AUTHOR INFORMATION

Section 1 of 11

Authored by Arnold C Paulino, MD, Associate Professor, Departments of Radiation Oncology and Pediatrics, Methodist Hospital and Texas Children's Hospital

Coauthored by Jerry L Barker, Jr, MD, Staff Physician, Clinical Associate Professor of Radiation Oncology, Department of Radiation Oncology, University of Texas Southwestern Moncrief Cancer Center

Arnold C Paulino, MD, is a member of the following medical societies: American College of Radiology, American Society for Clinical Oncology, American Society for Therapeutic Radiology and Oncology, Children's Oncology Group, and International Society of Paediatric Oncology

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Arnold C Paulino, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, June 21 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 11

Background: Testicular tumors in children are rare, accounting for only 1-2% of all solid tumors in this age group. In both children and adults, the vast majority of testis tumors arise from germ cells. Seminoma is one type of testicular germ cell tumor that is believed to originate from the germinal epithelium of the seminiferous tubules. In recent years, these tumors have been shown to have dramatic sensitivity to both radiotherapy and cytotoxic chemotherapy. In most patients with testis tumors (including seminoma), the disease is cured readily with minimal long-term morbidity. The management of childhood seminoma is similar to that of adult seminoma.

Pathophysiology: Germ cell tumors account for 95% of testicular tumors and include seminomas, teratomas, choriocarcinomas, and mixed tumors. Seminomas comprise approximately 50% of all germ cell tumors. Seminomas are generally believed to arise from the germinal epithelium of the seminiferous tubules because "seminoma cells" are morphologically similar to spermatogonia and also because seminomas are frequently found within the seminiferous tubules in early stages.

Most researchers believe that seminomas can arise from any or all of the spermatocytic elements because undifferentiated seminomas can resemble primordial germ cells, spermatogonia, or spermatocytes. Unlike the nonseminomatous germ cell tumors, pure seminoma tends to remain localized or to involve only lymph nodes. Seminoma is confined to the testis in 85% of patients at presentation. It spreads in an orderly fashion, initially to draining lymph nodes in the retroperitoneum; from there it spreads proximally to involve the next echelon of draining lymphatics in the mediastinum and supraclavicular fossa. Only rarely does pure seminoma spread hematogenously to involve lung parenchyma, bone, liver, or brain (ie, stage IV). Fewer than 5% of patients present with stage III or IV disease.

Frequency:

• In the US: Germ cell tumors are the most common solid tumor in men aged 15-35 years. The worldwide incidence has more than doubled over the past 40 years, and approximately 7500 cases are diagnosed annually in the United States. Seminomas account for nearly 50% of these cases.

Mortality/Morbidity: With recent advances in radiologic staging, serum tumor marker surveillance, and platinum-based chemotherapy for advanced disease, overall survival (ie, cure) rates for patients with seminoma have increased to greater than 90%. Nearly 100% of patients with stage I testicular seminoma are cured. Potential adverse effects/morbidity related to therapy for this malignancy are discussed below; in general, morbidity includes infertility, second cancers, chemotherapy-related nausea and vomiting, nephrotoxicity, and cardiovascular toxicity or peptic ulcer disease from mediastinal or retroperitoneal irradiation, respectively.

Race: Geographic distribution of testicular cancer varies considerably, with the highest rates in North American whites, Scandinavians, and Western Europeans. The lowest rates occur in Asians, Africans, Puerto Ricans, and North American blacks. Recent data show a white-to-black incidence ratio of approximately 5:1, and a report from the US military showed a relative white-to-black incidence ratio of 40:1.

Sex: Seminomas arise from the male testicle.

Age:

• As noted above, germ cell tumors are the most common solid tumors in men aged 15-35 years. Seminoma (the most common germ cell tumor) occurs most commonly in the fourth decade of life.

• Children represent only 2-5% of all patients with testicular cancer. Seminoma is considered a postpubertal tumor, although it has been reported in a patient as young as 8 years.

CLINICAL

Section 3 of 11

History:

• The most common presenting symptom is a painless testicular mass. Other symptoms can include testicular pain (45%) or heaviness.



• A history of previous testicular trauma is common, although usually coincidental. The trauma typically draws the patient’s attention to the mass.



• Seminoma that has spread to retroperitoneal lymph nodes can cause back pain or abdominal discomfort.



• Widely disseminated metastatic disease to lungs, liver, bone, or brain is rare but may produce systemic symptoms.



• A history of cryptorchidism or other genitourinary anomalies can be elicited in some patients (see Causes).

Physical:

• When a testicular mass is suspected, physical examination should include transillumination of the scrotum, which can differentiate a solid mass from a fluid-filled hydrocele or varicocele.



• The contralateral testis should be examined carefully because patients with seminoma have a higher risk of contralateral testis cancer than the general population of healthy males.



• Pay careful attention to possible sites of lymph node metastases. Specifically, the abdomen should be examined to rule out the presence of large abdominal masses (suggesting bulky paraaortic/retroperitoneal lymphadenopathy), and both supraclavicular fossae should be palpated to rule out metastatic lymphadenopathy in those locations.



• A general physical examination that includes lungs, liver, nervous system, and musculoskeletal structures can aid in ruling out widespread metastatic disease.

Causes:

• The cause of germ cell tumors is unknown. Familial clustering has been observed, particularly among siblings.



• Prior testicular cancer is a major risk factor for a contralateral malignancy. The cumulative risk 25 years after original diagnosis is 3.6% for patients with seminoma.



• Cryptorchidism is a predisposing factor in the development of germ cell tumors arising from the testis. In fact, 7-10% of testis tumors occur in association with cryptorchidism. Orchiopexy performed before puberty reduces the risk of germ cell tumors and improves the ability to observe the testis. Interestingly, however, 25% of the cancers found in association with cryptorchidism occur in the contralateral normally descended testis, which suggests that a developmental defect is responsible for both the maldescent and the tumor. The risk of a cryptorchid patient developing testicular cancer is related directly to the degree of maldescent: 1 in 20 if the testis is intra-abdominal and 1 in 80 if it is within the inguinal canal. Hypospadias and hydrocele are other genitourinary anomalies that have been associated with testicular cancers.



• Klinefelter syndrome is associated with the development of mediastinal germ cell tumors.



• HIV infection may be associated with an increased risk of germ cell tumors. Other possible associations include mumps, orchitis, history of testicular trauma, immunosuppression after organ transplant, and prior vasectomy.



• No clear association between seminoma or other testicular germ cell tumors and previous exposure to diethylstilbestrol has been identified.

DIFFERENTIALS

Section 4 of 11

Hydrocele and Hernia in Children
Non-Hodgkin Lymphoma
Varicocele in Adolescents

Other Problems to be Considered:

Testicular torsion
Spermatocele
Epididymitis

WORKUP

Section 5 of 11

Lab Studies:

• Measurements of alpha-fetoprotein (AFP), human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH) are important in the management of patients with testis tumors. In fact, these tests are incorporated in the current staging system for testis tumors (see Staging).



• Beta-human chorionic gonadotropin


• • Beta-hCG is a glycoprotein typically produced by the placenta.
  
  
  
  • Elevations in this protein are found in the serum of approximately 15% of patients with seminoma.
  
  
  
  • The half-life of beta-hCG is approximately 22 hours.
  
  
  
• Alpha-fetoprotein


• • AFP is a glycoprotein typically associated with the human fetus and is the fetal equivalent of albumin.
  
  
  
  • It occurs in nonseminomatous germ cell tumors, as well as in hepatocellular carcinomas, cirrhosis, hepatitis, and pregnancy.
  
  
  
  • The half-life of AFP is approximately 5 days.
  
  
  
  • AFP elevation is rare in pure seminomas and indicates that nonseminomatous elements are also present (ie, mixed tumor).
  
  
  
• Both AFP and beta-hCG are suggestive of malignancy when elevated before orchiectomy. The rate of decline after orchiectomy indicates the likelihood of residual tumor. Tumor marker levels are used to assess response to treatment and to predict the likelihood of complete remission, and, in regular follow-up, tumor marker levels indicate recurrence, often in the absence of symptoms, physical findings, or abnormal findings on imaging studies.



• Lactate dehydrogenase: LDH level is an independent prognostic factor in patients with germ cell tumors (including seminoma). It is thought to reflect tumor burden.

Imaging Studies:

• Plain chest radiography, computed tomography (CT) imaging of the abdomen and pelvis, and bipedal lymphangiography (LAG) are the most important radiologic investigations in determining the extent of disease in patients with seminoma.


• • Chest radiography is adequate screening to rule out pulmonary parenchymal metastases.
  
  
  
  • CT imaging of the abdomen is the best technique for identifying the presence and extent of retroperitoneal lymphadenopathy and is necessary in all patients; it has largely replaced bipedal LAG in the radiographic staging of patients with seminoma. Retroperitoneal lymph nodes measuring 1-2 cm are confirmed to be involved pathologically with metastatic tumor in approximately 70% of cases.
  
  
  
  • Although radiologists skilled in the technique are increasingly difficult to find, bipedal LAG is uniquely able to define abnormal lymph nodes by both size and internal architecture, unlike CT imaging. In addition, LAG is useful to the radiation oncologist, who is able to minimize irradiation of normal tissues when such a study is available to facilitate portal design.
  
  
  
  • Further radiologic investigation is obtained only if the patient has symptoms suggesting further metastatic disease, eg, bone imaging in the setting of skeletal pain or brain CT imaging when neurologic signs are elicited.
  
  
  
• Scrotal ultrasonography


• • The typical testicular tumor is intratesticular and may produce one or more discrete hypoechoic masses or diffuse abnormalities with microcalcifications.
  
  
  
  • Calcifications are more frequent in seminoma than in nonseminomatous tumors.
  
  
  

• Classic seminomas (85%) demonstrate a monotonous sheet of large cells with abundant cytoplasm and round hyperchromatic nuclei with prominent nucleoli. A lymphocytic infiltrate or granulomatous reaction with giant cells or both is frequently present. Trophoblastic giant cells capable of producing hCG are present in 15-20% of tumors. Mitoses are infrequent.

• Anaplastic seminoma (10%) is an older term used to describe seminomas with 3 or more mitotic figures per high-power field. This finding has no clinical or prognostic significance because the response of anaplastic seminomas to standard therapy is equivalent to that of classic seminomas.

• Spermatocytic seminoma (5%) is a rare histologic variant that is not associated with carcinoma in situ. These well-differentiated tumors usually contain cells resembling secondary spermatids or spermatocytes. Spermatocytic seminomas rarely metastasize, and they occur almost exclusively in elderly men. The only recommended treatment is orchiectomy.

Staging: Testicular seminoma is staged according to the American Joint Committee on Cancer (AJCC) 2002 staging guidelines. This is a TNM staging system comprising separate categorizations for the primary tumor, regional lymph nodes, distant metastases, and serum tumor markers; these 4 categories are used to determine the stage of the patient's disease. Modern treatment decisions are based, in part, on the subdivisions of this staging system. Formal staging is a complex process involving particular required and allowable tests and procedures; the following is a quick overview. (For full staging information, see the AJCC Staging Manual.)

• Primary tumor staging
  • Tis - Intratubular germ cell neoplasia (carcinoma in situ)

  • T1 - Tumor limited to testis/epididymis without vascular or lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis

  • T2 - Tumor limited to testis/epididymis with vascular or lymphatic invasion or tumor extending through tunica albuginea with involvement of the tunica vaginalis

  • T3 - Tumor invading spermatic cord with or without vascular/lymphatic invasion

  • T4 - Tumor invading scrotum with or without vascular/lymphatic invasion



• Regional lymph node staging
  • N0 - No regional lymph node metastases

  • N1 - Metastasis with lymph node(s) 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension

  • N2 - Metastasis with lymph node(s) greater than 2 cm but not greater than 5 cm in greatest dimension, or multiple lymph nodes, any 1 mass greater than 2 cm, but not more than 5 cm, in greatest dimension

  • N3 - Metastasis with lymph node(s) greater than 5 cm in greatest dimension



• Distant metastatic staging
  • M0 - No distant metastases

  • M1a - Nonregional nodal or pulmonary metastasis

  • M1b - Distant metastases other than M1a



• Serum tumor marker staging
  • S0 - Marker studies within normal limits

  • S1 - LDH less than 1.5 times the reference range, beta-hCG less than 5000 mIU/mL, and AFP less than 1000 ng/mL

  • S2 - LDH 1.5-10 times the reference range , beta-hCG 5,000-50,000 mIU/mL, or AFP 1,000-10,000 ng/mL

  • S3 - LDH greater than 10 times the reference range, beta-hCG greater than 50,000 mIU/mL, or AFP greater than 10,000 ng/mL



• Stage grouping
  • Stage IA - T1 N0 M0 S0

  • Stage IB - T2,3,4 N0 M0 S0

  • Stage IS - Any T N0 M0 S1,2,3

  • Stage IIA - Any T N1 M0 S0,1

  • Stage IIB - Any T N2 M0 S0,1

  • Stage IIC - Any T N3 M0 S0,1

  • Stage IIIA - Any T Any N M1a S0,1

  • Stage IIIB - Any T Any N M0,1a S2

  • Stage IIIC - Any T Any N M1a,1b S3

TREATMENT

Section 6 of 11

Medical Care: See Further Outpatient Care for more information about postsurgical adjuvant radiation therapy and chemotherapy.

Surgical Care: The appropriate surgical treatment for any patient with suspected testicular tumor is radical inguinal orchiectomy with high ligation of the spermatic cord. Transscrotal biopsy or transscrotal orchiectomy is inappropriate because the testis and scrotum have different lymphatic drainage patterns and these procedures can result in tumor recurrence in the scrotal skin or inguinal/pelvic lymph nodes. In addition, an inguinal approach allows for more generous resection of the spermatic cord, improving surgical margins. Orchiectomy provides pathologic material for histologic diagnosis and primary pathologic staging information as well.

Consultations: Pediatric urologist, radiation oncologist, pediatric hematologist/oncologist, reproductive endocrinologist/sperm banking specialist

Diet: No specific dietary concerns are associated with the care of these patients.

Activity: Any activity limitations are related to surgery (orchiectomy); for example, the patient's surgeon may recommend avoidance of heavy lifting or contact sports for a short time.

MEDICATION

Section 7 of 11

As discussed in Follow-up below, adjuvant moderate-dose pelvic and/or paraaortic radiotherapy remains the standard treatment for patients with early-stage seminoma (stage I, IIA, or IIB) after orchiectomy. However, patients who are found to have more advanced disease (stage IIC, III, IV) have a high risk of systemic relapse if treated with surgery and radiation alone, and the standard treatment for these patients is combination chemotherapy. These patients can be generally divided into good risk and poor risk categories. For good risk patients, several combination chemotherapy regimens are available; one common schedule for adults includes 3 cycles of cisplatin/etoposide/bleomycin (detailed below). Poor risk patients should be enrolled in clinical trials because the ideal chemotherapeutic strategy has not been determined.

Drug Category: Antineoplastics agents -- Adjuvant chemotherapy regimens are for stages IIC and III disease.

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), then finally a mitotic cell division (phase M).

The rate of cell division varies for different tumors. Most common cancers increase very slowly in size compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy; it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Name	Cisplatin (Platinol) -- Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix.
Adult Dose	20 mg/m2 IV on days 1-5 and repeat q3-4wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur

Drug Name	Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.
Adult Dose	100 mg/m2 IV on days 1-5
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IT administration (may cause death)
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Bleeding and severe myelosuppression may occur

Drug Name	Bleomycin (Blenoxane) -- Glycopeptide antibiotic that inhibits DNA synthesis. For palliative measure in the management of several neoplasms.
Adult Dose	30 U IV push weekly on days 1, 8, and 15
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
Interactions	May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; vaso-occlusive phenomenon with distal necrosis of digits, permanent damage to nail matrix may occur

Drug Name	Carboplatin (Paraplatin) -- Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase. Has same efficacy as cisplatin but with better toxicity profile. Main advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive prehydration, less likely to induce nausea and vomiting, but more likely to induce myelotoxicity. Dose is based on the following formula: total dose (mg) = (target area under plasma concentration-time curve [AUC]) x (glomerular filtration rate [GFR]+25) where AUC is expressed in mg/mL/min and GFR is expressed in mL/min.
Adult Dose	360 mg/m2 IV q3wk as monotherapy or 300 mg/m2 q4wk as combination therapy
Pediatric Dose	600 mg/m2 IV on day 2 of therapy, or the following formula has been used in clinical trials to determine dose: 6 X (uncorrected GFR + [15 X surface area])
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor bone marrow function

FOLLOW-UP

Section 8 of 11

Further Outpatient Care:

• Fertility evaluation/sperm banking


• • As a group, patients with testicular cancer are more likely to have subfertility characteristics (eg, lower motile sperm count, decreased sperm mobility, suboptimal motility characteristics) than a healthy, age-matched cohort.

  • Modern adjuvant therapies for seminoma have a limited propensity to further negatively affect semen quality.

  • All male cancer patients of reproductive age who have treatment that may affect testicular function and who may desire children in the future should cryopreserve sperm before initiation of therapy.
  
  
  
• Adjuvant radiation therapy: Most men with seminoma present with clinical stage I disease (confined to the testis); only 15-20% of patients are found to have pelvic or paraaortic lymphadenopathy during postoperative radiographic staging. However, in another 15-20% of patients, disease that is apparently confined locally ultimately relapses in subdiaphragmatic lymph nodes if treated with orchiectomy alone. Adjuvant postoperative radiotherapy remains the current standard method to significantly reduce the incidence of regional nodal failure, and its use is determined by disease stage.


• • Stage I
    • After radical orchiectomy, patients with stage I seminoma are treated with moderate-dose external beam radiotherapy to retroperitoneal and ipsilateral pelvic lymph nodes, typically 2500 cGy in 20 fractions (125 cGy per fraction). Using this approach, the in-field disease control rate approaches 100%. Contraindications to the use of adjuvant radiotherapy for these patients include the presence of a horseshoe kidney (more common among these patients than among the general population), previous abdominopelvic radiotherapy, and severe inflammatory bowel disease. Recently, reports have indicated that paraaortic lymph node irradiation may suffice without adverse impact on overall survival.

    • Some patients with stage I disease prefer to avoid adjuvant radiation because their risk of relapse after orchiectomy is relatively low (15-20%) and because disease recurrences are usually treated with subsequent salvage radiation or chemotherapy. However, patients who choose this approach must understand that they will require frequent (and therefore expensive) follow-up evaluations with serum tumor markers and CT imaging of the abdomen and pelvis so that nodal recurrences may be identified early.

    • An accumulating amount of literature states that 1 or 2 courses of carboplatin may give results similar to adjuvant radiotherapy without the carcinogenic risks of irradiation.
  
  
  
  • Stage IIA-B
    • Patients with stage IIA or IIB seminoma are those who have been found to have regional nodal metastases no larger than 5 cm on postoperative imaging studies. Historically, these patients have been treated with external beam radiotherapy to the pelvic and paraaortic lymph nodes to a dose of 2500 cGy in 20 fractions (125 cGy per fraction) followed by a boost of 1000 cGy in 5-8 fractions (125-200 cGy per fraction); this has provided freedom from any relapse in approximately 90% of patients. As in patients with stage I disease, in-field control remains nearly universal.

    • Contraindications to the use of adjuvant radiotherapy for these patients include the presence of a horseshoe kidney (more common among these patients than among the general population), previous abdominopelvic radiotherapy, and severe inflammatory bowel disease. Adjuvant combination chemotherapy in lieu of radiotherapy has been used with increasing frequency over the past 2 decades, according to patterns of care studies; current randomized protocols are attempting to define which approach (adjuvant radiation versus adjuvant chemotherapy) carries the lowest morbidity while maximizing the cure rate.
  
  
  
• Adjuvant combination chemotherapy


• • In advanced seminoma (stage II-C or III), although local control with radiotherapy remains excellent, the risk of distant relapse is high. This risk mandates the use of systemic chemotherapy to achieve cure. Approximately 70-80% of these patients are curable with platinum-based chemotherapeutic regimens.
  
  
  
  • Patients with bulky nodal disease or systemic metastases are best treated with combination chemotherapy using cisplatin-containing regimens; a representative regimen is 4 cycles of cisplatin/etoposide administered intravenously in an outpatient setting.
  
  
  

Complications:

• Patients treated with orchiectomy and adjuvant radiotherapy are at increased risk for subfertility, even though the contralateral testis is not located directly within the radiotherapy field. Scrotal shielding during radiation treatments reduces the dose of scattered radiation and should be employed routinely (see Further Outpatient Care).



• Second malignancies have been reported following orchiectomy and postoperative adjuvant radiotherapy for seminoma. Although such malignancies are uncommon, the actuarial risk increases with time from diagnosis; second cancer sites have included the rectum, small intestine, stomach, and bladder.



• Potential long-term complications of cisplatin/etoposide chemotherapy include loss of high-frequency hearing, nephrotoxicity, hypomagnesemia/Raynaud phenomenon, subfertility, and acute nonlymphocytic leukemia.



• Although cardiovascular toxicity has been reported following treatment of seminoma with orchiectomy and adjuvant radiotherapy, it was associated with the use of radiotherapy fields that treated the mediastinum and supraclavicular fossae. These fields no longer are treated routinely because the incidence of recurrence in these areas is low for patients with stage I, IIA, or IIB disease.

Prognosis:

• Early-stage seminoma: Relapse occurs in approximately 4% of patients with stage I and 10% of patients with stage IIA or IIB seminoma. Subsequent treatment with chemotherapy cures more than 90% of patients whose disease relapses after radiotherapy. Ultimately, therefore, approximately 99% of patients with early-stage seminoma are cured.



• Advanced seminoma: With the development of effective cytotoxic chemotherapy, many patients with advanced (70-80%), recurrent (50-60%), or even metastatic (20-30%) seminomas are cured of their disease. Further studies of alternative chemotherapy regimens and high-dose regimens with stem cell support are ongoing.

Patient Education:

• Patients diagnosed with testicular seminoma have an increased risk of developing a contralateral testis tumor and should be taught methods of testicular self-examination. This form of screening should be performed monthly so that a second primary tumor can be identified at the earliest possible stage.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• A painless testicular mass is pathognomonic of a primary testicular tumor, but this telltale sign is observed only in a minority of patients. More commonly, patients present with some combination of testicular pain, swelling, or hardness. Because infectious orchitis or epididymitis are much more common than testicular tumors, an antibiotic trial is often undertaken. If testicular pain does not resolve or physical findings do not revert to normal within 2-4 weeks, a testicular ultrasound examination is indicated.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is not part of routine staging for patients with newly diagnosed seminoma?

A: Chest radiography
B: Serum beta–human chorionic gonadotropin tumor marker
C: Serum alpha-fetoprotein tumor marker
D: Bone imaging
E: CT imaging of the abdomen and pelvis

The correct answer is D: Bone imaging is not necessary in the routine clinical staging of a patient with newly diagnosed seminoma, unless he reports symptoms of skeletal pain. Similarly, CT imaging of the brain is required only for patients with neurologic symptoms.

CME Question 2: Which of the following is not an acceptable procedure in the diagnosis and treatment of a patient with testicular seminoma?

A: Scrotal ultrasonography
B: Bipedal lymphangiography
C: Testicular biopsy
D: Adjuvant pelvic/paraaortic radiotherapy for early-stage seminoma
E: Adjuvant cytotoxic chemotherapy for advanced seminoma

The correct answer is C: Testicular biopsy and transscrotal orchiectomy are considered nonstandard approaches to the care of patients with suspicious testicular masses. The standard care remains radical inguinal orchiectomy with high ligation of the spermatic cord. This avoids possible surgical spread of tumor to a separate lymphatic drainage system (eg, inguinal).

Pearl Question 1 (T/F): Elevations in the serum tumor marker alpha-fetoprotein (AFP) are identified frequently among patients with seminoma.

The correct answer is False: AFP is associated with the presence of nonseminomatous elements; patients with pure seminoma should not have abnormal elevations of AFP.

Pearl Question 2 (T/F): Of patients with seminoma, 80-85% are identified as having stage I disease, and nearly 100% of those patients ultimately are cured.

The correct answer is True: The use of postoperative radiotherapy for patients with stage I disease reduces the incidence of regional recurrence from 15-20% to less than 5%. However, the cure rate remains good even for those rare patients whose disease relapses after surgery and adjuvant radiotherapy.

Pearl Question 3 (T/F): All males of reproductive age who have cancer have treatment that may affect testicular function; patients who desire children in the future should be referred for sperm banking.

The correct answer is True: This is now a standard recommendation for patients with seminoma. These patients are already at increased risk of subfertility despite their usual young age and otherwise good general health. Cancer therapies can have a further negative impact on their semen quality, and evaluations are warranted before radiation therapy and chemotherapy.

Pearl Question 4 (T/F): The cure rate for patients with stage III seminoma treated with orchiectomy and adjuvant radiotherapy is excellent.

The correct answer is False: For patients with advanced seminoma, although local control with radiotherapy is very good, the risk of distant disease relapse is high; this risk mandates the use of systemic chemotherapy to achieve cure.

BIBLIOGRAPHY

Section 11 of 11

• American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 2002: 347-360.
• Bauman GS, Venkatesan VM, Ago CT, et al: Postoperative radiotherapy for Stage I/II seminoma: results for 212 patients. Int J Radiat Oncol Biol Phys 1998 Sep 1; 42(2): 313-7[Medline].
• Bosl GJ, Motzer RJ: Testicular germ-cell cancer [published erratum appears in N Engl J Med 1997 Nov 6;337(19):1403]. N Engl J Med 1997 Jul 24; 337(4): 242-53[Medline].
• Bosl GJ, Sheinfeld J, Bajorin DF: Cancer of the Testis. In: Devita VT, ed. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1997: 1397-1425.
• Buchholz TA, Walden TL, Prestidge BR: Cost-effectiveness of posttreatment surveillance after radiation therapy for early stage seminoma. Cancer 1998 Mar 15; 82(6): 1126-33[Medline].
• Capelouto CC, Clark PE, Ransil BJ, Loughlin KR: A review of scrotal violation in testicular cancer: is adjuvant local therapy necessary? J Urol 1995 Mar; 153(3 Pt 2): 981-5[Medline].
• DeSantis M, Albrecht W, Holtl W, Pont J: Impact of cytotoxic treatment on long-term fertility in patients with germ-cell cancer. Int J Cancer 1999 Dec 10; 83(6): 864-5[Medline].
• Fernandes ET, Etcubanas E, Rao BN, et al: Two decades of experience with testicular tumors in children at St Jude Children's Research Hospital. J Pediatr Surg 1989 Jul; 24(7): 677-81; discussion 682[Medline].
• Fiveash J, Sandler HM: Controversies in the management of stage I seminoma. Oncology (Huntingt) 1998 Aug; 12(8): 1203-12; discussion 1212-21[Medline].
• Fossa SD, Horwich A, Russell JM, et al: Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 1999 Apr; 17(4): 1146[Medline].
• Foster RS, Nichols CR: Testicular cancer: what's new in staging, prognosis, and therapy. Oncology (Huntingt) 1999 Dec; 13(12): 1689-94; discussion 1697-700, 1703[Medline].
• Gordon W Jr, Siegmund K, Stanisic TH, et al: A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group. Int J Radiat Oncol Biol Phys 1997 Apr 1; 38(1): 83-94[Medline].
• Hallak J, Kolettis PN, Sekhon VS: Sperm cryopreservation in patients with testicular cancer. Urology 1999 Nov; 54(5): 894-9[Medline].
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