Testicular Cancer

1. Epidemiology
   1. Accounts for 1% of all cancers in males
   2. Age of onset
      1. Peak age: 30-34 years old (ranges 12 to 35)
      2. Most common cancers in males ages 15 to 34 years
      3. Rare in early childhood
   3. Incidence: Has doubled since 1960s
      1. New cases in U.S. (2017): 8560 (410 deaths)
      2. Cases per 100,000: 5.6 (14.6 at age 30-34 years old)
      3. Geographic variation
         1. Highest rates: Scandanavia and Germany, hispanic, native alaskan and native american
         2. Lowest rates: Asia and Africa
2. Risk Factors
   1. Cryptorchidism (Undescended Testicle)
      1. Accounts for 10% of cases
      2. Confers 2.9 to 6.3 fold increased risk
      3. Risk increases
         1. Intraabdominal Testicle (contrast with inguinal)
         2. Bilateral crytorchidism
         3. Repair after age 12 years old (5 fold increased risk)
         4. Even with early orchiopexy, Testicular Cancer Relative Risk is still 2.2
   2. Caucasian (4-5 fold increased risk)
   3. Testicular Cancer in the contralateral Testicle (Relative Risk 12)
   4. Family History of Testicular Cancer
      1. Father with Testicular Cancer increases Relative Risk 3.8 fold
      2. Brother with Testicular Cancer increases risk 6-10 fold
   5. Testicular Germ Cell Tumor 1 (Chromosome Xq27)
   6. Tobacco abuse
      1. Ongoing Tobacco use with a >12 pack year history confers 2 fold risk
   7. Infertility (Relative Risk 1.6 to 2.8)
   8. Testicular atrophy
   9. Testicular dysgnesis
3. Pathophysiology
   1. Germinal or Germ Cell Tumors (95-97%)
      1. Seminoma (most common, 50% of germ cell tumors)
      2. Non-Seminoma Germ Cell tumors (NSGCT)
         1. Embryonal cell carcinoma
         2. Yolk Sac tumor (postpubertal)
         3. Teratoma (postpubertal)
         4. Trophoblastic Tumor (e.g. Choriocarcinoma)
   2. Nongerminal tumors (sex cord-stromal tumors)
      1. Leydig cell tumor
      2. Sertoli cell tumor
      3. Granulosa Cell Tumor
   3. Mixed germ cell and stromal tumors
      1. Gonadoblastoma
   4. Miscellaneous tumors
      1. Hemangioma
      2. Hematolymphoid tumors
      3. Adenocarcinoma of the collecting duct or rete Testis
4. Symptoms
   1. Painless testicular mass found incidentally
   2. Dull ache in Scrotum
   3. Scrotal heaviness
   4. Vague Abdominal Pain
5. Symptoms: Red Flag Presentations
   1. Minor scrotal Trauma causes significant injury (Scrotal hematoma, Hydrocele)
   2. Epididymitis with swelling or tenderness that fails to improve with antibiotic therapy
6. Signs
   1. Painless asymmetric, hard, firm testicular mass
   2. Transilluminate for reactive Hydrocele
   3. Evaluate for Inguinal Lymphadenopathy (as well as Supraclavicular Lymphadenopathy)
   4. Evaluate for Gynecomastia
      1. Overall 10% of patients (30% of Leydig cell tumors) produce bHCG
   5. Evaluate for systemic disease (metastases present in 5% of patients)
      1. Hemoptysis, cough or Dyspnea from pulmonary metastases
      2. Supraclavicular mass from lymph node metastases
      3. Abdominal mass from retroperitoneal spread
      4. Lumbar back pain from Vertebral metastases
7. Staging
   1. Based on TNMS classification
      1. T: Tis (carcinoma in situ) to T4 (tumor invades Scrotum)
         1. T1: Tumor limited to Testis (T1a < 3cm in size)
         2. T2: Lymphovascular invasion or other spread short of spermatic cord
         3. T3: Spermatic cord involvement
         4. T4: Scrotal involvement
      2. N: N0 (no lymph nodes involved) to N3 (one lymph node and 5 cm mass)
         1. N1: One or more lymph node masses <2 cm
         2. N2: One or more lymph node masses 2-5 cm
         3. N3: Lymph node masses >5 cm
      3. M: M0 (no distant metastases) to M1 (distant metastases present)
         1. M1a: Nonretroperitoneal nodal or pulmonary metastases
         2. M1b: Nonpulmonary visceral metastases
      4. S: S0 (normal Tumor Markers) to S3 (Tumor Markers significantly increased)
   2. Staging Summary (* denotes ANY)
      1. Note: Each stage is subdivided (Ia-b, IIa-c, IIIa-c )
      2. Stage I: Testicular Cancer involving Testicle only (T* N0 M0 S0)
         1. LDH <1.5x normal, bHCG <5k mIU/ml, AFP <1k ng/ml
      3. Stage II: Metastases to retroperitoneal nodes (T* N* M0 S0-1)
         1. LDH 1.5-10x normal, bHCG 5-50k mIU/ml, AFP <1-10k ng/ml
      4. Stage III: Metastases above diaphragm or to viscera (T* N* M1 S*)
         1. LDH >10x normal, bHCG >50k mIU/ml, AFP >10k ng/ml
8. Imaging
   1. Scrotal and Testicular Ultrasound
      1. Differentiate intratesticular mass (presumed cancer) from extratesticular mass
      2. Efficacy in Testicular Cancer
         1. Test Sensitivity: 92-98%
         2. Test Specificity: 95-99.8%
   2. Additional studies for cancer staging and evaluation for metastases
      1. CT Abdomen and Pelvis
      2. Chest XRay or CT Chest
9. Labs: Tumor Markers
   1. Alpha fetoprotein (aFP)
      1. Secreted by non-seminoma GCT or mixed tumors
      2. Not secreted by a pure seminoma or Choriocarcinoma
      3. Falls to <25 ng/ml by 25-35 days after orchiectomy
   2. Human Chorionic Gonadotropin (bHCG)
      1. Secreted by 50% non-seminoma GCT or mixed tumors
      2. Secreted by 10% of seminomas
      3. Undetectable by 5 to 8 days after orchiectomy
   3. Lactate Dehydrogenase (LDH, especially LDH-1)
      1. Elevated in 60% of patients with non-seminoma GCT
      2. Increases with tumor burden (esp. widespread and metastatic cancer)
   4. Other lab testing
      1. Comprehensive metabolic panel
10. Management: Treatments
    1. Surgery: Radical orchiectomy by inguinal approach
       1. High ligation spermatic cord (to Internal Inguinal Ring)
       2. Further therapy directed by histology
    2. Chemotherapy
       1. Agents (typically Cisplatin combined with one or both of the other agents)
          1. Carboplatin
          2. Cisplatin (Platinol)
          3. Etoposide (Vepesid)
          4. Bleomycin (Blenoxane)
       2. Indications
          1. Advanced spread of disease
          2. Advanced stage seminoma and non-seminomas
    3. Radiotherapy
       1. Indicated for early-stage seminomas
11. Management: Seminoma
    1. Radical orchiectomy is performed for all stages
    2. Stage I (T1-T3 tumors)
       1. Active surveillance (preferred) OR
       2. Single-agent carboplatin or Radiotherapy
    3. Stage II
       1. Stage IIA
          1. Radiotherapy (preferred) OR
          2. Etoposide-Cisplatin for 4 cycles OR
          3. Bleomycin-Etoposide-Cisplatin for 3 cycles
       2. Stage IIB
          1. Etoposide-Cisplatin for 4 cycles (preferred) OR
          2. Bleomycin-Etoposide-Cisplatin for 3 cycles (preferred) OR
          3. Radiotherapy of regional lymph nodes
       3. Stage IIC
          1. Etoposide-Cisplatin for 4 cycles OR
          2. Bleomycin-Etoposide-Cisplatin for 3 cycles
    4. Stage III
       1. Etoposide-Cisplatin for 4 cycles OR
       2. Bleomycin-Etoposide-Cisplatin for 3 cycles
12. Management: Nonseminoma
    1. Radical orchiectomy is performed for all stages
    2. Stage I (IA and IB)
       1. Active surveillance (preferred for IA) OR
       2. Retroperitoneal lymph node dissection (RPLND) OR
       3. Bleomycin-Etoposide-Cisplatin for 1-2 cycles (if Stage IB)
    3. Stage II (IIA to IIC)
       1. Etoposide-Cisplatin for 4 cycles OR
       2. Bleomycin-Etoposide-Cisplatin for 3 cycles OR
       3. Radiotherapy (for Stage IIA and select Stage IIB cases)
    4. Stage III
       1. Stage IIIA
          1. Etoposide-Cisplatin for 4 cycles OR
          2. Bleomycin-Etoposide-Cisplatin for 3 cycles OR
       2. Stage IIIB
          1. Bleomycin-Etoposide-Cisplatin for 4 cycles
       3. Stage IIIC
          1. Bleomycin-Etoposide-Cisplatin for 4 cycles OR
          2. Etoposide-Ifosfamide-Cisplatin for 4 cycles (in select cases)
13. Monitoring: Five year
    1. Surveillance after initial management is typically for 5 years
       1. Exact monitoring protocols vary by tumor type and stage
       2. This section summarizes more specific guidelines
    2. History and physical
       1. Initially every 2-3 months, then every 3-6 months and then annually
    3. Abdominal and Pelvic CT
       1. Initially every 3-6 months, then every 6-12 months
       2. PET/CT surveillance may be obtained in higher stage cancers
    4. Chest XRay
       1. As indicated in Stage I Seminoma, and in other tumors every 2-6 months initially, then every 6-12 months
       2. CT Chest may be indicated in symptomatic patients
    5. Tumor Markers (Serum bHCG, AFP levels, Lactate Dehydrogenase)
       1. Obtained at each history and physical
       2. Optional in Stage I and IIA Seminoma
       3. False negatives in up to 35% of non-seminoma recurrence
14. Prevention
    1. Testicular Cancer screening is not recommended in asymptomatic men (USPTF, NCI, AAFP)
    2. Testicular Self-Exam
15. Prognosis
    1. Overall 5 year survival > 95% (Previously 63% in 1963)
       1. Stage I Five year survival: 98%
       2. Stage II Five year survival: 97%
       3. Stage III Five year survival: 72%
    2. Cure rate is 99% for early Testicular Cancer without metastases
    3. When relapse occurs, it is typically within 18 months of Chemotherapy
    4. Risk of cancer in opposite Testicle: 2 to 5%
16. Complications
    1. Testicular Cancer related
       1. Infertility
    2. Radiation-related
       1. Cardiac toxicity
       2. Leukemia or other secondary malignancy
    3. Chemotherapy-related
       1. General: Azoospermia, Leukemia or other secondary malignancy
          1. Cardiovascular mortality increases 5-fold in the first year after Chemotherapy
             1. Fung (2015) J Clin Oncol 33(28): 3105-15 [PubMed]
       2. Bleomycin: Lung toxicity
       3. Etoposide: Neurotoxicity with secondary Peripheral Neuropathy
       4. Cisplatin: Nephrotoxicity, Ototoxicity
17. Resources
    1. NCCN Clinical Practice Guidelines: Testicular Cancer
       1. https://www.nccn.org/professionals/physician_gls/default.aspx
18. References
    1. Walsh (1998) Campbell's Urology, Saunders, p. 2411-45
    2. Baird (2018) Am Fam Physician 97(4):261-8 [PubMed]
    3. Horwich (2006) Lancet 367: 754-65 [PubMed]
    4. Kinkade (1999) Am Fam Physician 59(9):2539-44 [PubMed]
    5. Shaw (2008) Am Fam Physician 77: 469-76 [PubMed]