Robert H. Blackwell, MD
Marcus L. Quek, MD, FACS
BASICS
DESCRIPTION
• Nonseminomatous germ cell tumors (NSGCTs) are malignant neoplasms of the testicle originating from germ cells, excluding seminoma
• 4 histologic types: Choriocarcinoma, embryonal cell, teratoma, and yolk sac
• >50% of NSGCT have a mixed histology; may also include a seminoma component (mixed GCT)
• Testicular cancer accounts for 1–1.5% of male cancer, of which GCTs make up 90–95%
• This section provides an overview of NSGCT. Details on each subtype can be found in their respective chapters
EPIDEMIOLOGY
Incidence
• SEER age-adjusted incidence of testicular cancer in US is 5.5 per 100,000 men
• In US (2014), ∼8,820 new cases will be diagnosed with about 370 deaths
Prevalence
SEER prevalence of testicular cancer in US in 2010 was 221,020
RISK FACTORS
• Family history: ∼1.4% of patients with newly diagnosed GCTs report a family history
– Sons have a 4–6× increased risk of GCT, siblings have a 8–10× increased risk
• Cryptorchidism: ∼3.7× increased risk of GCT
– 7–10% incidence in cryptorchid patients in the ipsilateral undescended testicle, ∼5% in the contralateral testicle
• Environment: Higher incidence in Northern Europe > North America > Africa/Asia
• Prior testicular tumor: 2% incidence of malignancy in the contralateral testicle
• ITGCN: 70% progresses to GCT over 7 yr
Genetics
• Identification of isochromosome 12p amplification; found in nearly all GCTs
• 2–3% incidence of bilateral testis tumors may suggest congenital predisposition
PATHOPHYSIOLOGY
• ITGCN (intracellular germ cell neoplasia also referred to as CIS) is believed to be the precursor lesion of all GCTs, excluding spermatocytic seminoma
– ∼2.5% of patients with a GCT will have ITGCN in the contralateral testicle
• GCTs typically spread in a predictive manner via the retroperitoneal lymph nodes (although choriocarcinoma also spreads hematogenously)
– Left-sided tumors typically spread to para-aortic lymph nodes, right-sided tumors spread to interaortocaval lymph nodes. Tumor may spread right-to-left, but usually not left-to-right
– Subsequent drainage through the cisterna chyli, thoracic duct, and supraclavicular nodes (usually left) or retrograde to iliac/inguinal nodes
• Nearly 60% of NSGCTs contain >1 histologic subtype in varying amounts (mixed GCTs)
• Choriocarcinoma
– Expected presenting age: 20–30 yr
– Tumor markers: Markedly elevated HCG, normal AFP
– Rare in pure form (1%)
– Often presents as small primary tumor
– Can spread hematogenously to lung/brain
• Embryonal cell carcinoma
– Expected presenting age: 25–35 yr
– Tumor markers: Elevated or normal HCG/AFP
– Present in up to 85% of mixed GCTs
– Only pure embryonal in 2–3% of cases
– >40% of embryonal component in primary tumor puts patient at high risk for relapse
• Teratoma
– Expected presenting age: 25–35 yr
– Tumor markers: Normal AFP and HCG
– Composed of 2 or more germ cell layers: Endoderm, mesoderm, ectoderm
– Benign lesions when prepubertal, malignant lesions after puberty
– May be mature (completely differentiated cell types and somatic tissue) or immature (incompletely differentiated) teratoma
– Areas may undergo malignant transformation according to which layer transforms (eg, endoderm to adenocarcinoma).
• Yolk sac (endodermal sinus)
– Expected presenting age: 0–10 yr
– Tumor markers: Markedly elevated AFP, normal HCG
– Most common prepubertal testicular tumor
– Absence of yolk sac elements in mixed GCT is a predictor of relapse
ASSOCIATED CONDITIONS
• Cryptorchidism
• Infertility
GENERAL PREVENTION
• In cases of cryptorchidism, orchiopexy does not decrease incidence of malignancy, but allows for earlier detection
• USPSTF: Against routine screening for testicular cancer in asymptomatic adolescent and adults including routine testicular self-exams.
• American Cancer Society suggests that men with family history do monthly self-exams.
• American Urological Association (AUA): Monthly self-exams for all young men.
DIAGNOSIS
HISTORY
• Presents as painless mass or swollen testicle
• May be initially detected following testicular trauma, but not associated with trauma
• Back or flank pain present in ∼10% of cases
PHYSICAL EXAM
• Scrotal exam including both testes, epididymis, and cord structures
• Abdominal exam with attention to palpable lymphadenopathy and/or viscera
• Supraclavicular nodes
• Gynecomastia (present in ∼7%)
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Tumor markers: Used preop, postop, surveillance
– β-HCG: Produced by syncytiotrophoblasts. Half-life 24–36 hr
– AFP: Produced by epithelial lining of endodermal sinus. Half-life 5–7 days
– LDH: Elevated with increased tumor burden. Half-life 4–4.5 days
Imaging
• Scrotal US: Tumors tend to be hypoechoic, with blood flow seen within the tumor
– Microlithiasis: Prevalence of ∼6% in patients undergoing testicular ultrasound, although controversial if associated with malignancy
Diagnostic Procedures/Surgery
• No role for percutaneous biopsy for intratesticular masses
• Radical inguinal orchiectomy for histologic confirmation and may be therapeutic
• Metastatic evaluation: Abdominal/pelvic CT with CXR or chest CT
• MRI of brain and bone scan indicated only for suspicious symptoms or if choriocarcinoma
Pathologic Findings
• Choriocarcinoma: Have both syncytiotrophoblasts and cytotrophoblasts
• Embryonal: Distinct cell arrangements and vascular invasion often present
• Teratoma: At least 2 germ cell layers present
• Yolk sac: Schiller–Duval bodies are present in 50% of cases (resemble a glomerulus)
DIFFERENTIAL DIAGNOSIS
See Section I “Testis Cancer, Adult General Considerations” and “Testis Cancer, Pediatric, General Considerations”
ALERT
Encourage sperm banking prior to any definitive treatment.
TREATMENT
GENERAL-MEASURES (1)
• Radical inguinal orchiectomy standard of care
– Risk altering lymphatic drainage patterns with scrotal incision
– Additional therapy for NSGCTs depend on staging (TNM staging, risk stratification based on International Germ Cell Consensus Collaborative Group (IGCCCG) system
MEDICATION
First Line (2,3)
• Regardless of histology, patients with advanced germ cell tumors (cIIB—cIII) and those with persistently elevated tumor markers following radical orchiectomy (cIS), are initially treated with platinum-based chemotherapy according to the IGCCCG risk stratification.
– Patients with good-risk disease are treated with 3 cycles of bleomycin, etoposide, and cisplatin (BEP) or 4 cycles of etoposide and cisplatin (EP). While patients with intermediate-risk or high-risk disease receive 4 cycles of BEP, ∼30–40% of patients with poor-risk disease fail to achieve a durable response to conventional chemotherapy.
Second Line
Chemotherapy is reserved for patients with advanced disease where serum tumor markers do not normalize following initial chemotherapy.
SURGERY/OTHER PROCEDURES
• Radical inguinal orchiectomy for treatment and pathologic diagnosis
– Follow serum tumor markers and compare to preoperative values
– Pathologic risk factors for relapse
≥T2 disease
Lymphovascular invasion (50% chance of relapse)
>40% embryonal component
Absence of yolk sac component
• Testicular-sparing surgery can be selectively considered in patients with bilateral testicular tumors or a solitary testicle
• RPLND—if necessary (see below)
– For low-stage disease a unilateral sympathetic nerve-sparing template may be used
Superior boundary: Renal hilum bilaterally
Lateral boundary: Ipsilateral ureter down to level where it crosses the ipsilateral common iliac artery. The ipsilateral gonadal vessels and spermatic cord stump are included in the specimen.
Right-sided template medial boundary: Lateral edge of aorta down to level of IMA, then from aorta down along the right common iliac artery to where the right ureter crosses
Left-sided template medial boundary: Lateral edge of the IVC down to level of the IMA, then from the aorta down along the left common iliac artery to left ureter crossing
– Postchemotherapy: A full bilateral template is utilized with prospective nerve sparing
– The templates should not be strictly upheld should palpable disease be found.
ADDITIONAL TREATMENT
Radiation Therapy
Unlike seminomas, NSGCTs are not treated with radiation (teratoma is radioresistant).
Additional Therapies
• See Section III “Testis Cancer: Nonseminomatous Germ Cell Tumor” for treatment algorithm
• Stage Ia/Ib disease treatment options
– Surveillance: In reliable patients with no risk factors (no teratomatous elements, no lymphovascular invasion, and no embryonal cell carcinoma in the primary). Reliable patient; cure rate >95% with close follow-up
20–30% relapse rate; these patients can be salvaged with subsequent chemotherapy
– RPLND: Modified unilateral template/nerve-sparing. 70–75% will have no tumor (pN0)
Perform within 4 wk of CT and 7–10 days of tumor for accurate clinical staging
>95% cure rate if nodes negative, but may be curative for low-volume nodal disease
5% relapse rate
– Chemotherapy: 95% cure rate with BEP
• Stage IS disease: Elevated tumor markers postorchiectomy without radiographic evidence of disease. Treat with chemotherapy. Preferable to RPLND given suspected disseminated disease
• Stage IIa/IIb disease
– Postorchiectomy tumor markers positive; induction chemotherapy
– Postorchiectomy tumor markers negative; either RPLND or chemotherapy
No viable tumor (pN0), observe patient
Low-volume tumor, surgery curative in 60–90%; surveillance or chemotherapy
High-volume disease (pN2–3—risk of relapse >50%) or tumor left behind; adjuvant BEP chemotherapy decreases relapse to <1%
• Stage IIc or III disease
– Either 3 or 4 cycles of BEP chemotherapy
– Complete response, observe
– Partial response with residual masses, full bilateral RPLND (nerve sparing if applicable)
Residual masses: 40% fibrosis, 40% teratoma, 20% viable malignancy
Teratoma/fibrosis on pathology: Observe
Viable tumor and tumor markers are elevated or tumor is left behind; consider salvage chemotherapy
– If no response to primary chemotherapy consider second-line chemotherapy (ifosfamide, vinblastine, cisplatin) or bone marrow transplant
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Has been divided into good, intermediate, and poor prognosis based on stage and risk factors.
• See Section I “International Germ Cell Cancer Collaborative Group (ICGCCCG)”
– Good: 5-yr survival 94%.
– Intermediate: 5-yr survival 83%
– Poor: 5-yr survival 71%.
COMPLICATIONS
• Surveillance: Risk of recurrence, risk for secondary malignancy due to repeat CT imaging
• RPLND
– Ejaculatory dysfunction can impair fertility; a nerve-sparing template can preserve antegrade ejaculation in more than 90% of cases.
– Morbidity (atelectasis, ileus, lymphocele, pancreatitis, chylous ascites); rate 5–25%, late bowel obstruction rate 1–2%, mortality rate <1%
• Chemotherapy
– Bleomycin: Pulmonary fibrosis. Need to limit IV fluid hydration and supplemental oxygenation
– Cisplatin: Nephrotoxicity, ototoxicity, peripheral neuropathy
– Secondary malignancy, especially leukemias, skin malignancies, and lymphomas
– Metabolic syndrome
– Infertility (50% with normal semen 2 yr after chemotherapy, 25% remain azoospermic)
FOLLOW-UP
Patient Monitoring
• Physical exam, tumor markers, and imaging (CXR, abdominal/pelvic CT)
• Frequency of follow-up may be tailored depending on therapy, stage, and disease risk
Patient Resources
NCI Testicular Cancer Information. www.cancer.gov/cancertopics/types/testicular
REFERENCES
1. Albers P, Albrecht W, Algaba F, et al. EAU guidelines on testicular cancer: 2011 update. Eur Urol. 2011;60:304–319.
2. Mannuel HD, Mitikiri N, Hussain A. Update on testicular germ cell tumors. Curr Opin Oncol. 2011;23:265–270.
3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: testicular cancer. www.nccn.org. Version 1.2013. (Accessed January 21, 2014)
ADDITIONAL READING
Stephenson AJ, Sheinfeld K. The role of retroperitoneal lymph node dissection in the management of testicular cancer. Urol Oncol. 2004;22:335–235.
See Also (Topic, Algorithm, Media)
• International Germ Cell Cancer Collaborative Group (IGCCCG)
• Reference Tables: TNM: Testis Cancer Codes
• Scrotum and Testicle, Mass
• Testis Cancer, Nonseminomatous Germ Cell Tumor Algorithm 
• Testis Cancer, Nonseminomatous Germ Cell Tumors, General Images 
• Testis Cancer, Pediatric, General Considerations
• Testis, Tumor and Mass, Adult, General
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 752.51 Undescended testis
• V16.43 Family history of malignant neoplasm of testis
ICD10
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
• Q53.9 Undescended testicle, unspecified
• Z80.43 Family history of malignant neoplasm of testis
CLINICAL/SURGICAL PEARLS
• At radical inguinal orchiectomy, tag the residual spermatic cord stump with a long silk suture for identification at future RPLND.
• Lymphatic drainage is predictable unless there is a history of scrotal/inguinal surgery.
• Tumor marker half-lives can be followed to assess if they fall appropriately after treatment (should nadir after 5 half-lives).