26 - Testicular Cancer | Smiths General Urology, Seventeenth Edition (LANGE Clinical Medicine)

Authors: Macfarlane, Michael T.

Title: Urology, 4th Edition

> Table of Contents > Part Two - Selected Topics > Chapter 26 - Testicular Cancer

Chapter 26

Testicular Cancer

Pathology

Testicular cancers are rare overall, yet they are the most common solid tumor of young adult males. Approximately 8,000 new cases occur annually, with 390 deaths in the United States. Primarily because of effective chemotherapy, they have become the most curable of all cancers. Germ cell cancers account for 90% to 95% of all primary testicular neoplasms. No clear etiologic or genetic factors have been defined; however, 10% of patients have a history of an undescended testis, 50% of which were intraabdominal. Testis cancers will be bilateral in 2% to 3% of cases, either concurrent or in succession. Except for seminoma, generally a rapid growth rate is found, with doubling times of 10 to 30 days. Testis tumors are broadly classified as either seminomas or nonseminomas (choriocarcinoma, embryonal, or teratocarcinoma).

Peak Age Incidence (Age 20 40 YR)

Yolk Sac Tumors	Infants and Children
Choriocarcinoma	Age 20 30 yr
Embryonal or teratocarcinoma	Age 25 30 yr
Seminoma	Age 30 40 yr
Malignant lymphomas	Age >50 yr

Tumor Markers

Many germ cell tumors produce specific oncofetal protein markers, either -fetoprotein (AFP) or human chorionic gonadotropin (hCG), which can be detected in the patient's serum or tissues. Ninety percent of patients with nonseminomatous testis tumors will have elevations of one or both markers, and 5% to 10% of pure seminomas will demonstrate elevations of hCG only. The amount of tumor burden is proportional to the degree of marker elevation.

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Human Chorionic Gonadotropin

hCG is a 38,000 MW double-chain glycoprotein with - and -components, normally secreted by the syncytiotrophoblastic cells of the placenta. hCG is elevated in all patients with choriocarcinoma, in 40% to 60% of embryonal carcinomas, and in 5% to 10% of pure seminomas. Its -subunit is similar to those of luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone; therefore, antibodies to the -subunit must be used for measurement. It has a metabolic half-life of 24 hours, and normal adult levels should be less than 5 mIU/mL.

-Fetoprotein

AFP is a 70,000 MW single-chain glycoprotein normally secreted by the fetal yolk sac. It is also produced by trophoblastic cells of embryonal carcinoma and yolk sac tumors. It is not made by pure choriocarcinoma or seminoma. Elevated AFP is found in 50% to 70% of nonseminomatous testis tumors. It has a half-life of 4 to 6 days, and normal adult levels should be less than 40 ng/mL.

Lactate Dehydrogenase

Lactate dehydrogenase (LDH) is a nonspecific cellular enzyme that can be used in monitoring patients with metastatic germ cell tumors.

Metastases

More than half of patients with testicular tumors present with metastatic disease.

Local Metastases

Local metastatic spread is generally predictable and progresses in a systematic pattern to the regional lymphatics at the level of the renal hilum. Left-sided drainage is primarily to the paraaortic and preaortic areas at the level of L2 (left-to-right crossover has not been reported). Right-sided drainage is primarily to the interaortocaval, precaval, and preaortic areas at the level of L2 (right-to-left crossover is common). Retrograde spread to ipsilateral common and external iliac nodes can occur with advanced disease.

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Distant Metastases

Distant metastatic spread is most commonly hematogenous to the lungs, liver, brain, bones, and kidney.

Staging System

Clinical staging of testis cancer is essential for the appropriate decisions for treatment. The American Joint Committee on Cancer tumor-node-metastasis system is noted below.

American Joint Committee on Cancer Tumor-Node-Metastasis Staging for Testicular Cancer

Stage	Description
Tis	Intratubular tumor (carcinoma in situ)
T1	Tumor limited to testis
T2	Tumor extends outside tunic albuginea or shows vascular lymphatic invasion
T3	Tumor invades spermatic cord
T4	Tumor invades scrotum
N1	Regional lymph nodes <2 cm and/or 5 nodes
N2	Regional lymph nodes of 5 cm or >5 nodes involved
N3	Lymph nodes >5 cm
M1a	Nonregional lymph nodes or pulmonary metastases
M1b	Other distant metastases

Classification of Histologic Types

Sixty percent of germ cell tumors are of a single cell type, whereas 40% will be mixed. Germ cell tumor types tend to parallel their normal developmental counterparts, as illustrated.

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Single Cell Type (60%)

Seminomas (35%)

Seminomas tend to grow in sheets of cells at a slower rate than other germ cell tumors. At presentation, 75% will be confined to the testis, 15% will involve regional lymphatics, and 10% will have already spread to distant lymph nodes or viscera. Overall survival is 85%, with more than 90% survival when the tumor is confined to the testis. The tumor is very radiosensitive. hCG is produced by 5% to 10%, but no pure seminoma produces AFP. An elevated AFP level excludes the diagnosis of pure seminoma.

Three Subtypes

Classic seminoma (85%)
Anaplastic seminoma (10%) generally considered a more aggressive tumor with greater metastatic potential
Spermatocytic seminoma (5%) variable metastatic potential

Embryonal Carcinoma (20%)

Embryonal carcinoma is a grayish white fleshy tumor, often with extensive hemorrhage and necrosis. It produces both hCG and AFP.

Teratomas (5%)

Teratomas contain derivatives of all three cell layers: ectoderm (squamous epithelium or neuronal tissue), endoderm (gastrointestinal or respiratory tissue), and mesoderm (bone, cartilage, or muscle). They appear as clear or mucinous cystic areas interspersed with solid tissue, including bone, muscle, or cartilage. Immature and more mature varieties are differentiated. They have a somewhat less malignant potential. Pure teratomas do not produce hCG or AFP.

Choriocarcinomas (<1%)

Choriocarcinomas are highly malignant and appear as small grayish white tumors with central areas of hemorrhage. Both syncytiotrophoblasts and cytotrophoblasts must be demonstrated histologically to make the diagnosis. High titers of hCG are always present. Pure forms do not produce AFP. They often metastasize early.

Yolk Sac Tumor (<1%)

Also known as endodermal sinus tumor or orchioblastoma, this tumor occurs in a pure form primarily in children, whereas in adults, it can frequently occur in combination with other histologic types. It is the most common testicular neoplasm in infants and children. AFP is produced in high titers.

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Mixed-Cell Types (40%)

Teratocarcinoma (20%)

Teratocarcinoma is a combination of teratoma and embryonal carcinoma. It is the most frequent mixed-cell type and usually produces AFP or hCG or both.

Other Combinations (20%)

In mixed-cell tumors, the prognosis becomes that of the most malignant element. Combinations with seminomas are treated as nonseminomatous tumors.

Workup

The usual presentation of testicular cancer is the incidental finding of a painless lump, nodule, swelling, or hardness in the testis of a young adult, which may be accompanied by a heavy sensation or dull ache in the lower abdomen. Occasionally, acute pain may occur because of rapid growth, resulting in hemorrhage and necrosis. Ten percent of patients will present with epididymitis. Up to 50% of patients will present with metastases, but only 10% will have symptoms of metastatic disease. Gynecomastia is seen in 5%.

History

Ask about a history of undescended testis, past trauma, chronic or repeated epididymitis, pain, weight loss, fever, or chills.

Physical Examination

The testis must be carefully palpated, starting with the normal side. A testis tumor is usually nontender and firm. A hydrocele can be transilluminated and drained with a needle to facilitate palpation. Check for supraclavicular nodes, gynecomastia, and groin, flank, or abdominal mass.

Laboratory Tests

Complete blood count (CBC), urinalysis, blood urea nitrogen (BUN), creatinine, -hCG, and AFP are the recommended laboratory studies.

Imaging Studies

Ultrasound

Testicular ultrasound with color-flow Doppler is the mainstay for initial diagnosis of a testicular tumor to confirm physical findings

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or their absence. It should be performed in any patient in whom a testicular tumor is suspected. On occasion, surgical exploration will be necessary if a tumor cannot be ruled out by other means.

Computed Tomography Scan

Computed tomography (CT) scans of the abdomen and chest are the most effective imaging studies for metastatic evaluation. False-negative abdominal scans are not uncommon if nodal involvement measures less than 2 cm.

Metastatic Workup

After the diagnosis is confirmed by radical inguinal orchiectomy, further studies should include repeated markers for hCG (wait 1 week) and AFP (wait 4 weeks) and CT of the chest and abdomen. Note that staging accuracy is only 70% to 80%.

Treatment

Treatment strategies are based on the tumor's natural history (i.e., growth rate, pattern of spread, and radio- or chemosensitivity) and the clinical stage (i.e., nodal involvement and markers). A radical inguinal orchiectomy is the primary management for all solid testicular tumors. It confirms the diagnosis with pathologic identification of the histologic cell type and affords excellent local control. A retroperitoneal lymph node dissection (RPLND) has both staging and therapeutic value for selected patients with nonseminomatous tumors and spread to regional lymphatics. A limited nerve-sparing dissection can be used to preserve seminal emission in selected stage A patients with no gross disease on RPLND. Further treatment is based on the exquisite radiosensitivity of seminomas and the chemosensitivity of nonseminomas. Management of testicular cancer requires a team approach, including surgeon, medical oncologist, and radiation oncologist.

Seminomas

All patients receive a radical inguinal orchiectomy for diagnosis and local control. Because of the exquisite radiosensitivity of seminomas, external-beam radiotherapy continues to be the mainstay of treatment after orchiectomy for patients with low-volume retroperitoneal nodal involvement. Patients with high-volume

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retroperitoneal involvement or distant metastatic disease are managed with platinum-based chemotherapy.

Stage I: Tumor Confined to Scrotum

Radiation therapy (25 Gy) is delivered to periaortic and ipsilateral pelvic and inguinal lymph nodes. Supradiaphragmatic irradiation is not recommended. Five-year survival is 95%. Recent studies suggest that surveillance protocols may be offered to patients with stage I pure seminoma when the primary tumor is smaller than 6 cm, there is no vascular invasion, and -hCG is normal. Patients whose disease relapses can usually be salvaged with chemotherapy.

Stage II: Tumor Confined to Retroperitoneum

Patients with stage II disease smaller than 5 cm confined to the retroperitoneum can be managed with 30 to 35 Gy of radiation, with a 5-year survival of approximately 80%. Patients with bulky retroperitoneal masses larger than 5 cm (N3) should receive primary platinum-based chemotherapy.

Stage III: Distant Metastatic Disease

Primary platinum-based chemotherapy is recommended.

Nonseminomas

Radiation therapy is ineffective against nonseminomas. Primary multidrug combination chemotherapy has been playing an ever-increasing role in nonseminomatous germ cell tumors, whereas the role of RPLNDs has been increasingly questioned. Approximately 50% to 70% of patients with nonseminomas will have metastatic disease at the time of diagnosis. The modified Einhorn regimen [cis-platinum, etoposide, and bleomycin (PEB)] is the preferred regimen for initial chemotherapy of patients with disseminated germ cell tumors. All patients receive an inguinal orchiectomy for diagnosis and local control. Close posttreatment follow-up is necessary to salvage those whose disease relapses (10% 20%). Salvage rate approaches 90%.

Stage I: Tumor Confined to Scrotum

Treatment of patients with clinical stage I (T1 T3, N0, M0) disease includes surveillance therapy, primary chemotherapy, or a staging and therapeutic RPLND followed by observation, or chemotherapy with BEP (two cycles) for those found to have nodal spread (25%). Because only 25% of stage I patients have pathologic disease found on RPLND, the surveillance option has

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been offered in appropriate cases in the hope of avoiding RPLND (see Surveillance Therapy).

Stage II: Tumor Confined to Retroperitoneum

Primary chemotherapy is increasingly used for patients with stage II disease. An RPLND is an option for patients with clinical evidence of low volume (N2) nodal disease followed by chemotherapy with BEP (two cycles).

Stage III: Distant Metastatic Disease

Patients with distant metastatic disease should have primary chemotherapy with PEB (three to four cycles). Use of RPLND for patients with bulky residual tumor after chemotherapy is unclear. Postchemotherapy masses are found to be fibrous tissue (40%), mature teratoma (40%), or persistent viable tumor (20%).

Salvage Chemotherapy

PEI (cis-platinum, etoposide, and ifosfamide) is the recommended regimen for relapse after standard PEB.

Complications of RPLND

Complications of RPLND include mortality of less than 1% and morbidity of 5% to 35%. Loss of seminal emission occurs in 75% of cases in which nerve-sparing technique is not used. Complication rates are greater with RPLND for postchemotherapy residual masses.

Surveillance Therapy

Surveillance therapy (e.g., radical orchiectomy followed by rigorous periodic reassessment, including tumor markers, chest radiograph, and CT scan every 2 3 months for the first 2 years) has been proposed for early-stage disease (pTis or pT1 and cN0) because of the complications of RPLND and the high salvage rates with chemotherapy and because only 25% of patients with clinical stage I disease have pathologic nodal spread. However, this should be undertaken with caution and only in highly controlled and structured follow-up programs. Surveillance programs report a 28% relapse rate; of these patients, 7% succumb to the disease.