Lawrence H. Einhorn
I. EPIDEMIOLOGY AND ETIOLOGY
A. Epidemiology
1. Incidence. Testicular cancer constitutes only 1% of all cancers in men but is the most common malignancy that develops in men between the ages of 20 and 40 years. About 8,000 new cases are diagnosed annually in the United States.
2. Racial predilection. The incidence of testicular cancer in blacks is one-sixth that in whites. Asians also have a lower incidence than whites.
3. Bilateral cancer of the testis occurs in about 2% of cases.
B. Etiology
1. Cryptorchidism. Male patients with cryptorchidism are 10 to 40 times more likely to develop testicular carcinoma than are those with normally descended testes. The risk for developing cancer in a testis is 1 in 80 if retained in the inguinal canal and 1 in 20 if retained in the abdomen. Surgical placement of an undescended testis into the scrotum before 6 years of age reduces the risk for cancer. However, 25% of cancers in patients with cryptorchidism occur in the normal, descended testis.
2. Testicular feminization syndromes increase the risk for cancer in the retained gonad by 40-fold. Tumors in these patients are often bilateral.
3. Other risk factors. The magnitude of other suggested risk factors, such as a history of orchitis, testicular trauma, or irradiation, is not known.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Immunophenotypes of germ cell tumors are shown in Appendix C.4.VI.
1. Nearly all cancers of the testis in members of the younger age groups originate from germ cells (seminoma, embryonal cell, teratoma, and others). Other types, which account for <5% of cases, include rhabdomyosarcoma, lymphoma, and melanoma. Rarely, Sertoli cell tumors, Leydig cell tumors, or other mesodermal tumors develop.
2. In men >60 years of age, 75% of neoplasms are not germinal cancers. Lymphomas are the most common testicular tumors in this age group.
3. Metastatic cancer to the testis is most often associated with small cell lung cancer, melanoma, or leukemia.
B. Histogenesis. Each type of germinal cancer is thought to be a counterpart of normal embryonic development (Fig. 12.1). Seminoma is the neoplastic counterpart of the spermatocyte. The tissues of the early cleavage stage are the most undifferentiated and pluripotential and give rise to both the embryo and the placenta; the malignant counterpart is embryonal cell carcinoma. Teratomas are the neoplastic counterparts of the developing embryo. Choriocarcinoma is actually a more highly undifferentiated cancer; its aggressive biologic behavior reflects the capacity of its normal counterpart (the placenta) to invade blood vessels. The histologic similarity between germ cell cancer and normal embryology is illustrated by the following observations:
1. Pure choriocarcinomas usually metastasize only as choriocarcinomas, especially hematogenous. However, patients with pure choriocarcinoma in the orchiectomy specimen can have tumors in retroperitoneum comprised of both choriocarcinoma and teratoma.
Figure 12.1. Histogenesis of testicular neoplasms. Embryonic counterparts and tumor marker production are shown. (hCG, human chorionic gonadotropin; AFP, α-fetoprotein)
2. Seminomas usually metastasize as seminomas; those that do not are believed to represent mixed tumors undetected on the original histologic examination.
3. Metastases from embryonal carcinomas may be found to consist of teratoma or choriocarcinoma elements.
4. In metastases from mixed tumors, chemotherapy destroys the rapidly growing, drug-sensitive cell elements. The drug-resistant teratomatous elements persist after chemotherapy and require surgical resection.
C. Natural history. The natural history of testis cancer varies with the histologic subtype. Both blood-borne and lymphatic metastases occur. Lymphatic drainage usually occurs in an orderly progression. A right-sided primary will spread lymphatically to the interaortocaval nodes and a left-sided primary to paraaortic retroperitoneal nodes. Previous surgery, such as scrotal contamination with scrotal orchiectomy, disrupts normal lymphatic drainage patterns and can cause inguinal nodal metastases.
1. Seminoma (40% to 50% of testicular cancers) occurs in an older age group than other germ cell neoplasms, most commonly after the age of 30 years. Sixty percent of patients with cryptorchidism who develop testicular cancer have seminoma. Seminomas tend to be large, show little hemorrhage or necrosis on gross inspection, and metastasize in an orderly, sequential manner along draining lymph node chains. About 25% of patients have lymphatic metastases, and 1% to 5% have visceral metastases at the time of diagnosis. Metastases to parenchymal organs (usually lung or bone) can occur late. Seminoma is the type of testicular cancer most likely to produce osseous metastases.
a. Spermatocytic seminoma (4% of seminomas) occurs mostly after the age of 50 years and is the most common germ cell tumor after the age of 70 years. It is more often bilateral (6% compared with 2%) and appears to have a much lower incidence of both lymphatic and parenchymal metastases (even to draining lymph nodes) when compared with typical seminoma. These patients are usually cured with orchiectomy alone.
2. Pure choriocarcinoma (<0.5% of testicular cancers) metastasizes rapidly through the bloodstream to lungs, liver, brain, and other visceral sites. They have very high serum human chorionic gonadotropin (hCG) levels with normal α-fetoprotein (AFP) levels.
3. Yolk sac tumors are common cancers in children and have a relatively unaggressive clinical course. Yolk sac elements in testicular cancer found in adult patients, on the other hand, portend a worse prognosis compared with that of children. Pure yolk sac tumors have elevated AFP and normal hCG.
4. Embryonal cell carcinoma can be associated with elevated serum hCG, AFP, both, or neither tumor marker. When patients have clinical stage I testicular cancer with predominantly embryonal cell carcinoma, they are more likely to have occult microscopic disease in the retroperitoneum or elsewhere. Vascular invasion also predicts metastatic spread.
5. Teratoma appears pathologically inert as it is associated with cartilage, glandular, and glial tissue. Teratoma of and by itself usually does not have the capacity to metastasize, but it is often associated with embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and seminoma in the testis and can metastasize as a template. In that situation, chemotherapy will often completely eliminate the nonteratomatous elements, but the teratoma will remain and require surgical resection for cure. When teratoma remains after chemotherapy, it can and will grow by local extension and can even cause death from teratoma alone. In addition, because teratoma is pluripotential tissue that can differentiate along endodermal, ectodermal, or mesoderm elements, it can undergo malignant transformation. The most common of these is mesodermal differentiation to sarcomatous elements associated with teratoma. Malignant transformation of teratoma does have the potential to metastasize. These elements can sometimes briefly respond to chemotherapy directed at the dominant cell type of malignant transformation.
6. Rare testicular tumors
a. Sertoli cell and Leydig cell tumors are not germ cell tumors and are not associated with elevated serum hCG or AFP. They vary in malignant potential, but all can metastasize. Size, necrosis, and mitotic index predict potential for spread and need for retroperitoneal lymph node dissection. Leydig cell tumors rarely respond to chemotherapy. Sertoli cell tumors may benefit from platinum combination chemotherapy. These tumors are inhibin positive on immunohistochemical stain.
b. Rhabdomyosarcoma of the testis occurs most often before 20 years of age. Its clinical behavior is similar to that of embryonal carcinoma; metastases to draining lymph nodes and lung are common at the time it first appears. They are usually paratesticular.
III. DIAGNOSIS
A. Symptoms and signs. Postorchiectomy, most patients will have an otherwise normal history and physical examination.
1. Symptoms
a. Mass and pain. The most common symptom of testicular cancer is a painless enlargement, usually noticed during bathing or after a minor trauma. Painful enlargement of the testis occurs in 30% to 50% of patients and may be the result of bleeding or infarction in the tumor. Acute pain in a patient with a cryptorchid testis suggests the possibility of torsion of a testicular cancer.
b. Acute epididymitis. Nearly 25% of patients with mixed teratoma and embryonal cell tumor present with findings indistinguishable from acute epididymitis. The testicular swelling from tumor may even decrease somewhat after antimicrobial therapy.
c. Gynecomastia due to high levels of serum hCG is rarely a presenting sign.
d. Infertility is the primary symptom in about 3% of patients.
e. Back pain from retroperitoneal node metastases is a presenting feature in 10% of patients.
f. Other presenting symptoms. Thoracic symptoms are rare even when extensive pulmonary metastases are present. When there is extensive replacement of pulmonary parenchyma, patients may develop hemoptysis, chest pain, or dyspnea.
2. Physical findings
a. Scrotum. A testicular mass is nearly always present. The testis should be palpated using bimanual technique; the finding of irregularity, induration, or nodularity is indication for further evaluation, including a testicular ultrasound to look for a hypoechogenic mass.
b. Lymph nodes. Patients must be carefully examined for lymphadenopathy, particularly in the supraclavicular region. Scrotal contamination, such as following testicular biopsy, vasectomy, or herniorrhaphy, alters the normal lymphatic drainage; as a result, ipsilateral inguinal nodes may become involved. Large retroperitoneal masses may be palpable on abdominal examination.
c. Breasts. Gynecomastia is associated with tumors that secrete high levels of hCG.
B. Differential diagnosis
1. Hydroceles are usually benign, but about 10% of testicular cancers are associated with coexisting hydroceles. The finding of a hydrocele in a young man should increase suspicion for an associated neoplasm.
a. Benign hydroceles extend along the spermatic cord, often cause groin swelling, and can give the penis a foreshortened appearance. Hydroceles can be transilluminated.
b. If the fluid prevents adequate palpation of the testis, a testicular ultrasound should be performed.
2. Epididymitis produces acute enlargement of the testis with severe pain, fever, dysuria, and pyuria. The same symptoms may be caused by an underlying testicular cancer.
a. Persistent pain or swelling after treatment may result from a supervening testicular abscess or a coexisting tumor; testicular ultrasound is indicated.
b. Recurrent epididymitis with a completely normal testis occasionally occurs. Surgical exploration should not be considered if physical examination between episodes is completely normal and there is no evidence of a tumor on testicular ultrasound. Recurrent epididymitis per se does not necessarily indicate cancer.
3. Varicoceles are swollen veins in the pampiniform plexus of the spermatic cord. The scrotum feels like it contains a “bag of worms.” The veins collapse when the patient is in Trendelenburg position.
4. Spermatoceles are translucent masses that are located posterior and superior to the testis, and feel cystic.
5. Inguinal hernias generally are not a diagnostic problem.
6. Other masses include gummatous and tuberculous orchitis, hematoma, and acute swelling from testicular torsion. None of these can be distinguished clinically from cancer, and all require exploratory surgery.
C. Tumor markers are the most crucial and sensitive indicators of testicular cancer (Fig. 12.1). Serum hCG and AFP are the quintessential markers in oncology. One or both of these serum markers are present in more than 90% of patients with metastatic nonseminomatous germ cell cancer of the testis. The incidence rates of these markers according to tumor histology are shown in Table 12.1.
1. hCG is markedly elevated with pure choriocarcinoma and also elevated in embryonal cell carcinoma and may be mildly elevated in patients with pure seminoma. The blood half-life of hCG is 18 to 24 hours.
a. hCG may also be found in patients with a variety of other tumors, including melanoma, large cell lung cancer, breast, ovary, or pancreatic cancer.
b. Nonmalignant conditions associated with elevated hCG levels may occur with marijuana use or with testicular dysfunction due to cross-reactivity with luteinizing hormone. This may occasionally occur after chemotherapy. A repeat serum hCG level 2 weeks after the administration of 300 mg of depotestosterone intramuscularly will resolve this dilemma.
c. In testicular cancer, a rising hCG after orchiectomy constitutes proof that the patient has residual cancer and requires further treatment. The absence of hCG, however, does not exclude the presence of active cancer, particularly in previously treated patients.
2. AFP is produced by yolk sac elements and is most commonly associated with embryonal carcinomas and yolk sac tumors. Elevated levels of AFP are never found in patients with pure seminoma or pure choriocarcinoma. The blood half-life of AFP is 5 days, but may be much longer after successful chemotherapy.
a. Elevated levels may also be explained by hepatocellular carcinoma, other cancers (occasionally), fetal hepatic production in pregnant women, infancy, and nonmalignant liver diseases (e.g., hepatitis, cirrhosis, necrosis).
b. Rising levels of AFP after surgery or cytotoxic agent therapy for testicular cancer indicate the presence of residual disease and the need for further therapy.
Table 12.1 Incidence of Tumor Markers in Testicular Cancers
hCG, human chorionic gonadotropin; AFP, α-fetoprotein.
D. Laboratory evaluation
1. Routine preoperative studies
a. Complete blood count, liver function tests (especially lactate dehydrogenase [LDH] and alkaline phosphatase levels), and renal function tests.
b. Chest radiograph, including posteroanterior (PA) and lateral projections.
c. Blood levels of hCG and AFP.
2. Routine postoperative studies are undertaken after the diagnosis of testicular cancer is proved. Studies performed in patients with all cell types include the following:
a. Chest computed tomography (CT) scan can detect occult posterior mediastinal or pulmonary parenchymal metastases. This is not usually a necessary test if the PA and lateral chest x-rays are abnormal.
b. Abdominal and pelvic CT scans assist assessment of retroperitoneal or rarely pelvic adenopathy.
c. Positron emission tomography (PET scan) is never indicated in the initial staging. It can be of assistance in deciding the necessity of postchemotherapy surgery, especially in patients with pure seminoma. A PET scan will not be “positive” when a residual mass is teratoma, and it will not detect microscopic disease.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system and survival. The system presented is a pathologic staging system for nonseminomatous tumors, for which lymphadenectomy is a standard practice. The system is also used for clinical staging of seminomas, for which lymph node sampling is not part of management.
The survival statistics for testicular tumors have been drastically altered by modern therapy. The 5-year survival rate in patients with seminoma treated with radiation therapy (RT) alone is 95% to 99% for stage A disease and 80% to 90% for stage B; most patients with stage C disease are cured with chemotherapy. The 5-year survival rate in patients with stage C nonseminomatous tumors is 70% to 80%.
B. Prognostic factors
1. Elevated serum levels of AFP or hCG after orchiectomy is prima facie evidence that the patient has residual cancer. However, therapy should not be initiated until there is a rising AFP or hCG.
2. Serum LDH levels correlate fairly well with tumor burden.
3. Nonseminomatous tumor patients receiving chemotherapy are categorized as having advanced (poor-risk) disease, with a 50% cure rate in the presence of
a. Very high markers (serum hCG >50,000 IU/mL, AFP >10,000 ng/mL) or LDH levels >10 times the upper limits of normal
b. Nonpulmonary visceral metastases (such as liver, bone, or CNS)
c. Primary mediastinal nonseminomatous germ cell tumors
V. PREVENTION AND EARLY DETECTION. Cryptorchidism should be surgically corrected before puberty, usually before age 4 years, because the risk for malignancy is substantial. Prophylactic removal of undescended testes should be performed in postpubertal patients; the complication rate is minuscule, the testes are functionless, and prostheses are available to fill the empty scrotum.
The effectiveness of early detection by screening programs has not been tested. Most patients have symptoms or signs of a scrotal mass; few cases are detected by routine history and physical examination.
VI. MANAGEMENT
A. Transinguinal orchiectomy is performed to make the diagnosis for all testicular cancers in all stages and is the treatment for stage A disease. A transinguinal approach is essential; the blood supply of the spermatic cord is immediately controlled. Transscrotal orchiectomy has been proved to result in tumor seeding to the scrotum and inguinal nodes. Likewise, transscrotal needle biopsy of a suspected testicular mass is absolutely contraindicated.
The subsequent management of early-stage testicular tumors depends on whether the histopathology shows pure seminoma or nonseminomatous elements.
B. Management of seminomas: Stages A and B
1. Surgery. No further surgery is necessary after orchiectomy.
2. RT. Abdominal CT and often chest CT are performed postoperatively in patients with seminoma. Most patients with clinical stage A seminoma should be managed with surveillance. Other options are RT or one dose of carboplatin. RT is preferred in patients with stage B seminoma with lymph nodes that are <3 cm in diameter.
3. Chemotherapy with single-agent carboplatin (target AUC = 7) has been found to be equivalent to RT for clinical stage A seminoma. Patients with bulky stage B (>3 cm disease) or stage C disease are treated the same as those with nonseminomatous germ cell cancer, and the results are similar (see Section VI.D). Seminoma confers a favorable prognosis because none of these cases, even those with nonpulmonary visceral disease, is classified as poor-risk disease. Results with salvage chemotherapy are better for seminomatous than nonseminomatous patients.
4. Surveillance. The cure rate with orchiectomy alone for clinical stage A seminoma is 80% to 85%. Therefore, surveillance (vide infra) is the preferred option in compliant patients, thus avoiding serious late consequences of RT.
C. Management of nonseminomatous germ cell cancer: Stages A and B
1. Surgery. Retroperitoneal lymph node dissection (RPLND) is the standard of practice at most centers in the United States for stage B disease when staging evaluation does not reveal distant metastases, and when there is no lymph node with a maximal transverse diameter of 3 cm on abdominal CT and postorchiectomy hCG and AFP are normal. If lymph node metastases are demonstrated at surgery, patients either may be treated with two courses of adjuvant chemotherapy or observed without treatment and achieve the same nearly 100% cure rate. Lymphadenectomy previously interrupted the sympathetic pathways and invariably resulted in sterility from failure of ejaculation, but not impotence. Modern nerve-sparing retroperitoneal lymph node dissections, however, now routinely preserve fertility and allow antegrade ejaculation. Options for stage A include surveillance, RPLND, or primary chemotherapy.
2. Chemotherapy. The agents used are discussed in Section VI.D. Indications for chemotherapy include the following:
a. Rising serum levels of hCG or AFP after primary treatment or elevated levels of hCG or AFP with normal abdominal CT scan.
b. The presence of bulky retroperitoneal disease (>3 cm in maximal transverse diameter of a node on abdominal CT) requires chemotherapy. If the abdominal CT scan becomes normal, retroperitoneal lymphadenectomy is not necessary. Otherwise, postchemotherapy retroperitoneal lymph node dissection is usually performed.
c. A recent phase III study comparing one course of bleomycin and etoposide and cisplatin (BEP; see Section VI.D.1) with RPLND demonstrated superiority for chemotherapy for clinical stage A disease, with a relapse rate of only 1%.
3. Surveillance is an appropriate strategy for compliant patients with clinical stage A disease (normal markers, physical examination, and radiographic studies after orchiectomy). It is crucial that both the physician and the patient understand the necessity for close observation. Relapses are usually treated with chemotherapy. Surveillance is even appropriate in high-risk clinical stage A disease (embryonal predominant, and vascular invasion).
If surveillance is chosen, history and physical examinations, serum markers, and chest radiographs (PA and lateral views) are obtained every 2 months during the first year. The same studies are obtained every 4 months during the second year, every 6 months during the third, fourth, and fifth years after orchiectomy, and then annually. Abdominal CT is performed every 4 months during the first and second years, and then every 6 months during the third, fourth, and fifth years.
D. Management of disseminated disease: Stage C
1. Combination chemotherapy with etoposide and cisplatin (EP regimen) or with EP plus bleomycin (BEP regimen) produces complete remission in 70% to 80% of patients. Complete remissions are obtained with all cell types and are long lasting. Relapses may occur within 1 year of initiating therapy. Maintenance chemotherapy after achieving a complete remission is not necessary.
a. Standard chemotherapy for good-risk patients is either BEP for three courses or EP for four courses. Patients with poor-risk (advanced) disease are treated with four courses of BEP.
b. BEP is administered every 3 weeks for three or four cycles. Dosages are as follows:
Bleomycin, 30 U IV weekly on days 1, 8, and 15
Etoposide, 100 mg/m2 IV daily for 5 days
Cisplatin, 20 mg/m2 IV daily for 5 days
2. Resection of residual disease. After completion of chemotherapy, patients who do not achieve a complete remission are candidates for surgical resection of the residual localized disease in the chest or retroperitoneum. Radiologic findings cannot distinguish benign from malignant processes in these patients. PET scans can sometimes be helpful, but should not be used to dissuade the clinician from recommending surgery as normal PET scans are seen in the presence of microscopic cancer or gross teratoma.
a. The presence of elevated levels of tumor markers always signifies the continued presence of carcinoma and the need for further chemotherapy. The absence of tumor markers signifies that the residual disease in the thorax or retroperitoneum is a benign process (fibrosis, inflammation), teratoma, or carcinoma.
b. Surgical resection of residual disease defines the subsequent treatment strategy in all of these patients and is therapeutic in some.
(1) If surgical resection of residual disease reveals fibrosis or teratoma, no further treatment is required. Follow-up CT scans are indicated after resection of teratoma, as microscopic teratoma may have been present outside the surgical field.
(2) If surgical resection reveals carcinoma, usually two more cycles of EP therapy are given.
3. Salvage chemotherapy. Patients who do not achieve a complete remission with BEP are still curable with salvage chemotherapy. Options include cisplatin plus ifosfamide plus either vinblastine or paclitaxel followed by high-dose chemotherapy with peripheral blood stem cell transplant or four courses of a cisplatin–ifosfamide combination triplet regimen. Occasionally patients may be cured with a nonplatinum salvage regimen such as paclitaxel plus gemcitabine, even after progression following high-dose chemotherapy.
VII. SPECIAL CLINICAL PROBLEMS
A. Gynecomastia and elevated blood hCG levels are occasionally found in patients with clinically normal testes and no other evidence of cancer. A number of other cancers can also produce hCG. Patients should be evaluated with ultrasonography of the testes and CT of the abdomen and chest. Thereafter, it is best to follow such patients clinically until there is demonstrable cancer or rising hCG levels. Blind or random biopsies in this setting are not likely to reveal a diagnosis, can expose patients to unnecessary morbidity, and are contraindicated.
B. Extragonadal germ cell neoplasms can occur in any anatomic site through which the normal germ cells migrate in the embryo. Such sites include the pineal gland, anterior mediastinum, and middle retroperitoneal areas. Tumor markers (hCG and AFP) should be measured. Chemotherapy with BEP should be used for nonseminomatous germ cell cancers. Results of treatment are less successful for primary mediastinal nonseminomatous germ cell tumors. Etoposide (VP-16) plus ifosfamide plus cisplatin (VIP) is preferred for such patients as it mitigates postoperative complications due to bleomycin.
C. Solitary mediastinal or retroperitoneal masses with undifferentiated histology may represent germ cell cancer. Diagnosis by histopathology may be problematic. A reasonable approach would be to treat the patient for disseminated nonseminomatous germ cell cancer. Mediastinal germ cell tumors are discussed in Chapter 19, Section I.B.4.
Suggested Reading
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