Srinivas Vourganti, MD
Allen D. Seftel, MD, FACS
BASICS
DESCRIPTION
• Testis cancer is the most common malignancy in men aged 20–40 yr in US.
• Mortality has dropped from >50% in the 1970s to <5% today, due to improved imaging, better tumor markers, and multidrug chemotherapy.
• 95% of testicular tumors are germ cell tumors, other types are rare (sex cord/stromal)
• While benign lesions can be found in the testis (see section on “Differential Diagnosis”), all solid lesions should be considered cancer until definitively proven otherwise
EPIDEMIOLOGY
Incidence (1)
• ∼8,820 new cases of testis cancer in US in 2014, and 380 men will die of this disease.
• Median age at diagnosis was 33 (2006–2010)
• Incidence rate was 5.5/100,000 men per year:
– By race/100,000 men/yr: White men 6.6; black men 1.4, Asian men 1.9; Hispanic men 4.7
Prevalence
In 2010, in US there were ∼221,020 men alive with history of testicular cancer.
RISK FACTORS (2)
• History of cryptorchidism:
– 7–10% of cases; 4–6 times more likely to develop testicular cancer
– Seminoma is most common tumor type
– Orchiopexy reduces relative risk (RR) from 3 to 2 if performed prior to onset of puberty
• Family history (affected 1st-degree relative):
– Father with testis cancer—RR 4.63
– Brother with testis cancer—RR 8.3
– Son with testis cancer—RR 5.23
• Cannabis use controversial
• Testicular atrophy
• Infertility
• Klinefelter syndrome
Genetics
Isochromosome 12p amplification seen in the majority of tumors
PATHOPHYSIOLOGY
• Germ cell tumors (seminoma, embryonal cell carcinoma, teratoma, choriocarcinoma, and yolk sac tumor) comprise 90–95% of testicular tumors.
– Mixed germ cell tumors common (60% of all)
• Seminoma: 35–65% of germ cell tumors; classified into 3 subtypes:
– Typical (classic) seminoma: 82–85% of seminomas; most commonly men in 30s; less common in men in 40s–50s
Syncytiotrophoblast in 10–15% of typical seminomas and makes to β-hCG.
– Spermatocytic seminoma:
2–12%; roughly 1/2 in men >50 yr
– Lower malignant potential
• Embryonal cell carcinoma:
– Occurs in 40% of germ cell tumors
• Choriocarcinoma
– Rarely found in pure form; pure form is often advanced, with a small primary tumor.
– Prognosis for pure choriocarcinoma is poor.
• Yolk sac tumor: 92% stain for AFP
• Teratoma:
– Frequently found at metastatic sites
– Locally invasive, chemotherapy resistant
• Nongerm cell tumors (5–7%):
– Leydig cell tumors: 2–3% of tumors; not associated with cryptorchidism;10% malignant
– Sertoli cell tumors:
1% of testicular tumors; 90% benign
– Gonadoblastoma: Rare; most in men <30 yr
ASSOCIATED CONDITIONS
• Cryptorchidism
• Infertility seen in men upon diagnosis (half with oligospermia, 1/10th with azoospermia)
GENERAL PREVENTION
Testicular self-exam should be performed monthly for earlier diagnosis.
DIAGNOSIS
HISTORY
• Local symptoms: Change in testicular size or texture; testicular pain (uncommon)
• Systemic symptoms: Weight loss; abdominal pain/discomfort; fevers; mastodynia or other changes in secondary sex characteristics:
• History: Cryptorchidism, infertility, orchiopexy
PHYSICAL EXAM
• Check all lymph nodes, including supraclavicular nodes.
• Abdominal exam for masses
• Examine for gynecomastia (5% of cases).
• Testicular exam: Examine both testes:
– Any firm or hard area in the testis should be evaluated; determine if mass is distinct from epididymis. Note consistency of testis, whether it is fixed to scrotum, and size of lesion
– Palpate for hydrocele, hernia.
ALERT
Markers must be drawn prior to orchiectomy.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Tumor markers obtained prior to orchiectomy:
– 1 or more elevated in 85–90% of non-seminomatous germ cell tumor (NSGCT)
• β-hCG:
– Half-life: 24–36 hr
– Elevated in 40–60% with testis cancer; 100% of choriocarcinomas;10–15% pure seminomas
• AFP:
– Half-life: 5–7 days
– Produced by yolk sac tumors, embryonal cell carcinoma, and teratocarcinomas
– Not produced in pure seminoma or pure choriocarcinoma. If AFP elevated in case of pure seminoma, NSGCT elements are present.
• LDH
– Nonspecific marker for GCT
– Elevated in 20% of low stage and 50% of high-stage GCT
– Useful in prognosis as magnitude of elevation correlates with disease bulk
– Half-life: 1 day
• Serum and urine estrogens may be elevated in Leydig cell tumors
Imaging
• Scrotal US:
– Diagnostic imaging mainstay for identifying testicular tumors
– Any hypoechoic lesion within the testicular parenchyma should be considered cancer until proven otherwise.
– 80% of testicular tumors are hypoechoic.
• Abdominal CT:
– Critical for staging of testicular tumors
– Should be performed prior to orchiectomy if possible, as postoperative retroperitoneal hematoma can distort imaging.
– Accuracy is 70–90%, depending upon stage.
– Cannot detect micrometastasis in normal-sized lymph nodes
• Chest x-ray: Staging for metastases; if abnormal, chest CT is obtained.
Diagnostic Procedures/Surgery
• Radical inguinal orchiectomy:
– Important for determining pathology of primary tumor. Is also therapeutic in that chemotherapy does not penetrate testis well.
• Transscrotal testicular biopsy or orchiectomy should NOT be performed.
DIFFERENTIAL DIAGNOSIS
These are a delineation of testicular masses only. For a complete listing of intrascrotal and testicular masses see Section I “Scrotum and Testicle Mass”:
• Benign lesions
– Epididymitis/orchitis: Bacterial, STD/STI, mumps, TB
Often delayed testicular cancer diagnosis due to treatment of presumed epididymitis
– Testicular trauma: Usually blunt; contusion, rupture; usually associated hematocele
– Torsion (testicle or appendages)
– Incarcerated/strangulated hernia
– Cysts (simple, tunica albuginea, epidermoid)
– Adrenal rest tumors: In general benign, but can contribute to infertility in patients with congenital adrenal hyperplasia
– Fibrous pseudotumor of the tunica albuginea: Painless fibrous mass often associated with prior history of trauma or infection
– Adenomatoid tumor of testis or epididymis
– Other rare benign lesions: Angioma, fibroma, leiomyoma, hamartoma, carcinoid, neurofibroma
• Malignant lesions
– Testicular primary tumors (seminoma and nonseminomatous GCT)
– Leukemia involving testis—testis can be a site of solitary recurrence of leukemia post-treatment (sanctuary site). Biopsy can be utilized to confirm diagnosis in a patient with history of leukemia.
Treatment can be testis sparing with radiation, though contralateral testis should be treated as bilateral disease can be present.
– Lymphoma involving testis—usually represents extension from extratesticular sites, rarely can represent a primary lymphoma site (1% of lymphoma cases); can present bilaterally one-third of the time; mostly involves older men >60 yr; constitutional symptoms commonly present (fever, chills, night sweats, weight loss).
– Metastatic solid tumors: More common—prostate, lung, GI tract; more rare—kidney, malignant melanoma, pancreas, bladder, and thyroid
– Adenocarcinoma of the rete testis: Arises in the testis collecting system, high-stage presentation, poor response to chemotherapy and radiation, with median survival of 1 yr.
– Mesothelioma of tunica vaginalis: Rare, similar to the more common pleural histology, associated with asbestos exposure
– Paratesticular sarcomas: Rhabdomyosarcoma, malignant fibrous histiocytoma (most common soft tissue sarcoma in late adult life)
TREATMENT
GENERAL MEASURES
• Radical inguinal orchiectomy is considered standard of care for initial management.
• Additional therapy depends on staging. Commonly used staging system is the TNM staging and group staging by the AJCC.
– For NSGCT: RPLND, primary chemotherapy (platinum based), or surveillance
• For seminoma: Surveillance, primary radiotherapy, or primary chemotherapy (single-agent carboplatin)
• Surveillance, with serial imaging and tumor markers, is appropriate in well-selected low-risk patients:
– Stage I seminoma
– Stage I NSGCT: No teratomatous elements, no lymphovascular invasion, and no embryonal cell carcinoma in the primary specimens. Patients must be reliable.
MEDICATION
First Line
• Treatment depends upon primary cell type of tumor and stage at presentation.
• Cisplatin-based chemotherapy is the 1st-line regimen for treating testicular cancer:
– Commonly used for stage IIc and higher seminoma; numerous regimens used.
– 2 cycles of BEP (bleomycin/etoposide/cisplatinum) in stage I NSGCT
– 3 cycles of BEP commonly used for stage IIa, IIb; good-risk stage IIc and III disease
– Poor-risk stage IIc and II disease: 4 cycles of BEP have been used:
Some centers have replaced etoposide with ifosfamide and some use advocated 4 cycles of vinblastine, ifosfamide, and cisplatin.
Second Line
High-dose chemotherapy with autologous bone marrow transplantation in patients with residual disease and or recurrent disease or rather, enrollment in a clinical trial
SURGERY/OTHER PROCEDURES
• Radical orchiectomy:
– Inguinal approach is used to prevent violation of tissue planes
– May be adequate treatment for stage I seminoma and certain stage I NSGCTs
• Retorperitoneal lymph node dissection (RPLND):
– Indicated in patients with stage I and IIa NSGCT, particularly those with teratoma in the primary specimen
– With residual mass after chemotherapy
For low-stage disease, a modified nerve-sparing template is normally used.
– For RPLND description, see Section I: “Testis Cancer, Nonseminomatous Germ Cell Tumors”
ADDITIONAL TREATMENT
Radiation Therapy
• Commonly used in stage I and IIa seminomas
• External beam radiation to retroperitoneal and ipsilateral ilioinguinal lymph nodes
• Contralateral inguinal region is included if history of inguinal or scrotal procedures
Additional Therapies
Patients should consider sperm banking prior to treatment to aid in avoiding risk of infertility.
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
Depending upon stage and cell type of primary tumor, prognosis is excellent, with 95% of patients experiencing a long-term cure.
COMPLICATIONS
• Infertility
• RPLND: Retrograde ejaculation, ileus, atelectasis, chylous ascites, chylothorax, pneumonitis, lymphocele, pancreatitis, and vascular or bowel injury
• Increased risk of secondary malignancies in patients undergoing chemotherapy or radiation
FOLLOW-UP
Patient Monitoring
• In patients who underwent RPLND:
– Serial monitoring with chest x-ray, physical exam, and tumor markers. Retroperitoneal recurrence is rare, so imaging of this region is not usually needed.
– Follow-up depends upon initial stage and cell type of primary tumor and response to therapy.
• In patients who did not undergo RPLND:
– Follow-up similar; serial monitoring of retroperitoneum using CT scanning
– Frequency of follow-up is based on initial stage and cell type and the response to therapy.
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. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.
2. Nordsborg RB, Meliker JR, Wohlfahrt J, et al. Cancer in first-degree relatives and risk of testicular cancer in Denmark. Int J Cancer. 2011;129(10):2485–2491.
ADDITIONAL READING
• Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA. 2008;299:672–684.
• National Comprehensive Cancer Network Guideline Recommendations. http://www.nccn.org/clinical.asp
See Also (Topic, Algorithm, Media)
• Reference Tables: TNM: Testis Cancer
• Scrotum and Testicle, Mass
• Testis Cancer, Adult General Considerations
• Testis Cancer, Choriocarcinoma
• Testis Cancer, Embryonal Carcinoma
• Testis Cancer, Endodermal Sinus Tumors (Yolk Sac Tumors)
• Testis Cancer, Pediatric, General Considerations
• Testis Cancer, Seminoma
• Testis Cancer, Nonseminomatous Germ Cell Tumors, General
• Testis, Leydig Cell Tumor
• Testis, Pain (Orchalgia)
• Testis, Sertoli Cell Tumor
• Testis, Teratoma, Mature and Immature
• Testis, Tumor and Mass, Adult, General Considerations Images 
• Testis, Tumor and Mass, Pediatric, General Considerations
• Torsion, Testis or Testicular/Epididymal Appendages
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 239.5 Neoplasm of unspecified nature of other genitourinary organs
• 608.89 Other specified disorders of male genital organs
ICD10
• D49.5 Neoplasm of unspecified behavior of other genitourinary organs
• N50.8 Other specified disorders of male genital organs
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
CLINICAL/SURGICAL PEARLS
• Increased risk of malignancy in patients with history of cryptorchidism and family history of testis cancer.
• Ultrasound should be performed to resolve any concerns of abnormal scrotal exam.
• Initial diagnosis of radical orchiectomy using an inguinal approach to avoid scrotal violation.
• All testis masses in adults should be considered malignant until proven otherwise.