-fractionation as stage I. Gross LAD may be boosted with an additional 5–10 Gy in 2 Gy/fx (∼30 Gy for IIA, ∼35 Gy for IIB).

What pathologic subtype of seminoma can be uniformly treated with orchiectomy alone?

Spermatocytic seminoma can be treated with orchiectomy alone. This tumor is seen in older pts and, while the precursor cell is unknown, is probably not a true seminoma.