Testicular Cancer

Dx
Screen
Monitor
Background
Lab Tests

Diagnosis

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, choriocarcinoma^l4, 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 – >10 times the upper reference limit
  - LD 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

Screening

U.S. Preventive Services Task Force recommends against screening

Monitoring

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
Stage and Treatment Type	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

Clinical Background

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

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations
Alpha Fetoprotein, Serum (Tumor Marker) 0080428 Method: Quantitative Chemiluminescent Immunoassay	Aid in evaluation of germ-cell tumors	Cannot be interpreted as absolute evidence of the presence or absence of malignant disease Result is not interpretable in pregnant females
Beta-hCG, Quantitative (Tumor Marker) 0070029 Method: Quantitative Electrochemiluminescent Immunoassay	Aid in evaluation of germ-cell tumors	Cannot be interpreted as absolute evidence of the presence or absence of malignant disease Result is not interpretable as a tumor marker in pregnant females
Lactate Dehydrogenase, Serum or Plasma 0020006 Method: Quantitative Enzymatic	Aid in evaluation of germ-cell tumors
KIT (D816V) Mutation by PCR 0040137 Method: Polymerase Chain Reaction	Aid in evaluation of germ-cell tumors May help in detecting germline mutation	Results must always be interpreted in context of morphologic and other relevant data; should not be used alone for diagnosis of malignancy
Octamer Transcription Factor-3 and -4 (Oct 3/4) by Immunohistochemistry 2004058 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
CD117 (c-Kit) by Immunohistochemistry 2003806 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
Pan Cytokeratin (AE1,3) by Immunohistochemistry 2003433 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry 2003493 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
CD30 (Ki-1) by Immunohistochemistry 2003547 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
Alpha-1-Fetoprotein (AFP) by Immunohistochemistry 2003436 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
Human Chorionic Gonadotropin (Beta-hCG) by Immunohistochemistry 2003920 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
Placental Alkaline Phosphatase (PLAP) by Immunohistochemistry 2004097 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed
Sal-like 4 (SALL4) by Immunohistochemistry 2005432 Method: Immunohistochemistry	Aid in histologic diagnosis of testicular cancer Stained and returned to client pathologist for interpretation; consultation available if needed

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Beta-hCG, Quantitative (Tumor Marker), CSF 0020730 Method: Quantitative Electrochemiluminescent Immunoassay	Useful in suspected CNS metastatic disease
Alpha Fetoprotein, CSF (Tumor Marker) 0020729 Method: Quantitative Chemiluminescent Immunoassay	Useful in suspected CNS metastatic disease
Lactate Dehydrogenase Total, Body Fluid 0020505 Method: Quantitative Enzymatic