Nicholas J. Kuntz, MD
Judd W. Moul, MD, FACS
BASICS
DESCRIPTION
• Embryonal carcinoma (EC) is the most common (43%) nonseminoma germ cell tumor (NSGCT) histologic subtype of the testis (1)[B]
• Pure EC histology is present in 2–4% of all germ cell tumors (GCTs)
• EC is present in 85% of mixed GCTs
• Most common in age 20–40 yr
• Right more common, bilateral in 2–3%
EPIDEMIOLOGY
Incidence
• US age-adjusted incidence (SEER data)
– 5.5 per 100,000/yr (all testicular cancers)
• 2014 estimated new cases of testicular cancer
– 8,820 with 380 deaths
• Lifetime risk of developing testicular cancer:
– 1 in 270
Prevalence
Testicular cancer: 221,020 US men in 2010
RISK FACTORS
• Cryptorchidism
– 4–6-fold increased risk for all GCTs
– Increased risk in contralateral testes
• Previous testicular malignancy
– 12-fold increases risk to develop cancer in the contralateral testicle
• Family history
– 8–12-fold increased risk with affected brother
• Intratubular germ cell neoplasia (ITGCN)
• Testicular atrophy
– Nonspecific or mumps-associated
• Klinefelter syndrome
Genetics
• Isochromosome of the short arm of chromosome 12–i(12p) (2)[B]
• ITGCN
– p53 alterations found in 66% (3)[B]
PATHOPHYSIOLOGY
• EC is an aggressive GCT subtype
• 74% have metastases at presentation (1)[B]
• Predominant EC component (>50%) increases the risk of occult metastasis (3)[A]
• High associated relapse rate (35–40%)
• Predictable lymphatic spread
– Retroperitoneum (primary site)
Left-sided tumors spread to preaortic and para-aortic lymph nodes; left-to-right spread is rare.
Right-sided tumors spread to precaval, interaortocaval, and then may spread to preaortic and para-aortic nodes.
– Most common visceral sites
Lungs, liver
ASSOCIATED CONDITIONS
• Infertility
• Cryptorchidism
• Seminoma
GENERAL PREVENTION
• Possibly early orchidopexy for undescended testicle
• Testicular self-exam
DIAGNOSIS
HISTORY
• Signs and symptoms
– Painless testicular mass (50–60%)
– Testicular pain or dull ache (30–40%)
– Symptomatic metastases (10%)
Cough, dyspnea, supraclavicular nodal
– Gynecomastia (2%)
– Trauma (4%)
– Infertility
• History of undescended testes in 10%
PHYSICAL EXAM
• Thorough genital, lymph node, abdominal, chest, and neurologic exam
– 2–3% of patients with disseminated testicular cancer present with central nervous system (CNS) metastasis.
– Gynecomastia noted in 7% of GCTs (2)[B]
• Include palpation of spermatic cord structures
• Scrotal ultrasound (US) (see “Imaging”)
• Transillumination test
– Reactive hydrocele may be secondary to underlying malignancy
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Tumor markers (4)[A] (drawn at diagnosis and following orchiectomy according to half-life)
– α-Fetoprotein (AFP)
Produced by fet al gut, liver, and yolk sac
Half-life of ∼5 days.
Elevated in 80% of EC
Absent in pure seminoma and choriocarcinoma.
– Human chorionic gonadotropin (hCG)
Normally secreted by placental syncytiotrophoblasts
Half-life of ∼24–36 hr. Consists of α- and β-chains: α-chain analogous to luteinizing hormone and thyroid-stimulating hormone.
Elevated in 60% of all NSGCT, 30% of seminomas, and all choriocarcinomas.
– Lactate dehydrogenase (LDH)
Most useful when other markers are negative.
Relates to tumor bulk.
• Chemistry profile
– Renal function (future chemo, ureteral obstruction from RP disease)
Imaging
• Scrotal US (4)[A]
– Well circumscribed, heterogeneous, hypoechoic mass is highly suspicious for cancer
– Cannot distinguish subtypes on imaging
• Clinical staging
– Computed tomography (CT) of chest abdomen and pelvis (4)[A]
– Head magnetic resonance imaging (MRI) if:
Neurologic symptoms
High risk for CNS disease (mets, high hCG, or choriocarcinoma)
– Positron emission tomography (PET): Not indicated for NSGCT (2)[B]
Diagnostic Procedures/Surgery
• Biopsy of primary mass is contraindicated
– Contamination of lymph drainage
• Consider inguinal biopsy of contralateral testis if (2)[B]:
– Concerning US findings
– Cryptorchid testis
– Significant atrophy
Pathologic Findings
• Gross
– Tan to yellow, fleshy tumor
– Areas of necrosis or hemorrhage
– Poorly defined capsule
• Histologic
– Epithelioid cells arranged in glands or tubules, indistinct cell borders
– Pale or vacuolated cytoplasm
– Rounded nuclei with coarse chromatin
– Large nucleoli; pleomorphism, mitotic figures, and giant cells
– Staining:
Positive: AE1/AE3, PLAP, and OCT3/4
Negative: c-KIT
DIFFERENTIAL DIAGNOSIS
See Section I “Testis, Tumor and Mass, Adult, General Considerations” and Testis, tumor and mass, pediatric, general considerations
ALERT
Up to 33% of testicular tumors are initially misdiagnosed
TREATMENT
ALERT
Discuss sperm banking prior to treatment, due the increased risk of infertility following treatment (4)[A].
GENERAL MEASURES
• Surgery (radical inguinal orchiectomy) is the primary treatment for all testicular malignancies (4)[A]
• Chemotherapy prior to orchiectomy may be warranted in severe cases (4)[A]
• Subsequent primary treatments include chemo, radiation, or retroperitoneal lymph node dissection (RPLND)
• Treatment options for EC are based on clinical stage (4)[A]. (see Table “TNM: Testis Cancer”)
– Stage IA, IB:
Surveillance (IA or IB T2 only)
RPLND
Chemotherapy (2 cycles bleomycin, etoposide, cisplatinum (BEP) × 2 or BEP × 1
– Stage IIA and IIB:
RPLND
Chemotherapy (EP × 4, or BEP × 3)
– Stage IIc or stage III:
Good risk (EP × 4 or BEP × 3)
Intermediate risk (BEP × 4)
Poor risk (BEP × 4, clinical trial, VIP × 4)
MEDICATION
First Line
• BEP or EP regimens
• See Section I: “Testis, Cancer, Adult General Considerations” for specific regimens
Second Line
• Vinblastine, ifosfamide, cisplatinum (VIP)
– Poor tolerance to bleomycin
– Salvage protocol
– Pretreat with MESNA to reduce incidence of hemorrhagic cystitis
• Paclitaxel, ifosfamide, cisplatin (TIP)
• High-dose chemotherapy
SURGERY/OTHER PROCEDURES
• Radical inguinal orchiectomy
– Recommended first-line treatment for testicular tumors (4)[A]
• Partial orchiectomy
– Small tumor (<30% of testicular volume), solitary testes, or bilateral tumors
– Adjuvant radiation at some point (16–20 Gy) given high rate of associated ICGCN (2)[B]
• RPLND
– Nerve-sparing approach minimizes ejaculatory dysfunction
– stage IIa, IIb, or high-risk stage I (4)[A]
• Salvage RPLND
– Consider referral to high-volume center
– Full bilateral template recommended in this setting
ADDITIONAL TREATMENT
Radiation Therapy
No role in treatment of NSGCT
Additional Therapies
Palliative chemotherapy
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Stage I:
– >30% relapse with observation alone
• Stage II and III:
– >60% have complete response following adjuvant treatment
COMPLICATIONS
• RPLND:
– Loss of seminal emission: 10%
– Bowel obstruction: 1–3% lifetime risk
– ARDS: Patients previously been treated with bleomycin
• Chemotherapy:
– Bleomycin: Pulmonary fibrosis, ARDS
– Etoposide: Myelosuppression, alopecia secondary leukemia
– Cisplatin: Renal insufficiency, nausea/vomiting, neuropathy
– Ifosfamide: Hemorrhagic cystitis
– Vinblastine: Neuromuscular toxicity
FOLLOW-UP
Patient Monitoring
• Primary surveillance
– ∼30% recurrence, most common 1st 2 yr
– NCCN follow-up protocol:
Year 1: Tumor markers and chest x-ray every 1–2 mo; abdominal CT every 3–4 mo
Year 2: Tumor markers and chest x-ray every 2 mo; abdominal CT every 4–6 mo
Years 3–5: Tumor markers and chest x-ray every 3–6 mo; abdominal CT every 6–12 mo
After year 5: Tumor markers and chest x-ray once a year; abdominal CT every 1–2 yr
• RPLND
– Most likely site of recurrence is the chest (3)
– NCCN follow-up protocol:
Year 1: Tumor markers and chest x-ray every 2–3 mo, baseline abdominal/pelvic CT
Year 2: Tumor markers and chest x-ray every 2–3 mo, abdominal/pelvic CT as indicated
Years 3–5: Tumor markers and chest x-ray every 3–12 mo, abdominal/pelvic CT as indicated.
After year 5: Tumor markers and chest x-ray once a year
• Chemotherapy and RPLND
– NCCN follow-up protocol:
Year 1: Tumor markers and chest x-ray every 2–3 mo; abdominal/pelvic CT every 6 mo
Year 2: Tumor markers and chest x-ray every 2–3 mo; abdominal/pelvic CT every 6–12 mo
Years 3–5: Tumor markers and chest x-ray every 3–12 mo; abdominal/pelvic CT every year
After year 5: Tumor markers and chest x-ray once a year; abdominal/pelvic CT as indicated
Patient Resources
• NCI 1-800-4-CANCER. http://www.cancer.gov/cancertopics/pdq/treatment/testicular/Patient
• American Cancer Society. http://www.cancer.org/cancer/testicularcancer/index
REFERENCES
1. Vugrin D, Chen A, Feigl P, et al. Embryonal carcinoma of the testis. Cancer. 1988;61(11):2348–2352.
2. Albers P, Albrecht W, Algaba F, et al. EAU guidelines on testicular cancer: 2011 update. Eur Urol. 2011;60(2):304–319.
3. Albers P, Siener N, Kliesch S, et al. Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: Results of the German Testicular Cancer Study Group Trial. J Clin Oncol. 2003;21(8):1505–1512.
4. National Guideline Clearinghouse. Guidelines on testicular cancer Rockville MD: Agency for Healthcare Research and Quality (AHRQ); [5/15/2013]. www.guideline.gov/content.aspx?id=34061&search=embryonal+carcinoma.
ADDITIONAL READING
• National Cancer Institute. www.cancer.gov/cancertopics/types/testicular/ (Accessed August 20, 2014)
• National Comprehensive Cancer Network. Available at www.nccn.org (Accessed August 20, 2014)
See Also (Topic, Algorithm, Media)
• International Germ Cell Cancer Collaborative Group (IGCCCG)
• Reference Tables: TNM: Testis Cancer
• Scrotum and Testicle, Mass
• Testis Cancer, Adult General Considerations
• Testis Cancer, Embryonal Carcinoma Image 
• Testis Cancer, Pediatric, General Considerations
• Testis, Tumor and Mass, Adult, General Considerations
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 608.3 Atrophy of testis
• 752.51 Undescended testis
ICD10
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
• Q53.9 Undescended testicle, unspecified
• N50.0 Atrophy of testis
CLINICAL/SURGICAL PEARLS
• Painless testicular mass is testicular cancer until proven otherwise.
• Transscrotal orchiectomy or biopsy is contraindicated.
• EC is aggressive histologic subtype with increased risk of occult disease.
• Second opinion of pathologic specimens by experienced pathologists is encouraged.
• Current treatment approaches achieve excellent long-term survival rates.