Indications for Testing

• Testicular mass, testicular pain, initially diagnosed epididymitis that is unresolved

Laboratory Testing

• In suspected testicular cancer, determining concentrations of serum AFP, β-hCG and LD prior to treatment is mandatory
• Genetic testing – KIT (D816V) mutation in tissue by PCR may be helpful

Histology

• Immunohistochemistry
• Comparison of different biochemical markers for testicular cancer

  Comparison of Different Biochemical Markers for Testicular Cancer
  Immunostain Class	PP1	OCT42	CD1173	AE1/AE34	CAM 5.25	CD306	AFP7	β-hCG8	PLAP9	HLA-G10	Glypican 311
  ITGCN12 Classical seminoma	+	+	+	-	-	-	-	+STC16	+	-	-
  Spermatocytic seminoma	-	-	-/+	-	-	-	0	-	-	?	-
  YST13	-	-	-	+	+	-/+	+	-	-/+	-	+
  CC14	-	-	-	+	+	-	-	+STC16	+	+	+
  ED15	-	+	-	+	+	+	-/+	-	+	-	-
  Podoplanin1, POU-family transcription factor2, cytokeratin stain3, cytokeratin stain4, cytokeratin stain5, cell membrane antigen6, alpha fetoprotein7, beta human chorionic gonadotropin8, placental-like alkaline phosphatase9, human antibody stain10, glycoprotein stain11, intratubular germ cell neoplasia12, yolk sac tumor13, choriocarcinomal4, embryonal carcinoma15, syncytiotrophoblastic cells16

• Testicular removal provides tissue for diagnosis
• Do not perform fine-needle aspiration (FNA) or trans-scrotal biopsy due to risk of tumor seeding along needle track

Imaging Studies

• Trans-scrotal ultrasonography – provides imaging of mass
• Chest x-ray
• CT of abdomen and pelvis – for staging purposes; performed after tissue diagnosis
• Brain MRI and/or bone scan if indicated by symptoms and clinical findings

Prognosis

• For risk stratification, levels of AFP, β-hCG and LD must be measured in serum
• High serum concentrations in nonseminoma associated with poor prognosis (seminoma not associated with poor prognosis)
  • AFP – >10,000 ng/mL
  • β-hCG – >50,000 IU/L
  • LD-1 – >10 times the upper reference limit
    • LD-1 isoenzyme activity is the best indicator of prognosis
• Fertility usually affected by surgery and therapy; consider discussions of sperm banking

Differential Diagnosis

• Painful testicle
  • Epididymitis
  • Testicular torsion
• Painless testicle
  • Hydrocele
  • Varicocele
  • Epididymal cyst
  • Spermatocele

• U.S. Preventive Services Task Force recommends against screening

• If serum markers are elevated prior to therapy, monitor weekly until normalized then follow the appropriate schedule below (see tables)
• Post-orchiectomy elevation in markers suggestive of metastatic disease
• Testicular cancer monitoring – nonseminomatous and seminomatous
• Testicular cancer – nonseminomatous

  Testicular Cancer – Nonseminomatous
  Surveillance for Stages 1A and 1B
  Year	Months between serum markers and chest x-ray	Months between abdominal/pelvic CT
  1	1-2	2-3
  2	2	3-4
  3	3	4
  4	4	6
  5	6	12
  6+	12	12
  Surveillance After Complete Response to Chemotherapy and/or Retroperitoneal Lymph Node Dissection
  Year	Months between visits, markers, chest x-ray	Months between abdominal/pelvic CT*
  1	2-3	6
  2	2-3	6-12
  3	4	12
  4	4	12
  5	6	12
  6+	12	If indicated
  *CT scans recommended for patients treated with chemotherapy alone. Baseline CT scan recommended for post-RPLND patients with additional scans as clinically indicated

  Testicular cancer – seminomatous

  Testicular Cancer – Seminomatous
  Monitoring After Primary Treatment
  Stage and Treatment Type	Stages 1S and 1A-1B	Stage 1A-1B	Stage 2A-2B	Stage 2C to Stage 3
  	Radiation only	Surveillance only or radiation or single-agent carboplatin	Radiation or primary chemotherapy	Chemotherapy
  Serum Markers (AFP, β-hCG, LD)	3-4/yr during yr 1 2/yr during yr 2 Annually thereafter	3-4/yr during yrs 1-3 2/yr during yrs 4-7 Annually thereafter	3-4/yr during yrs 1-3 2/yr during yr 4 Annually thereafter	6/yr during yr 1 4/yr during yr 2 3/yr during yr 3 2/yr during yr 4 Annually thereafter
  Chest x-ray	Each visit	Alternate visits (up to 10/yr)	Each visit
  Abdominal/pelvic CT	1S – annual pelvic CT during yrs 1-3 1A-1B – each visit	Each visit	Abdominal CT 4 months post treatment	4 months post surgery then as indicated PET scan as indicated

Testicular cancer is the most common cancer in young adult men and is highly curable with prompt treatment.

Epidemiology

• Incidence – 5-6/100,000
• Age – peak onset is 15-35 years
• Sex – exclusively male
• Ethnicity – rare in African Americans

Risk Factors

• Personal history of testicular cancer
• Cryptorchidism – three- to fourfold increased risk
• Infertility/subfertility
• Klinefelter syndrome
• Family history of testicular cancer
  • Father with cancer history – fourfold increased risk
  • Brother with cancer history – eight- to tenfold increased risk

Pathophysiology

• Cell types
  • Germ-cell tumors represent >95% of testicular cancers and occasionally appear in extragonadal sites
    • Seminomatous
    • Non-seminomatous germ-cell tumors (NSGCT) – more clinically aggressive
      • Embryonal carcinomas
      • Choriocarcinoma
      • Yolk sac tumors
      • Teratoma – mature or immature
  • Lymphomas – uncommon
  • Leydig and Sertoli cell tumors – rare
• Tumors may produce hormones used as markers – beta human chorionic gonadotrophin (β-hCG) and alpha fetoprotein (AFP)
• Markers of testicular cancer
  • AFP
    • Synthesized in fetal yolk sac, liver, intestine
    • Produced by nonseminomatous cells but may be found in both seminomatous and nonseminomatous tumors
    • Low levels may be present in normal males with benign disease
    • Elevated levels also occur in hepatocellular and gastrointestinal tumors and nephritis
  • β-hCG
    • Synthesized in placental trophoblastic cells
    • Found in germ cell tumors (seminomatous, choriocarcinoma)
    • Increased serum hCG concentrations also observed in melanoma, carcinomas of the breast, gastrointestinal tract and lung, and in benign conditions, including cirrhosis, duodenal ulcer, and inflammatory bowel disease
  • Lactate dehydrogenase (LD)
    • Most useful in seminomatous testicular tumors
    • Direct relationship between serum LD activity and tumor burden
    • LD-1 isoenzyme is elevated in testicular cancer
  • Placental-like alkaline phosphatase (PLAP) 
    • Expressed in many testicular tumors
    • Most useful in identifying seminomatous testicular tumors by immunohistochemistry

Clinical Presentation

• Testicular mass/nodule
  • Painless or painful
  • May be mistaken as epididymitis; however, does not respond to antibiotic therapy
• Metastatic disease
  • Systemic – anorexia, malaise, weight loss
  • Gynecomastia
  • Thromboembolic events
  • Adenopathy – lymphatic
  • Cough – pulmonary

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Albers P, Albrecht W, Algaba F, Bokemeyer C, Cohn-Cedermark G, Fizazi K, Horwich A, Laguna MP. EAU guidelines on testicular cancer: 2011 update. Eur Urol. 2011; 60 (2) :304-319.PubMed
• American Society of Clinical Oncology clinical practice guideline on uses of serum tumor markers in adult males with germ cell tumor. American Society of Clinical Oncology - Medical Specialty Society. 2010 March. NGC:007880
• College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Malignant Germ Cell and Sex Cord-Stromal Tumors of the Testis. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: October 2009. [Accessed: 29 Jun 2010] 
• Lin K, Sharangpani R. Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010; 153 (6) :396-399.PubMed
• NACB Committee members. Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers. American Association for Clinical Chemistry. Washington, DC [Accessed: 23 Oct 2009] 
• NCCN Clinical Practice Guidelines in Oncology, Testicular Cancer. National Comprehensive Cancer Network. Fort Washington: Pennsylvania [Accessed: 24 Jan 2011] 

General

• Bahrami A, Ro JY, Ayala AG. An overview of testicular germ cell tumors. Arch Pathol Lab Med. 2007; 131 (8) :1267-1280.PubMed
• Barlow LJ, Badalato GM, McKiernan JM. Serum tumor markers in the evaluation of male germ cell tumors. Nat Rev Urol. 2010; 7 (11) :610-617.PubMed
• Emerson RE, Ulbright TM. The use of immunohistochemistry in the differential diagnosis of tumors of the testis and paratestis. Semin Diagn Pathol. 2005; 22 (1) :33-50.PubMed
• Favilla V, Cimino S, Madonia M, Morgia G. New advances in clinical biomarkers in testis cancer. Front Biosci (Elite Ed). 2010; 2 :456-477.PubMed
• Ilic D, Misso ML. Screening for testicular cancer. Cochrane Database Syst Rev. 2011; (2) :CD007853.PubMed
• Khan O, Protheroe A. Testis cancer. Postgrad Med J. 2007; 83 (984) :624-632.PubMed
• Mannuel HD, Hussain A. Update on testicular germ cell tumors. Curr Opin Oncol. 2010; 22 (3) :236-241.PubMed
• Salem M, Gilligan T. Serum tumor markers and their utilization in the management of germ-cell tumors in adult males. Expert Rev Anticancer Ther. 2011; 11 (1) :1-4.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Willmore-Payne C, Holden JA, Chadwick BE, Layfield LJ. Detection of c-kit exons 11- and 17-activating mutations in testicular seminomas by high-resolution melting amplicon analysis. Mod Pathol. 2006; 19 (9) :1164-1169.PubMed

Infertility
Paraneoplastic Neurological Syndromes
Tumor Markers