Bethesda Handbook of Clinical Oncology, 2nd Edition

Genitourinary

16

Testicular Carcinoma

Avi S. Retter*

Barnett S. Kramer^†

*Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

^†Office of Disease Prevention, National Institutes of Health, Bethesda, Maryland

The opinions expressed in this chapter represent those of the authors and do not necessarily represent official positions or opinions of the U.S. government or of the U.S. Department of Health and Human Services.

Testicular cancer is rare (less than 1% of all tumors) but represents one of the most frequently occurring malignancies in young men. In most cases, the reproductive organs are the sites of the primary tumors; these tumors usually arise from the malignant transformation of primordial germ cells. Testicular cancer is highly curable, and life expectancy of affected individuals is long. Consequently, careful long-term follow-up of survivors is required. Not only oncologists but also primary care providers are likely to observe an increasing number of successfully treated patients in their practice. For these patients, careful monitoring for recurrent disease and therapy-related long-term sequelae is imperative.

CLINICAL FEATURES

EPIDEMIOLOGY

• For 2003, 7,600 new cases of testicular cancer and 400 deaths from this cancer were estimated.
• Testicular cancer accounts for 1% of all malignancies in men.
• Incidence in whites is greater than that in African Americans.
• Peak frequency is in early adulthood (greatest incidence is between the age of 20 and 35 years).
• Testicular cancer is uncommon after the age of 40.

RISK FACTORS

• Undescended (cryptorchid) testes (intraabdominal testes are at higher risk than inguinal testes)—in cryptorchidism, the contralateral normally descended testicle is also at high risk
• Testicular cancer in contralateral testis
• Klinefelter syndrome (increased risk of mediastinal germ cell tumors)
• HIV positivity.

History and Signs and Physical Examination

• Asymptomatic nodule or swelling
• Testicular mass, feeling of heaviness, pain, and/or hardness

P.212

• Patients with advanced disease may experience back or abdominal pain (due to retroperitoneal adenopathy), weight loss, gynecomastia [due to elevated β-human chorionic gonadotropin (β-HCG)], supraclavicular lymphadenopathy, superior vena cava syndrome (due to mediastinal disease), urinary obstruction, dyspnea and hemoptysis (secondary to extensive pulmonary metastases), and headaches or seizures (due to brain metastases) or bone pain (due to bone metastases).

DIFFERENTIAL DIAGNOSIS

• Epididymitis (may coexist with germ cell tumors)
• Hydrocele, varicocele, spermatocele, or orchitis
• Lymphoma
• Leukemia
• Metastasis from prostate cancer, melanoma, and lung cancer
• Tuberculosis, gumma, or other infections.

DIAGNOSTIC

Goals

• Any testicular mass requires prompt evaluation to exclude testicular carcinoma.
• Testicular cancer is highly curable (85% of cases).
• Histologic determination of tumor type and stage have prognostic and therapeutic significance.

Evaluation

The diagnostic workup for testicular carcinoma is outlined in Fig. 16.1.

FIG. 16.1. Diagnostic workup for testicular carcinoma.

Imaging

• Ultrasound:Ultrasound detects the presence of testicular parenchymal abnormality in the ipsilateral as well as the contralateral testes.
• Radiographic studies:Standard two-view chest radiograph rules out pulmonary metastases.
• Computerized tomography (CT):CT scans of chest, abdomen, and pelvis establish the extent of disease dissemination.
• Magnetic resonance imaging (MRI):MRI is used especially when results of the physical examination and testicular ultrasound are equivocal. Brain MRI in the setting of central nervous system (CNS) symptoms suggestive of brain metastases (e.g. headache, neurological deficit, seizure).
• Positron emission tomography (PET) scan:The exact role for PET scan in the diagnostic and follow-up process in germ cell tumors is evolving.

Laboratory

Serum α-fetoprotein

• Serum α-fetoprotein (AFP) has a half-life of approximately 5 to 7 days.
• It is commonly excreted by embryonal cell cancers or yolk sac elements.
• It is not produced by pure seminoma, and its detection implies the presence of nonseminomatous elements (primary or metastatic site).

Serum β-human Chorionic Gonadotropin

• The half-life of β-HCG is approximately 24 hours.
• It may be biologically active, causing enhanced estrogen production by the testes and consequent gynecomastia.

P.213

• It is secreted by syncytiotrophoblastic giant cells and chorionic elements.
• It is present in choriocarcinomas.
• It may occasionally be modestly elevated in pure seminomas.

Serum Lactate Dehydrogenase

• Serum lactate dehydrogenase (LDH) is a nonspecific tumor marker but is independently useful as a prognostic factor.
• It can reflect tumor burden and growth rate.

PATHOLOGIC EVALUATION

High inguinal orchiectomy with complete removal of the testis and spermatic cord through the inguinal ring is the procedure of choice for pathologic evaluation of suspected testicular tumors. Transcrotal testicular biopsy is not recommended because of concerns about local and nodal dissemination of tumor, although empirical evidence supporting this notion is weak.

• Germ cell tumors display an array of histopathology (see Table 16.1).
• Placental alkaline phosphatase (PLAP)–positive midline tumors of uncertain histogenesis, which are negative for low–molecular-weight keratins on immunohistochemical study, are

P.214

suggestive of seminomas. Those tumors that express low–molecular-weight keratins are usually embryonal carcinomas.

• Germ cell tumors usually are hyperdiploid.
• Loss of heterozygosity is often demonstrated in early stage disease and is not associated with progression of disease.
• Eighty percent of cases have an isochromosome of the short arm of chromosome 12 [i(12p)], implicating one or more genes on 12p in the malignant transformation of primordial germ cells.

TABLE 16.1. Histopathologic characteristics of germ cell tumors

Tumor type Pathologic feature Germ cell tumors (95%) Seminomas (40%–50%) Single cell-type tumors (60%) Primordial germ cell Combination tumors (40%) Nonseminomas (50%–60%) Embryonal cell tumors Yolk sac tumors Teratomas Choriocarcinomas Tumors of gonadal stroma (1%–2%) Leydig cell Sertoli cell Primitive gonadal structures Gonadoblastoma (1%) Germinal cell + stromal cell

STAGING

Tables 16.2. and 16.3. contain thetumor–node–metastasis (TNM) classification and staging criteria of the American Joint Committee for Cancer (AJCC).

TABLE 16.2. American Joint Committee on Cancer (AJCC) TNM classification and staging

LDH, lactate dehydrogenase; HCG, human chorionic gonadotropin; AFP, α-fetoprotein; NL, normal limits; ULN, upper limit of normal. Primary tumor (pT) (The extent of primary tumor is classified after radical orchiectomy) pTX: Primary tumor cannot be assessed (if no radical orchiectomy has been performed) pT0: No evidence of primary tumor (e.g., histologic scar in testis) pTis: Intratubular germ cell neoplasia (carcinoma in situ) pT1: Tumor limited to testis and epididymis without lymphatic or vascular invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis testis pT2: Tumor limited to testis and epididymis with vascular or lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis testis pT3: Tumor invades the spermatic cord with or without vascular or lymphatic invasion pT4: Tumor invades the scrotum with or without vascular or lymphatic invasion Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in a single lymph node, ≤2 cm in greatest dimension, or multiple lymph nodes, none >2 cm in greatest dimension N2: Metastasis in a single lymph node, >2 cm but ≤5 cm in greatest dimension; or multiple lymph nodes, any one mass >2 cm but none >5 cm in greatest dimension N3: Metastasis in a lymph node >5 cm in greatest dimension Pathologic lymph nodes (pN) pNX: Regional lymph nodes can not be assessed pN0: No regional lymph node metastasis pN1: Metastasis with a lymph node mass 2 cm or less in greatest dimension and ≤5 nodes positive, none >2 cm in greatest dimension pN2: Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension; or more than 5 nodes positive, none >5 cm; or evidence of extra nodal extension of tumor pN3: Metastasis with a lymph node more than 5 cm in greatest dimension Distant metastasis (M) MX: Presence of distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis M1a: Nonregional nodal or pulmonary metastasis M1b: Distant metastasis other than to nonregional nodes and lungs Serum tumor markers (S) LDH β-HCG (mIU/mL) AFP (ng/mL) SX Marker studies not available or not performed S0 NL NL NL S1 <1.5 × ULN and <5,000 and <1,000 S2 1.5–10 × ULN or 5,000–50,000 or 1,000–10,000 S3 >10 × ULN or >50,000 or >10,000

TABLE 16.3. American Joint Committee for Cancer stage groupings

Stage 0 pTis N0 M0 S0 Stage I pT1–4 N0 M0 SX Stage IA pT1 N0 M0 S0 Stage IB pT2–4 N0 M0 S0 Stage IS Any pT/Tx N0 M0 S1–3 Stage II Any pT/Tx N1–3 M0 SX Stage IIA Any pT/Tx N1 M0 S0–1 Stage IIB Any pT/Tx N2 M0 S0–1 Stage IIC Any pT/Tx N3 M0 S0–1 Stage III Any pT/Tx any N M1 SX Stage IIIA Any pT/Tx any N M1a S0–1 Stage IIIB Any pT/Tx N1–3 M0 S2 Any pT/Tx any N M1a S2 Stage IIIC Any pT/Tx N1–3 M0 S3 Any pT/Tx any N M1a S3 Any pT/Tx any N M1b any S

PROGNOSIS

Table 16.4 outlines the international consensus risk classification for germ cell tumors, and Table 16.5 discusses the expected survival.

TABLE 16.4. International Consensus Risk Classification for germ cell tumors

Prognosis Nonseminoma Seminoma AFP, α-fetoprotein; HCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; ULN, upper limit of normal; NL, normal limit. Good Testis/retroperitoneal primary and no nonpulmonary visceral metastases and AFP <1,000 µg/mL HCG <5,000 IU/L (1,000 µg/mL) LDH <1.5 × ULN Any primary site and no nonpulmonary visceral metastases and AFP <1,000 µg/mL, any concentration of HCG any concentration of LDH Intermediate Testis/retroperitoneal primary and no nonpulmonary visceral metastases and AFP ≥1,000 and ≤10,000 µg/mL or HCG ≥5,000 IU/L and ≤50,000 IU/L or LDH ≥1.5 × NL and ≤10 × NL Any primary site and nonpulmonary visceral metastases and AFP <1,000 µg/mL Any concentration of HCG Any concentration of LDH Poor Mediastinal primary or nonpulmonary visceral metastases or AFP >10,000 µg/mL or HCG >50,000 IU/L (10,000 µg/mL) or >10 × ULN None of the patients are classified as poor prognosis

TABLE 16.5. Expected survival

5-yr progression-free survival (%) 5-yr overall survival (%) Prognosis Seminoma Nonseminoma Seminoma Nonseminoma a There is no poor prognosis category for seminoma. Good 82 89 86 92 Intermediate 67 75 72 80 Poora — 41 — 48

THERAPY

Treatment Modalities According to Histology and Stage

Testicular cancer is highly treatable and can be broadly divided into seminoma and nonseminoma types (see Figs. 16.1, 16.2, 16.3, 16.4 and16.5). Seminomas are better cured by both radiation and chemotherapy (see Table 16.6). For patients with seminoma (all stages combined), the cure rate exceeds 90%. For those patients with low-stage disease, the cure rate approaches 100%. The management of tumors that contain a mixture of seminoma and nonseminoma components should be the same as that of nonseminomas. Tumors that appear to have a seminoma histology with elevated serum levels of AFP should be treated as nonseminomas. Elevation of only the β subunit of HCG is found in approximately 10% of patients with pure seminoma. Patients with brain metastasis should receive whole brain radiotherapy in addition to chemotherapy.

• A randomized study has shown similar overall survival and time-to-treatment failure results for BEP (bleomycin, etoposide, and cisplatin) and PVB (cisplatin, vinblastine, and bleomycin) regimens. Another randomized study has shown similar results for BEP and VIP (etoposide, ifosfamide, and cisplatin) regimens.
• BEP causes fewer instances of paresthesias, abdominal cramps, and myalgias than does PVB.

P.215

• VIP has more hematologic (myelosuppressive) toxicity than BEP.
• A randomized study showed that four cycles of EP (etoposide and cisplatin) were equivalent to three cycles of BEP in patients with good- and intermediate-risk disease. However, four cycles of BEP is the standard of care for initial treatment of poor-risk disease.

TABLE 16.6. Commonly used chemotherapeutic regimens

BEP Bleomycin, 30 units i.v. weekly on days 2, 9, and 16 Two to four cycles administered at 21-d intervals Etoposide, 100 mg/m2 i.v. daily × 5 d Cisplatin, 20 mg/m2 i.v. daily × 5 d EP Etoposide, 100 mg/m2 i.v. daily × 5 d Four cycles administered at 21-d intervals Cisplatin, 20 mg/m2 i.v. daily × 5 d VIP VePesid (etoposide) 75 mg/m2 i.v. daily × 5 d Ifosfamide 1.2 g/m2 i.v. daily × 5 d Platinol (cisplatin) 20 mg/m2 i.v. daily × 5 d Mesna 400 mg i.v. bolus prior to first ifosfamide dose then 1.2 g/m2 i.v. infused continuously daily for 5 d VeIP Vinblastine, 0.11 mg/kg wk 1 and 2 Three to four cycles administered at 21-d intervals Ifosfamide, 1.2 g/m2 i.v. daily × 5 d Mesna 400 mg i.v. bolus prior to first ifosfamide dose then 1.2 g/m2 i.v. infused continuously daily for 5 d, Cisplatin, 20 mg/m2 i.v. daily × 5 d PVB Cisplatin, 20 mg/m2 i.v. daily × 5 d Three cycles administered at 21-d intervals Vinblastine, 0.11 mg/kg wk 1 and 2 Bleomycin, 30 units i.v. weekly on d 2, 9, 16

P.216

P.217

FIG. 16.2. Treatment algorithm for seminoma. XRT, Abdominal/Retroperitenial irradiation.

FIG. 16.3. Treatment algorithm for nonseminoma: stages IA, IB, and IS. *Some would give BEP × 2.

FIG. 16.4. Treatment algorithm for nonseminoma: stages IIA, IIB, and IIC (high-risk disease). *Some would give BEP × 2.

FIG. 16.5. Treatment algorithm for nonseminoma: stages IIC (intermediate and poor-risk disease) and III.

Follow-up

Appropriate surveillance of patients with testicular cancer is essential and should be determined by the tumor's histology, stage, and treatment (see Tables 16.7 and 16.8).

TABLE 16.7. Surveillance for seminomaa

H&P, history and physical; CXR, chest x-ray; ABD, abdomen. aThese are National Comprehensive Cancer Network (NCCN) guidelines. However, there is considerable interinstitutional variation in the standard of follow-up care, with little evidence that different schedules lead to different outcomes. (a) Stage IA, IB, IS (postradiation) Yr H & P, CXR, markers (monthly interval) ABD/pelvic CT (monthly interval) 1 3 12 2 4 12 3–5 6 12 (only 3rd yr) (b) Stage IIA, IIB (postradiation) or stage IIC, III (postchemotherapy) Yr H & P, CXR, markers (monthly interval) ABD/pelvic CT 1 2 After fourth mo and every 3 mo until stable 2 3 3 4 4 6 5+ 12

TABLE 16.8. Surveillance for nonseminomaa

H&P, history and physical; CXR, chest x-ray; ABD, abdomen. aThese are National Comprehensive Cancer Network (NCCN) guidelines. However, there is considerable interinstitutional variation in the standard of follow-up care, with little evidence that different schedules lead to different outcomes. (a) Observation/surveillance for stage IA, IB nonseminoma Yr H & P, CXR, markers (monthly interval) ABD/pelvic CT (monthly interval) 1 1–2 3–4 2 2 3–4 3 3 4 4 4 6 5 6 12 6+ 12 12 (b) Surveillance after complete response to chemotherapy and/or retroperitoneal lymph node dissection (RPLND) in nonseminoma Yr H & P, CXR, markers (monthly interval) ABD/pelvic CT (monthly interval) 1 1–2 6 2 2 6 3 3 12 4 4 12 5 6 12 6+ 12 12

Salvage THERAPY

• Salvage therapy is usually given to patients who fail to achieve an initial complete response.
• VIP is commonly used as an initial salvage therapy.
• High-dose chemotherapy with autologous bone marrow or peripheral stem cell support is investigational and may represent a therapeutic option for selected patients.

Therapy-related Toxicity

Fertility

• Approximately 25% of patients have oligospermia or sperm abnormalities before therapy.
• Almost all patients become oligospermic during chemotherapy.
• Sperm banking should be recommended for all patients desiring to father children after therapy; however, many patients recover sperm production after completion of therapy and can father children.
• Children of treated patients do not appear to have an increased risk of congenital malformations.

P.218

Pulmonary Toxicity

• Pulmonary toxicity is associated with bleomycin.
• The toxicities are rarely fatal when total cumulative doses of bleomycin are less than 400 units.
• Bleomycin should be discontinued if early signs of pulmonary toxicity develop.
• Asymptomatic decreases in pulmonary function are frequent and are usually reversible after the completion of chemotherapy.
• Routine use of pulmonary function tests (PFTs) [e.g., diffusing capacity of lung for carbon monoxide (DLCO)] is rarely indicated and should be reserved for patients with signs and symptoms of pulmonary toxicity (e.g., dry rales on physical examination and shortness of breath or dyspnea on exertion).
• Patients should be questioned about their smoking history and current smokers should be encouraged to stop.
• If deemed medically necessary, supplemental oxygen should be used with caution by minimizing exposure and by using low fraction of inspired oxygen (Fio2) settings.
• If fluids are indicated, i.v. colloids rather than crystalloids are preferred.

Nephrotoxicity

• Minor decreases in creatinine clearance can occur with platinum-based regimens, but these appear to remain stable in the long term without clinically significant deterioration.

P.219

Neurologic

• Hearing deficits occur with cisplatin-based regimens, but they generally occur at sound frequencies higher than the range of conversational tones; for most patients, routine monitoring for hearing deficit is not indicated, and use of hearing aids after therapy is rarely needed.

Cardiovascular

Cardiovascular events include:

• Angina, myocardial infarction, and sudden cardiac death
• Hypertension
• Raynaud phenomenon
• Hypercholesterolemia.

Secondary Malignancies

• Secondary malignancies are associated with use of alkylating agents (e.g., cisplatin), etoposide, and radiation.

P.220

P.221

P.222

• Secondary leukemias are primarily of myeloid lineage and are associated with etoposide-containing regimens; these are often characterized by an 11q23 translocation and usually occur within several years after therapy.
• Cancers of the stomach, the bladder, and possibly the pancreas are associated with radiation therapy, which is often used in the management of pure seminomatous germ cell cancers; these are often limited to the radiation portal and may have a latency period of a decade or more.

SUGGESTED READINGS

American Cancer Society. Cancer facts and figures 2003. Atlanta, GA: American Cancer Society, 2003.

Baniel J, Foster RS, Gonin R, et al. Late relapse of testicular cancer. J Clin Oncol 1995;13:1170–1176.

Bosl GJ, Chaganti RSK. The use of tumor-markers in germ-cell malignancies. Hematol Oncol Clin North Am 1994;8:573–587.

Bosl GJ, Motzer RJ. Testicular germ-cell cancer. N Engl J Med 1997;337:242–253.

Bosl GJ, Steinfeld J, Barjorin DF, et al. Cancer of the testis. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. Philadelphia, PA: Lippincott–Raven Publishers, 1997:1397–1425.

Einhorn LH. Testicular cancer: an oncological success story. Clin Cancer Res 1997;3:2630–2632.

Einhorn LH, Donohue JP. Advanced testicular cancer: update for urologists. J Urol 1998;160:1964–1969.

Fox EP, Loehrer PJ. Chemotherapy for advanced testicular cancer. Hematol Oncol Clin North Am 1991;5:1173–1187.

P.223

Harland SJ, Cook PA, Fossa SD, et al. Intratubular germ cell neoplasia of the contralateral testis in testicular cancer: defining a high risk group. J Urol 1998;160:1353–1357.

Huddart RA, Norman A, Shahidi M, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 2003;21:1513–1523.

Lehne G, Johansen B, Fossa SD. Long-term follow-up of pulmonary function in patients cured from testicular cancer with combination chemotherapy including bleomycin. Br J Cancer 1993;68:555–558.

Mead GM. Testicular cancer: staging, treatment and outcome. Eur J Cancer 1997;33:6.

Mead GM, Stenning SP, Cook P, et al. International germ cell consensus classification: a prognostic factor-erased staging system for metastatic germ cell cancers. J Clin Oncol 1997;15:594–603.

Miller KD, Loehrer PJ, Gonin R, et al. Chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol1997;15:1427–1431.

Murty VS, Bosl GJ, Houldsworth J, et al. Allelic loss and somatic differentiation in human male germ-cell tumors. Oncogene 1994;9:2245–2251.

Osanto S, Bukman A, Vanhoek F, et al. Long-term effects of chemotherapy in patients with testicular cancer. J Clin Oncol 1992;10:574–579.

Stephenson WT, Poirier SM, Rubin L, et al. Evaluation of reproductive capacity in germ-cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. J Clin Oncol 1995;13:2278–2280.

Travis LB, Curtis RE, Storm H, et al. Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 1997;89:1429–1439.

Vanbasten JP, Koops HS, Sleijfer DT, et al. Current concepts about testicular cancer. Eur J Surg Oncol 1997;23:354–360.