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Testicular Malignancies
Huy Tan Tran, MD, LCDR, MC, USN
Moses H. Cheng, MAJ, MC, USA
image BASICS
DESCRIPTION
  • Testicular cancer accounts for 1% of all cancers in men; it is the most common solid malignancy in men aged 15 to 34 years (1).
  • An estimated 8,430 new cases were diagnosed, and an estimated 380 deaths occurred in the United States in 2015 (2).
  • Treatment produces an overall 5-year survival of
    95.3%; for African American patients, this 5-year survival rate is alarmingly lower but has improved from 86% to 90% (2).
ETIOLOGY AND PATHOPHYSIOLOGY
95% of all malignant tumors arising in the testes are germ cell tumors (GCTs), which are subclassified as follows:
  • Seminomatous GCTs: most common type overall
  • Nonseminomatous GCTs (NSGCTs): These include embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, teratomas, or often multiple cell types; these are more clinically aggressive tumors.
RISK FACTORS
  • Cryptorchidism is the most firmly established risk factor: Relative risk of testicular cancer in all patients with cryptorchidism is 3 to 8, with a lower relative risk of 2 to 3 in those undergoing orchiopexy by age 12 years; in patients with unilateral cryptorchidism, the relative risk of testicular cancer in the contralateral normally descended testis is negligible (3).
  • Personal history of testicular cancer
  • Use of muscle building supplements
  • Positive family history for testicular cancer
  • Testicular dysgenesis
  • Klinefelter syndrome
  • Caucasian race
  • HIV infections
GENERAL PREVENTION
No evidence that screening for testicular cancer is effective (4).
image DIAGNOSIS
PHYSICAL EXAM
  • Testicular exam: Palpate for size, consistency, and nodules; masses do not transilluminate; a firm, hard, or fixed area should be considered suspicious.
  • Lymph node and abdominal exam
  • Gynecomastia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • &agr;-Fetoprotein (AFP), &bgr;-human chorionic gonadotropin (&bgr;-hCG), lactate dehydrogenase (LDH), creatinine, chemistry profile, complete blood count, liver enzymes, chest x-ray (CXR), and testicular ultrasound (US)
  • Tumor markers AFP, &bgr;-hCG, and LDH are used to assist with diagnosis, prognosis, assessing treatment outcome, and monitoring for relapse:
    • AFP
      • Produced by nonseminomatous testicular cancer and is therefore associated with this histologic type
      • Those with a histologically “pure” testicular seminoma and an elevated AFP are assumed to possess an undetected focus of nonseminoma tumor.
    • -&bgr;-hCG
      • May be associated with both seminomatous or nonseminomatous tumors
      • Hypogonadism and marijuana use may cause benign elevations of &bgr;-hCG.
  • LDH is less specific than AFP.
  • Testicular US is the initial study.
  • If an intratesticular mass is identified, measure serum AFP, LDH, and &bgr;-hCG and order a CXR.
  • CT scan of the abdomen/pelvis, positron emission tomography (PET) scan, MRI of the brain, and bone scan are used for staging and metastases evaluation as clinically indicated.
Diagnostic Procedures/Other
  • Radical inguinal orchiectomy is the primary procedure for diagnosis and treatment.
  • Testicular biopsy may be rarely considered if a suspicious intratesticular abnormality is identified on US; however, testicular microcalcification on US without any other abnormality can simply be observed and does not demand a biopsy.
  • For those with unilateral testicular cancer, contralateral testicular biopsy is not routinely performed but should be considered when there is a cryptorchid testis, marked testicular atrophy, or a suspicious US for intratesticular abnormalities.
Test Interpretation
Clinical staging (5):
  • Stage 0: carcinoma in situ
  • Stage IA: tumor limited to testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis; normal serum tumor markers
  • Stage IB: tumor limited to testis and epididymis with vascular/lymphatic invasion or tumor extending through tunica albuginea with involvement of tunica vaginalis; tumor invades the spermatic cord with or without vascular/lymphatic invasion; tumor invades the scrotum with or without vascular/lymphatic invasion; no lymph node involvement or distant metastasis; normal serum tumor markers
  • Stage IS: any tumor with elevated serum tumor markers but no nodal involvement or metastasis
  • Stage IIA: any tumor with lymph node mass/masses <2 cm
  • Stage IIB: any tumor with lymph node mass/masses 2 to 5 cm
  • Stage IIC: any tumor with lymph node mass >5 cm
  • Stage IIIA: any tumor/lymph node presence; with nonregional nodal or pulmonary metastasis; either serum tumor markers normal or with mild elevation
  • Stage IIIB: any tumor/lymph node presence; no distant metastasis or nonregional nodal involvement or pulmonary metastasis; with moderately elevated serum tumor markers
  • Stage IIIC: any tumor/lymph node presence; with or without any metastasis; with greatly elevated serum tumor markers
DIFFERENTIAL DIAGNOSIS
Epidermoid cyst, epididymitis, hernia, hydrocele, hematoma, lymphoma, orchitis, spermatocele, testicular torsion, varicocele
image TREATMENT
GENERAL MEASURES
  • Seminoma: Specifics are noted in the National Comprehensive Cancer Network guidelines (1):
    • Stages IA, IB: Options may include surveillance (preferred) (for low tumor load malignancy, i.e., pT1-pT3), single-agent carboplatin, or radiotherapy (2)[A].
    • Stage IS: Repeat elevated serum tumor marker and abdominal/pelvic CT scan (2)[A].
    • Stage IIA: radiotherapy to include para-aortic and ipsilateral iliac lymph nodes (preferred) or primary chemotherapy (2)[A]
    • Stage IIB: primary chemotherapy (preferred) or radiotherapy in select nonbulky cases to include para-aortic and ipsilateral iliac lymph nodes (2)[A]
    • Stages IIC, III
      • Good risk (any primary site and no nonpulmonary visceral metastases and normal AFP with any &bgr;-hCG or LDH): primary etoposide and cisplatin (EP) or bleomycin, etoposide, and cisplatin (BEP) chemotherapy (1)
      • Intermediate risk (any primary site and nonpulmonary visceral metastases and normal AFP with any &bgr;-hCG or LDH): primary BEP chemotherapy (1)
  • Nonseminoma: Tumors with both seminomatous and nonseminomatous histology are managed as nonseminomatous. See “National Comprehensive Cancer Network guidelines” (1):
    • Stage IA: nonseminomatous surveillance protocol (preferred) or nerve-sparing retroperitoneal lymph node dissection (RPLND) (2)[A]
    • Stage IB: nerve-sparing RPLND or primary BEP chemotherapy (2)[A]; for T2 only can enter nonseminomatous surveillance protocol (2)[B]
    • Stage IS: primary chemotherapy followed by response evaluation:
      • Complete response, negative tumor markers: nonseminomatous surveillance protocol (2)[A]
      • Partial response, negative tumor markers: surgical resection of all residual masses (2)[A]
      • Incomplete response: Consider second-line therapy (2)[A].
    • Stage IIA
      • Negative tumor markers: nerve-sparing RPLND (2)[A] or primary chemotherapy (2)[B]
      • Persistent marker elevation: primary chemotherapy followed by response evaluation
        • Complete response, negative tumor markers: nonseminomatous surveillance protocol (2)[A] or bilateral RPLND + / - nerve-sparing in select cases (2)[B]
        • Partial response, negative tumor markers: surgical resection of all residual masses (2)[A]
        • Incomplete response: Consider second-line therapy (2)[A].
    • Stage IIB
      • Negative tumor markers: primary chemotherapy or nerve-sparing RPLND in highly selected cases (2)[A]
      • P.1021

      • Persistent marker elevation: primary chemotherapy followed by response evaluation
        • Complete response, negative tumor markers: nonseminomatous surveillance protocol (2)[A] or bilateral RPLND + / - nerve-sparing in selected cases (2)[B]
        • Partial response, negative tumor markers: surgical resection of all residual masses (2)[A]
        • Incomplete response: Consider second-line therapy (2)[A].
    • Stage IIC: primary chemotherapy followed by response evaluation as per stages IIA and IIB (2)[A]
    • Stages IIIA, IIIB, and IIIC: primary chemotherapy depending on risk profile, which is based on tumor, metastases, and postorchiectomy serum tumor markers (2)[A]
  • Brain metastases: primary chemotherapy + / - radiotherapy, + / - surgery, as clinically indicated
MEDICATION
First Line
Primary chemotherapy regimens for GCTs:
  • EP: Etoposide 100 mg/m2/day IV on days 1 to 5, cisplatin 20 mg/m2/day IV on days 1 to 5; repeat every 21 days (1)[A].
  • BEP: Etoposide 100 mg/m2/day IV on days 1 to 5, cisplatin 20 mg/m2/day IV on days 1 to 5; bleomycin 30 U/dose IV weekly on days 1, 8, and 15 or days 2, 9, and 16; repeat every 21 days (1)[A].
  • VIP: Etoposide 75 mg/m2/day IV on days 1 to 5; mesna 120 mg/m2 slow IV push before ifosfamide on day 1, then mesna 1,200 mg/m2 IV continuous infusion on days 1 to 5; ifosfamide 1,200 mg/m2/day on days 1 to 5; cisplatin 20 mg/m2 /day IV on days 1 to 5, repeat every 21 days (1)[A].
Second Line
  • These agents are considered in patients who do not respond to first-line therapy or those who experience a recurrence: carboplatin, cisplatin, etoposide, ifosfamide, mesna, paclitaxel, and vinblastine (1)[A].
  • Gemcitabine, oxaliplatin, and paclitaxel are used in palliative chemotherapy regimens (1)[A].
ADDITIONAL THERAPIES
Consider sperm banking before treatment that may compromise fertility; rarely covered by insurance.
SURGERY/OTHER PROCEDURES
  • Radical inguinal orchiectomy: primary treatment for testicular cancer for all patients; prosthesis can be inserted at this time.
  • RPLND identifies nodal metastases and provides accurate pathologic staging of the retroperitoneum.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Pure seminoma: Specifics are noted in the National Comprehensive Cancer Network guidelines (1),(2)[A]:
    • Stages IA, IB: in general, H&P, optional tumor markers, every 3 to 6 months for 1 years, every 6 to 12 months for years 2 to 33, then annually for years 4 to 5; abdominal/pelvic CT at 3, 6 and 12 months then every 6 to 12 months for years 2 to 3, every 12 to 24 months for years 4 to 5; CXR, as clinically indicated; less frequent if adjuvant therapy is given
    • Stage IS: repeat elevated serum tumor marker and assess with abdominal/pelvic CT scan for evaluable disease
    • Stages IIA, IIB (select): in general, H&P, optional tumor markers every 3 months for year 1, every 6 months for years 2 to 5; abdominal/pelvic CT at 3 and 6 to 12 months, then annually for years 2 to 3, then as clinically indicated; CXR every 6 months for years 1 to 2
    • Stages IIB (select), IIC, and III: Check all serum tumor markers along with chest, abdominal, and pelvic CT:
      • Residual mass 0 to 3 cm and normal serum tumor markers: H&P, AFP, &bgr;-hCG, LDH, CXR every 2 months for year 1, every 3 months for year 2, every 6 months for years 3 to 4, then annually; abdominal/pelvic CT scan at 3 to 6 months then as clinically indicated, PET scans as clinically indicated
      • Residual mass >3 cm and normal serum tumor markers: PET scan 6 weeks after chemotherapy:
        • Negative PET scan: abdominal/pelvic CT scans every 6 months for year 1, then annually for 5 years
        • Positive PET scan: Consider RPLND or second-line chemotherapy or radiotherapy
    • Any recurrence: Treat according to extent of disease at relapse.
  • Nonseminoma: Specifics are noted in the National Comprehensive Cancer Network guidelines (1):
    • Stages IA and IB on surveillance only: H&P, AFP, &bgr;-hCG, LDH, every 2 months for year 1, every 3 months for year 2, every 4 to 6 months for year 3, every 6 months for year 4, annually thereafter; CXR and abdominal/pelvic CT depending on IA or IB
    • Follow-up after complete response to chemotherapy and RPLND in general: H&P, AFP, &bgr;-hCG, LDH every 2 to 3 months for years 1 to 2, every 6 months for years 3 to 5, annually thereafter; abdominal/pelvic CT every 6 months for year 1, annually for year 2, as clinically indicated thereafter
    • Follow-up after RPLND only: H&P, AFP, &bgr;-hCG, LDH, CXR every 2 months for year 1, every 3 months for year 2, every 4 months for year 3, every 6 months for year 4, annually thereafter; abdominal/pelvic CT at 3 to 4 months and, as clinically indicated, thereafter; CXR every 2 to 4 months year 1, 3 to 6 months year 2, annually thereafter
PROGNOSIS
>90% of patients diagnosed are cured, including 70-80% with advanced tumors (1).
REFERENCES
1. Motzer RJ, Jonasch E, Agarwal N, et al. Testicular cancer, Version 2.2015. J Natl Compr Canc Netw. 2015;13(6):772-799.
2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2012/. Accessed 2015.
3. Lip SZ, Murchison LE, Cullis PS, et al. A metaanalysis of the risk of boys with isolated cryptorchidism developing testicular cancer in later life. Arch Dis Child. 2013;98(1):20-26.
4. Ilic D, Misso ML. Screening for testicular cancer. Cochrane Database Syst Rev. 2011;(2):CD007853.
5. Testis. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:469-478.
6. Efstathiou E, Logothetis CJ. Review of late complications of treatment and late relapse in testicular cancer. J Natl Compr Canc Netw. 2006;4(10): 1059-1070.
Additional Reading
&NA;
  • Hanna NH, Einhorn LH. Testicular cancer— discoveries and updates. N Engl J Med. 2014;371(21):2005-2016.
  • Marcell AV, Bell DL, Joffe A, et al. The male genital examination: a position paper of the Society for Adolescent Health and Medicine. J Adolesc Health. 2012;50(4):424-425.
  • U.S. Preventive Services Task Force. Screening for testicular cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2011;154(7):483-486.
  • Wood HM, Elder JS. Cryptorchidism and testicular cancer: separating fact from fiction. J Urol. 2009;181(2):452-461.
Codes
&NA;
ICD10
  • C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
  • C62.00 Malignant neoplasm of unspecified undescended testis
  • C62.10 Malignant neoplasm of unspecified descended testis
Clinical Pearls
&NA;
  • Testicular cancer is the most common solid organ tumor in men aged 15 to 34 years.
  • Testicular US is initial imaging of choice for testicular pathology.
  • Radical inguinal orchiectomy is used for both diagnosis and treatment, with possible radiotherapy or chemotherapy as adjuvant treatment.
  • 96% overall survival at 10 years after diagnosis and treatment