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A. Characteristics

  1. Often called Testicular Germ Cell Tumors
  2. Most common cancer in men age 15-35 (1:10,000 white males)
  3. Rate 4 per 100,000 per year, 6900 new cases per year in USA
  4. Peak in childhood and age 20-30
  5. Risk Factors
    1. Cryptorchism (undescended testes)
    2. Mumps Orchitis
    3. Family history of cryptorchism
    4. Epididymitis which does not resolve within 10 days
  6. Cryptorchism
    1. Overall malignancy in <10% if treated
    2. Age at surgery (orchiopexy) for treatment affects risk of malignancy [6]:
    3. For orchiopexy age <13 years, relative risk only 2.23X general population
    4. For orchiopexy age >13 years, relative risk 5.40X general population
  7. Primary testicular tumors are malignant in 96% of cases
  8. Believed to be derived from germ cell lineage cells blocked in maturation
    1. All progress through non-invasive carcinoma in situ stage
    2. These progress to seminomas or non-seminomas around or after puberty
    3. Tumors are invariably aneuploid
  9. Most patients are cured of disease and long term followup is important [1]

B. Types

  1. Seminoma (~45%) - usually older patients [3]
  2. Non-Seminomatous Germ Cell Tumors (50%) [4]
    1. Pure (15%) versus mixed (~35%) non-seminomatous germ cell tumors
    2. Embryonal Carcinoma (10%) - very aggressive; usually AFP+ and 10% HCG+
    3. Teratoma (~4%) - two or more germ cell layers
    4. Choriocarcinoma (<1%) - most malignant, HCG+
    5. Yolk-sac tumor (<1%)
  3. Chromosomal Abnormalities in Non-Seminomatous Germ Cell Tumors
    1. About 80% of these tumors have isochromosome 12p (3 copies of chr 12p)
    2. Other germ cell tumors of the ovary and mediastinum have iso(12p)
    3. Likely that these germ cell tumors arise through seminomatous intermediate
  4. Metastatic Lymphoma (5%) [8]
    1. Most common testicular mass in >40yr old patients
    2. Primary testicular lymphoma is uncommon
    3. Most are diffuse large B-cell non-Hodgkin lymphomas
    4. Pre-lymphoblastic B cell lymphoma is extremely unusual
  5. Mediastinal Germ Cell Tumors - ~20% are germinomas [5]

C. Clinical Presentation

  1. Painless mass (swelling) in testes
  2. Gynecomastia / Increased Feminization
    1. Increased HCG or prolactin levels
    2. Estrogen from Leydig Cell and Sertoli Cell tumors
    3. Feminizing germ cell tumors (HCG)
  3. Need to do frequent physical exams
  4. Distinguish between seminomatous and non-seminomatous
  5. Unresolving epididymitis - pain but not swelling decreases [4]
  6. Mediastinal Germ Cell Tumors [5]
    1. Vertebral mass ± fracture (may present with pain)
    2. Lymphadenopathy
    3. Mediastinal symptoms related to bulky disease
  7. Paraneoplastic limbic encephalopathy (uncommon) [10]

D. Differential Diagnosis of Testicular Mass

  1. Neoplasm [8]
    1. Germ cell tumors: seminoma, teratoma, choriocarcinoma, yolk-sac tumor, embryonal
    2. Leydig or Serterli Cell Tumor
    3. Rare: mesothelioma, sarcoma, adenocarcinoma of collecting system
    4. Primary Testicular lymphoma: rare
    5. Metastases to testes are rare
  2. Epididymitis - usually accompanied by fever, pain, leukocytosis, pyuria
  3. Orchitis - pain, usually associated with mumps infection
  4. Inguinal Hernia
  5. Hydrocele, Spermatocele: painless, transilluminates
  6. Testicular Torsion - very painful

E. Evaluation

  1. Urology consultation
  2. Transcrotal Ultrasonography
  3. Inguinal orchiectomy pathologic examination
  4. AFP and hCG levels - most useful for relapse
  5. Lactate Dehydrogenase - non-specific marker, useful to follow therapy
  6. Germinomas typically positive for placenta-like alkaline phosphatase
  7. Chest CT scan on all patients to rule out lung metastases
  8. CT Scan to evaluate lymph nodes (LN), mainly size, pattern of involvement
  9. Abnormal (iso-) chromosome 12p present in ~80% of germinomas

F. North American Staging System

  1. Stage I (A) - confined to testes, epididymis or spermatic cord
  2. Stage II (B) - metastases to retroperitoneal LN
    1. Stage IIa - LN <2cm in diameter
    2. Stage IIb - LN 2-5cm in diameter
    3. Stage IIc - LN >5cm in diameter
  3. Stage III (C) - visceral involvement, or metastases above the diaphragm
  4. Note that the TNM staging system also includes tumor markers AFP and hCG

G. Prognosis [1,4]

  1. Good Prognosis (~90% 5-year survival)
    1. Non-seminoma: testis/retroperitoneal primary, no non-nonpulmonary visceral metastases, AFP <1000 IU/L, HCG <5000 IU/L, LDH<1.5X normal
    2. Seminoma: any primary, no non-pulmonary visceral metastases, any marker level, normal AFP
  2. Intermediate Prognosis (~80% 5-year survival)
    1. Non-seminoma: testis/retroperitoneal primary, no non-nonpulmonary visceral metastases, AFP <10,000 IU/L, HCG <50,000 IU/L, LDH<10X normal
    2. Seminoma: any primary site, allow non-pulmonary visceral metastases, any marker level, (normal AFP)
  3. Poor Prognosis (~50% 5 year survival)
    1. Mediastinal primary or non-pulmonary visceral metastases, or AFP >10,000 U/L, HCG > 50,000 IU/L, or LDH >10X normal
    2. Seminoma: none classified as poor prognosis

G. Treatment [4]

  1. Initial
    1. Radical inguinal orchiectomy in ALL patients
    2. Anterograde ejaculation preserved in >90% of patients
    3. Radiation therapy is used most commonly for seminomatous tumors
  2. Seminoma
    1. Early - radiotherapy. Cures >95% stage I, >85% stage II (30Gy radiation over 3-4 weeks)
    2. Single dose carboplatin is at least as effective and better tolerated than radiation for stage I seminoma [9]
    3. For early disease after surgery, some will opt for watch and wait, close followup
    4. Late - combination platinum based chemotherapy and radiotherapy
    5. Carboplatin is probably the most effective single agent
  3. Non-Seminomatous
    1. Stage I - orchiectomy ± active surveillance versus retroperitoneal LN dissection [4]
    2. Radiotherapy is not used in adjuvant setting, unless disease relapse occurs
    3. Active surveillance usually preferred for good prognosis tumors
    4. Stage II - orchiectomy / LN dissection + chemotherapy
    5. Adjuvant chemotherapy is recommended for Stage II and Stage I with positive LN
    6. Surveillance with serial AFP and HCG is very effective for relapse detection
    7. Bleomycin + etoposide + cisplatin has been used effectively
    8. Three cycles are effective with dose intensive cisplatin (20mg/m2 x 5 days) [7]
    9. Progression free survival ~90% over 3 years with good-prognosis cancers [7]
    10. Ifosfamide, cisplatin, etoposide (ICE) regimen also used with reduced lung toxicity [5]
    11. Radiation therapy may be added
  4. Advanced Disease [12]
    1. Late Stage II and Stage III
    2. Combination chemotherapy with surgical reduction of mass
    3. Cisplatin based chemotherapy with etoposide and bleomycin (3 or 4 cycles)
    4. Risk stratification (good, intermediate, poor prognosis) to determine number of cycles
    5. Overall 5 year survival with combination chemotherapy >80% for metastatic disease
    6. For good prognosis testicular cancer, 3 cycles chemotherapy provides 90% durable complete remissions [12]
    7. Chemotherapy toxicities - see below
  5. Recurrent Disease or Partial Remission [11,12]
    1. About 25% of patients are cured with ifosfamide + cisplatin (second line therapy)
    2. High dose chemotherapy + autologous marrow or stem cell rescue is third line
    3. This therapy cures up to 50% of patients in whom second line therapy failed [11]
    4. Consider high dose chemotherapy with rescue in patients with poor prognoses
    5. For metastatic disease and poor prognosis, ifosfamide, etoposide, carboplatin used
    6. Vinblastine is often added to ifosfamide plus cisplatin for major cytoreduction
    7. Resect residual mass(es) after chemotherapy is completed
    8. Overall, ~60% of patients who relapse remit with high dose therapy; many are cured [11]
  6. Poor Prognostic Factors (see above)
    1. Early progression of disease after therapy
    2. High serum hCG levels
    3. Non-seminomatous histology which arise from mediastinal primary site
  7. Monitoring for Recurrence
    1. Tumor markers (AFP and HCG) annually
    2. Chest radiography annually
    3. Most recurrences occur within 2 years after end of treatment
    4. Semiannual evaluation by oncologist in first 2 years after treatment
  8. Fertily after Chemotherapy
    1. ~13% require testosterone supplements
    2. Most patients have initial azoospermia, but ~80% recover within 5 years

H. Long Term Followup [1,12]

  1. Most patients are cured; long term followup is required
  2. Annual comprehensive medical exams is recommended
  3. Late Chemotherapy Toxicities [12]
    1. Vascular: Raynaud phenomenon, hyperlipidemia, hypertension (HTN)
    2. Renal: insufficiency, hypomagnesemia, hyperreninemia with HTN
    3. Tinnitus and hearing loss
    4. Peripheral neuropathy
    5. Impaired spermatogenesis
  4. Second testicular cancers develop in 3-4% of cases
  5. Risk of Second Cancers
    1. Overall 1.4X increased risk versus general population
    2. Radiation therapy increases risk to 2-3X
    3. Acute myelogenous leukemia associated with etoposide use (0.5-2%, dose dependent)
  6. Angiotensin converting enzyme inhibitors are recommended for HTN

References

  1. Horwich A, Shiipley J, Huddart R. 2006. Lancet. 367(9512):754 abstract
  2. Vaughn DJ, Gignac GA, Meadows AT. 2002. Ann Intern Med. 136(6):463 abstract
  3. Kantoff PW and Oliva E. 2000. NEJM. 342(2):115
  4. Kaufman DS, Saksena MA, Young RH, Tabatabaei S. 2007. NEJM. 356(8):842 (Case Record) abstract
  5. Friedmann AM, Oliva E, Zietman AL, Aquino SL. 2003. NEJM. 34(12):1150 (Case Record)
  6. Petersson A, Richiardi L, Nordenskjold A, et al. 2007. NEJM. 356(18):1835
  7. Toner GC, Stockler MR, Boyer MJ, et al. 2001. Lancet. 357(9258):739 abstract
  8. Ballen KK and Hasserjian RP. 2004. NEJM. 350(20):2081 (Case Record) abstract
  9. Oliver RTD, Mason MD, Mead GM, et al. 2005. Lancet. 366(9482):293 abstract
  10. Voltz R, Gultekin SH, Rosenfeld MR, et al. 1999. NEJM. 340(28):1788
  11. Einhorn LH, Williams SD, Chamness A, et al. 2007. NEJM. 357(4):340 abstract
  12. Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. 2008. JAMA. 299(6):672 abstract