Testicular Nonseminomatous Germ Cell Tumor
BACKGROUND
Approximately how many cases of germ cell tumor (GCT) are diagnosed annually in the U.S.?
~8,000 cases/yr in the U.S.
What % of testicular malignancies are GCTs?
~95% of testicular malignancies are GCTs.
What is the most common solid tumor in men age 15–34 yrs?
GCT is the most common solid tumor in men age 15–34 yrs.
How has the incidence of GCTs changed in the past 40 yrs?
The incidence of GCTs has more than doubled in the past 40 yrs.
Name 5 risk factors for GCTs.
Risk factors for GCTs:
1. Prior personal Hx of GCT
2. Positive family Hx
3. Cryptorchidism
4. Testicular dysgenesis
5. Klinefelter syndrome
How are GCTs classified?
GCTs are classified as seminomatous or nonseminomatous.
What % of testicular GCTs are nonseminomatous germ cell tumors (NSGCTs)?
40% of testicular GCTs are NSGCTs.
Name 5 histologic types of NSGCTs.
Histologic types of NSGCTs:
1. Embryonal cell carcinoma
2. Choriocarcinoma
3. Yolk sac tumor
4. Teratoma
5. Mixed
In what 2 ways are teratomas classified?
Teratomas are classified as either mature or immature depending on whether they contain adult-type differentiated cell types (mature) or partial somatic differentiation similar to that found in a fetus (immature).
What is a teratoma with malignant transformation?
A teratoma with malignant transformation is a teratoma that histologically resembles a somatic cancer, such as an adenocarcinoma or a sarcoma.
How does the presence of a seminoma component influence outcomes in pts with histologically confirmed NSGCTs?
The presence of a seminoma component within a histologically confirmed NSGCT has no major impact on the clinical outcome. Such pts are treated based on the NSGCT algorithm.
What is the median age of presentation for pts with NSGCTs, and how does this compare to the median age of presentation for pts with seminomatous germ cell tumors (SGCTs)?
The median age of presentation for NSGCTs is 27 yrs vs. age 36 yrs for SGCTs and 33 yrs for mixed tumors.
How does the presence of pure choriocarcinoma affect the prognosis?
Pure choriocarcinoma typically presents with widespread mets and a very high β-HCG and has a poor prognosis. Note that elements of choriocarcinoma are found in 10% of NSGCTs and do not affect the prognosis.
Which histology of NSGCTs is most commonly associated with an elevated AFP?
Yolk sac tumors are composed of cells that produce AFP.
What is the most common GCT histology in childhood?
Yolk sac tumors are the most common histology of GCT in childhood.
WORKUP/STAGING
Per NCCN 2014, what 3 blood tests should be performed in the workup of a suspicious testicular mass?
There are 3 blood tests that should be performed in a man with a suspicious testicular mass: AFP, β-HCG, and a chemistry panel including LDH.
What is the half-life of AFP?
The half-life of AFP is 5–7 days.
What is the half-life of β-HCG?
The half-life of β-HCG is 24–36 hrs.
How should a pt with pure seminoma histology and an elevated AFP be classified?
A pt with pure seminoma histology and an elevated AFP should be considered and treated as an NSGCT pt. AFP is not considered to be elevated in SGCT.
Per NCCN 2014, what imaging study should be performed in the workup of a suspicious testicular mass?
CXR and testicular ultrasound should be performed in the workup of a suspicious testicular mass.
How is the AJCC 7th edition (2011) staging for NSGCTs different from staging for SGCTs?
The AJCC staging is the same for both NSGCTs and seminomas. See seminoma staging for details.
How should an NSGCT be definitively diagnosed?
Definitive Dx of an NSGCT should be via a radical inguinal orchiectomy. Do not Bx a testicular mass (separate inguinal lymphatic drainage of scrotum).
Per NCCN 2014, what should be discussed preoperatively with a pt who has a testicular mass?
The pros and cons of sperm banking should be discussed prior to orchiectomy.
Per NCCN 2014, what imaging study should be ordered postoperatively after Dx of NSGCT?
CT abdomen/pelvis ± chest imaging should be performed postoperatively after the Dx of NSGCTs.
Per the International Germ Cell Cancer Collaborative Group, what 5 factors must be met to be classified as good–risk NSGCT?
Per the International Germ Cell Cancer Collaborative Group (JCO 1997), good-risk NSGCT must meet all of the following:
1. Testicular or retroperitoneal primary tumor
2. No nonpulmonary visceral mets
3. AFP <1,000 ng/mL
4. β-HCG <5,000 mIU/mL
5. LDH <1.5 times the upper limit of normal
Per the International Germ Cell Cancer Collaborative Group, what 3 factors must be met to be classified as intermediate-risk NSGCT?
Per the International Germ Cell Cancer Collaborative Group (JCO 1997), intermediate-risk NSGCT must meet both of the following:
1. Testicular or retroperitoneal primary tumor
2. No nonpulmonary visceral mets
and any of the following intermediate risk factors:
3a. AFP 1,000–10,000 ng/mL
3b. β-HCG 5,000–50,000 mIU/mL
3c. LDH 1.5–10 times the upper limit of normal
Per the International Germ Cell Cancer Collaborative Group, the presence of any of which 5 factors leads to classification of poor-risk NSGCT?
Per the International Germ Cell Cancer Collaborative Group (JCO 1997), poor-risk NSGCT has any of the following:
1. Mediastinal primary tumor
2. Nonpulmonary visceral mets
3. AFP >10,000 ng/mL
4. β-HCG >50,000 mIU/mL
5. LDH >10 times the upper limit of normal
TREATMENT/PROGNOSIS
Per NCCN 2014, what is the Tx of stage I good- or intermediate-risk NSGCT?
The Tx of stage I good- or intermediate-risk NSGCT is observation after orchiectomy (preferred for stage IA) if compliant vs. retroperitoneal lymph node dissection (RPLND) vs. bleomycin/etoposide/cisplatin (BEP) chemo × 2 cycles (stage IB only).
What is the risk of relapse after orchiectomy alone for stage I good- or intermediate-risk NSGCT if tumor markers are normal postoperatively?
The risk of relapse after orchiectomy alone for stage I good- or intermediate-risk NSGCT if tumor markers are normal postoperatively is ~30%.
Per NCCN 2014, how should pts with stage I NSGCT be monitored in an observation protocol?
Observation in pts with stage I NSGCT should consist of visits, tumor markers, and CXR q1–2 mos for yr 1, q2 mos for yr 2, q3 mos for yr 3, q4 mos for yr 4, q6 mos for yr 5, and q12 mos if >6 yrs. CT abdomen/pelvis should be done q3-4 mos for yr 1, q4–6 mos for yr 2, q6-12 mos for yrs 3-4, q12 mos for yr 5, and q12-24 mos if >6 yrs..
What did the MRC trial TE08 show for pts with stage I NSGCT?
MRC TE08 randomized 414 pts with stage I NSGCT s/p orchiectomy with normal serum markers (10% high risk with LVI) to CT chest/abdomen at 3 and 12 mos vs. CT scans at 3, 6, 9, 12, and 24 mos. At median follow-up of 3.3 yrs, 2-yr RFS was 79% with 2 scans vs. 84% with 5 scans (NSS). The 1st indication of relapse was markers in 39% and CT abdomen in 39%. The conclusion is that CT scans at 3 and 12 mos after orchiectomy might be reasonable in low-risk pts and that chest CT may be unnecessary. (Rustin GJ et al., JCO 2007)
What is the chance of positive nodes on RPLND despite a negative CT scan in pts with stage I NSGCT?
The risk of positive nodes on RPLND despite negative CT scan in pts with stage I NSGCT is 30%.
What is the relapse rate in pts with stage I NSGCT after orchiectomy → RPLND?
The relapse rate in pts with stage I NSGCT after orchiectomy → RPLND is 5%–10%, most commonly to the lungs.
Per NCCN 2014, how should pts with NSGCT and persistently positive tumor markers after orchiectomy be treated?
Pts with NSGCT and persistently positive tumor markers after orchiectomy should be treated with either BEP × 3 cycles or cisplatin/etoposide (EP) × 4 cycles.
What did the German Testicular Study Group AUO trial AH 01/94 show for pts with stage I NSGCT?
The AUO AH 01/94 trial randomized 382 pts with clinical stage I NSGCT to RPLND vs. BEP × 1 cycle. At median follow-up of 4.7 yrs, 2-yr RFS was 92% with surgery and 99% with BEP (HR 7.9, SS). The authors concluded that 1 course of BEP is superior to RPLND in clinical stage I Dz. (Albers P et al., JCO 2008) Some question the quality of RPLND in this study.
Per NCCN 2014, how should pts with stage II NSGCT with a +node diagnosed only after RPLND be treated?
pN1 (1-5 nodes <2cm) may be observed (preferred) or offered 2 cycles of BEP or EP chemo. pN2 (extranodal extension or any number of nodes <5cm) chemotherapy is preferred over surveillance. pN3 (any number of nodes >5cm) should receive 3 cycles of BEP or 4 cycles of EP. Node should be observed.
Per NCCN 2014, what is the Tx of pts with bulky stage II or III NSGCT?
Pts with bulky stage II or III NSGCT should be treated with either BEP × 3 cycles or EP x 4 cycles (good risk) or BEP × 4 cycles (intermediate risk).
What is the role of RT in the primary Tx of NSGCT?
Although RT may be used for palliation of metastatic Dz, there is no established role for RT in the primary Tx of NSGCT.
Per NCCN 2014, what is the follow-up for pts with NSGCT with CR to chemo and/or RPLND?
Surveillance of pts with NSGCT after CR to chemo and/or RPLND should consist of visits, tumor markers, and CXR q2–3 mos for yrs 1–2, q3-6 mos for yr 3, q6 mos for yr4, q6-12 mos for yr 5, and q12 mos if >6 yrs. CT abdomen/pelvis should be done q6 mos for yr 1, q6–12 mos for yr 2, q12 mos for yrs 3–5, and as clinically indicated if >6 yrs.
TOXICITY
What is the major toxicity associated with RPLND?
The major toxicity associated with RPLND is retrograde ejaculation resulting in infertility; however, nerve-sparing techniques can preserve ejaculation in 95% of cases.
What is the pathognomonic complication of bleomycin chemo?
The pathognomic complication of bleomycin chemo is bleomycin-induced pneumonitis.
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