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Testicular Malignancies

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).

DIAGNOSIS

HISTORY

  • A painless solid testicular mass is pathognomonic for testicular cancer.
  • Clinical symptoms of epididymitis or orchitis that do not respond to treatment warrant further evaluation.
  • Gynecomastia can be a rare systemic endocrine manifestation of testicular neoplasm.

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)

  • α-Fetoprotein (AFP), ²-human chorionic gonadotropin ( ²-hCG), lactate dehydrogenase (LDH), creatinine, chemistry profile, complete blood count, liver enzymes, chest x-ray (CXR), and testicular ultrasound (US)
  • Tumor markers AFP, ²-hCG, and LDH are used to assist with diagnosis, prognosis, assessing treatment outcome, and monitoring for relapse:AFPProduced by nonseminomatous testicular cancer and is therefore associated with this histologic typeThose with a histologically "pure " testicular seminoma and an elevated AFP are assumed to possess an undetected focus of nonseminoma tumor. ²-hCGMay be associated with both seminomatous or nonseminomatous tumorsHypogonadism and marijuana use may cause benign elevations of ²-hCG.
  • LDH is less specific than AFP.
  • Testicular US is the initial study.
  • If an intratesticular mass is identified, measure serum AFP, LDH, and ²-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

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, IIIGood risk (any primary site and no nonpulmonary visceral metastases and normal AFP with any ²-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 ²-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 IIANegative tumor markers: nerve-sparing RPLND (2)[A] or primary chemotherapy (2)[B]Persistent marker elevation: primary chemotherapy followed by response evaluationComplete 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 IIBNegative tumor markers: primary chemotherapy or nerve-sparing RPLND in highly selected cases (2)[A]Persistent marker elevation: primary chemotherapy followed by response evaluationComplete 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.

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 givenStage IS: repeat elevated serum tumor marker and assess with abdominal/pelvic CT scan for evaluable diseaseStages 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 2Stages 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, ²-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 indicatedResidual 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 yearsPositive PET scan: Consider RPLND or second-line chemotherapy or radiotherapyAny 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, ²-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 IBFollow-up after complete response to chemotherapy and RPLND in general: H&P, AFP, ²-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 thereafterFollow-up after RPLND only: H&P, AFP, ²-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).

COMPLICATIONS

  • Surgical: hematoma, hemorrhage, infection, and infertility
  • Radiotherapy: radiation enteritis and infertility
  • Late complications (6):Cardiovascular toxicity and second malignancies each have a 25-year risk of about 16% in those treated with chemotherapy and/or radiotherapy.Risk for secondary malignancies remains increased for at least 35 years after treatment.Increased incidence of metabolic syndrome occurs and is likely associated with lower testosterone levels.Other late complications associated with chemotherapy, depending on the regimen, include chronic neurotoxicity, ototoxicity, renal function impairment, and pulmonary fibrosis.
  • The incidence of late relapse in treated testicular cancer is now estimated to be 2 " 6%; the time to late relapse ranges from 2 to 32 years, with a median of 6 years (6).

REFERENCES

11 Motzer RJ, Jonasch E, Agarwal N, et al. Testicular cancer, Version 2.2015. J Natl Compr Canc Netw. 2015;13(6):772 " 799.22 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 2015.33 Lip SZ, Murchison LE, Cullis PS, et al. A meta-analysis of the risk of boys with isolated cryptorchidism developing testicular cancer in later life. Arch Dis Child. 2013;98(1):20 " 26.44 Ilic D, Misso ML. Screening for testicular cancer. Cochrane Database Syst Rev. 2011;(2):CD007853.55 Testis. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:469 " 478.66 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

  • 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

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
  • C62.91 Malig neoplm of right testis, unsp descended or undescended
  • C62.02 Malignant neoplasm of undescended left testis
  • C62.01 Malignant neoplasm of undescended right testis
  • C62.12 Malignant neoplasm of descended left testis
  • C62.11 Malignant neoplasm of descended right testis
  • C62.92 Malig neoplasm of left testis, unsp descended or undescended

ICD9

  • 186.9 Malignant neoplasm of other and unspecified testis
  • 186.0 Malignant neoplasm of undescended testis

SNOMED

  • 363449006 Malignant tumor of testis (disorder)
  • 188219004 malignant tumor of undescended testis (disorder)
  • 94087009 Primary malignant neoplasm of testis (disorder)
  • 255107005 Seminoma of testis (disorder)
  • 188235006 Malignant tumor of tunica vaginalis (disorder)
  • 313428008 Seminoma of undescended testis
  • 313429000 Seminoma of descended testis
  • 416769008 Malignant teratoma of testis (disorder)
  • 278491007 Mixed seminoma teratoma of testis

CLINICAL PEARLS

  • 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