Testicular cancer

Testicular Cancer

(From Harrison's Principle of Internal Medicine, 17th Ed)

Introduction

Primary germ cell tumors (GCTs) of the testis, arising by the malignant transformation of primordial germ cells, constitute 95% of all testicular neoplasms. Infrequently, GCTs arise from an extragonadal site, including the mediastinum, retroperitoneum, and, very rarely, the pineal gland. This disease is notable for the young age of the afflicted patients, the totipotent capacity for differentiation of the tumor cells, and its curability; about 95% of newly diagnosed patients are cured. Experience in the management of GCTs leads to improved outcome.

Incidence and Epidemiology

In 2007, 7920 new cases of testicular GCT were diagnosed in the United States; the incidence is decreasing after having increased slowly over the past 40 years. The tumor occurs most frequently in men between the ages of 20 and 40. A testicular mass in a male > 50 years should be regarded as a lymphoma until proved otherwise. GCT is at least four to five times more common in white than in African-American males, and a higher incidence has been observed in Scandinavia and New Zealand than in the United States.

Etiology and Genetics

Cryptorchidism is associated with a severalfold higher risk of GCT. Abdominal cryptorchid testes are at a higher risk than inguinal cryptorchid testes. Orchiopexy should be performed before puberty, if possible. Early orchiopexy reduces the risk of GCT and improves the ability to save the testis. An abdominal cryptorchid testis that cannot be brought into the scrotum should be removed. About 2% of men with GCTs of one testis will develop a primary tumor in the other testis. Testicular feminization syndromes increase the risk of testicular GCT, and Klinefelter's syndrome is associated with mediastinal GCT.

An isochromosome of the short arm of chromosome 12 [i(12p)] is pathognomonic for GCT of all histologic types. Excess 12p copy number, either in the form of i(12p) or as increased 12p on aberrantly banded marker chromosomes, occurs in nearly all GCTs, but the gene(s) on 12p involved in the pathogenesis are not yet defined.

Clinical Presentation

A painless testicular mass is pathognomonic for a testicular malignancy. More commonly, patients present with testicular discomfort or swelling suggestive of epididymitis and/or orchitis. In this circumstance, a trial of antibiotics is reasonable. However, if symptoms persist or a residual abnormality remains, then testicular ultrasound examination is indicated.

Ultrasound of the testis is indicated whenever a testicular malignancy is considered and for persistent or painful testicular swelling. If a testicular mass is detected, a radical inguinal orchiectomy should be performed. Because the testis develops from the gonadal ridge, its blood supply and lymphatic drainage originate in the abdomen and descend with the testis into the scrotum. An inguinal approach is taken to avoid breaching anatomic barriers and permitting additional pathways of spread.

Back pain from retroperitoneal metastases is common and must be distinguished from musculoskeletal pain. Dyspnea from pulmonary metastases occurs infrequently. Patients with increased serum levels of human chorionic gonadotropin (hCG) may present with gynecomastia. A delay in diagnosis is associated with a more advanced stage and possibly worse survival.

The staging evaluation for GCT includes a determination of serum levels of fetoprotein (AFP), hCG, and lactate dehydrogenase (LDH). After orchiectomy, a chest radiograph and a CT scan of the abdomen and pelvis should be performed. A chest CT scan is required if pulmonary nodules or mediastinal or hilar disease is suspected. Stage I disease is limited to the testis, epididymis, or spermatic cord. Stage II disease is limited to retroperitoneal (regional) lymph nodes. Stage III disease is disease outside the retroperitoneum, involving supradiaphragmatic nodal sites or viscera. The staging may be "clinical"—defined solely by physical examination, blood marker evaluation, and radiographs—or "pathologic"—defined by an operative procedure.

The regional draining lymph nodes for the testis are in the retroperitoneum, and the vascular supply originates from the great vessels (for the right testis) or the renal vessels (for the left testis). As a result, the lymph nodes that are involved first by a right testicular tumor are the interaortocaval lymph nodes just below the renal vessels. For a left testicular tumor, the first involved lymph nodes are lateral to the aorta (para-aortic) and below the left renal vessels. In both cases, further nodal spread is inferior, contralateral, and, less commonly, above the renal hilum. Lymphatic involvement can extend cephalad to the retrocrural, posterior mediastinal, and supraclavicular lymph nodes. Treatment is determined by tumor histology (seminoma versus nonseminoma) and clinical stage (Table 1).

Table 1 Germ Cell Tumor Staging and Treatment

Treatment Stage Extent of Disease Seminoma Nonseminoma IA Testis only, no vascular/lymphatic invasion (T1) Radiation therapy RPLND or observation IB Testis only, with vascular/lymphatic invasion (T2), or extension through tunica albuginea (T2), or involvement of spermatic cord (T3) or scrotum (T4) Radiation therapy RPLND IIA Nodes <> Radiation therapy RPLND or chemotherapy often followed by RPLND IIB Nodes 2–5 cm Radiation therapy RPLND +/– adjuvant chemotherapy or chemotherapy followed by RPLND IIC Nodes > 5 cm Chemotherapy Chemotherapy, often followed by RPLND III Distant metastases Chemotherapy Chemotherapy, often followed by surgery (biopsy or resecti

Pathology

GCTs are divided into nonseminoma and seminoma subtypes. Nonseminomatous GCTs are most frequent in the third decade of life and can display the full spectrum of embryonic and adult cellular differentiation. This entity comprises four histologies: embryonal carcinoma, teratoma, choriocarcinoma, and endodermal sinus (yolk sac) tumor. Choriocarcinoma, consisting of both cytotrophoblasts and syncytiophoblasts, represents malignant trophoblastic differentiation and is invariably associated with secretion of hCG. Endodermal sinus tumor is the malignant counterpart of the fetal yolk sac and is associated with secretion of AFP. Pure embryonal carcinoma may secrete AFP or hCG, or both; this pattern is biochemical evidence of differentiation. Teratoma is composed of somatic cell types derived from two or more germ layers (ectoderm, mesoderm, or endoderm). Each of these histologies may be present alone or in combination with others. Nonseminomatous GCTs tend to metastasize early to sites such as the retroperitoneal lymph nodes and lung parenchyma. One-third of patients present with disease limited to the testis (stage I), one-third with retroperitoneal metastases (stage II), and one-third with more extensive supradiaphragmatic nodal or visceral metastases (stage III).

Seminoma represents about 50% of all GCTs, has a median age in the fourth decade, and generally follows a more indolent clinical course. Most patients (70%) present with stage I disease, about 20% with stage II disease, and 10% with stage III disease; lung or other visceral metastases are rare. Radiation therapy is the treatment of choice in patients with stage I disease and stage II disease where the nodes are <5>

Tumor Markers

Careful monitoring of the serum tumor markers AFP and hCG is essential in the management of patients with GCT, as these markers are important for diagnosis, as prognostic indicators, in monitoring treatment response, and in the detection of early relapse. Approximately 70% of patients presenting with disseminated nonseminomatous GCT have increased serum concentrations of AFP and/or hCG. While hCG concentrations may be increased in patients with either nonseminoma or seminoma histology, the AFP concentration is increased only in patients with nonseminoma. The presence of an increased AFP level in a patient whose tumor shows only seminoma indicates that an occult nonseminomatous component exists and the patient should be treated for nonseminomatous GCT. LDH levels are not as specific as AFP or hCG but are increased in 50–60% patients with metastatic nonseminoma and in up to 80% of patients with advanced seminoma.

AFP, hCG, and LDH levels should be determined before and after orchiectomy. Increased serum AFP and hCG concentrations decay according to first-order kinetics; the half-life is 24–36 h for hCG and 5–7 days for AFP. AFP and hCG should be assayed serially during and after treatment. The reappearance of hCG and/or AFP or the failure of these markers to decline according to the predicted half-life is an indicator of persistent or recurrent tumor.

Treatment

Stage I Nonseminoma

If, after an orchiectomy (for clinical stage I disease), radiographs and physical examination show no evidence of disease and serum AFP and hCG concentrations are either normal or declining to normal according to the known half-life, patients may be managed by either a nerve-sparing retroperitoneal lymph node dissection (RPLND) or surveillance. The retroperitoneal lymph nodes are involved by GCT (pathologic stage II) in 20–50% of these patients. The choice of surveillance or RPLND is based on the pathology of the primary tumor. If the primary tumor shows no evidence for lymphatic or vascular invasion and is limited to the testis (T1), then either option is reasonable. If lymphatic or vascular invasion is present or the tumor extends into the tunica, spermatic cord, or scrotum (T2 through T4), then surveillance should not be offered. Either approach should cure >95% of patients.

RPLND is the standard operation for removal of the regional lymph nodes of the testis (retroperitoneal nodes). The operation removes the lymph nodes ipsilateral to the primary site and the nodal groups adjacent to the primary landing zone. The standard (modified bilateral) RPLND removes all node-bearing tissue down to the bifurcation of the great vessels, including the ipsilateral iliac nodes. The major long-term effect of this operation is retrograde ejaculation and infertility. Nerve-sparing RPLND, usually accomplished by identification and dissection of individual nerve fibers, may avoid injury to the sympathetic nerves responsible for ejaculation. Normal ejaculation is preserved in ~90% of patients. Patients with pathologic stage I disease are observed, and only the <10%>

RPLND, then a decision regarding adjuvant chemotherapy is made on the basis of the extent of retroperitoneal disease (see below).

Surveillance is an option in the management of clinical stage I disease when no vascular/lymphatic invasion is found (T1). Only 20–30% of patients have pathologic stage II disease, implying that most RPLNDs in this situation are not therapeutic. Surveillance and RPLND lead to equivalent long-term survival rates. Patient compliance is essential if surveillance is to be successful. Patients must be carefully followed with periodic chest radiography, physical examination, CT scan of the abdomen, and serum tumor marker determinations. The median time to relapse is about 7 months, and late relapses (>2 years) are rare. The 70–80% of patients who do not relapse require no intervention after orchiectomy; treatment is reserved for those who do relapse. When the primary tumor is classified as T2 through T4 (extension beyond testis and epididymis or lymphatic/vascular invasion is identified), nerve-sparing RPLND is preferred. About 50% of these patients have pathologic stage II disease and are destined to relapse without the RPLND.

Stage II Nonseminoma

Patients with limited, ipsilateral retroperitoneal adenopathy (nodes usually <3><2>and <6>>50% of patients with "high-volume" metastases (>6 nodes involved, or any involved node >2 cm in largest diameter, or extranodal tumor extension), two cycles of adjuvant chemotherapy should be considered, as it results in cure in >98% of patients. Regimens consisting of etoposide (100 mg/m² daily on days 1–5) plus cisplatin (20 mg/m² daily on days 1–5) with or without bleomycin (30 units per day on days 2, 9, and 16) given at 3-week intervals are effective and well tolerated.

Stages I and II Seminoma

Inguinal orchiectomy followed by retroperitoneal radiation therapy cures ~98% of patients with stage I seminoma. The dose of radiation therapy (2500–3000

cGy) is low and well tolerated, and the in-field recurrence rate is negligible. About 2% of patients relapse with supradiaphragmatic or systemic disease. Surveillance has been proposed as an option, and studies have shown that about 15% of patients relapse. The median time to relapse is 12–15 months, and late relapses (>5 years) may be more frequent than with nonseminoma. The relapse is usually treated with chemotherapy. Surveillance for clinical stage I seminoma is not recommended.

Nonbulky retroperitoneal disease (stage IIA and IIB) is also treated with radiation therapy. Prophylactic supradiaphragmatic fields are not used. Relapses in the anterior mediastinum are unusual. Approximately 90% of patients achieve relapse-free survival with retroperitoneal masses <5>

Chemotherapy for Advanced GCT

Regardless of histology, patients with stage IIC and stage III GCT are treated with chemotherapy. Combination chemotherapy programs based on cisplatin at doses of 100 mg/m² plus etoposide at doses of 500 mg/m² per cycle cure 70–80% of such patients, with or without bleomycin, depending on risk stratification (see below). A complete response (the complete disappearance of all clinical evidence of tumor on physical examination and radiography plus normal serum levels of AFP and hCG for >= 1 month) occurs after chemotherapy alone in ~60% of patients, and another 10–20% become disease-free with surgical resection of residual masses containing viable GCT. Lower doses of cisplatin result in inferior survival rates.

The toxicity of four cycles of the cisplatin/bleomycin/etoposide (BEP) regimen is substantial. Nausea, vomiting, and hair loss occur in most patients, although nausea and vomiting have been markedly ameliorated by modern antiemetic regimens. Myelosuppression is frequent, and symptomatic bleomycin pulmonary toxicity occurs in ~5% of patients. Treatment-induced mortality due to neutropenia with septicemia or bleomycin-induced pulmonary failure occurs in 1–3% of patients. Dose reductions for myelosuppression are rarely indicated. Long-term permanent toxicities include nephrotoxicity (reduced glomerular filtration and persistent magnesium wasting), ototoxicity, and peripheral neuropathy. When bleomycin is administered by weekly bolus injection, Raynaud's phenomenon appears in 5–10% of patients. Other evidence of small blood vessel damage is seen less often, including transient ischemic attacks and myocardial infarction.

Risk-Directed Chemotherapy

Because not all patients are cured and treatment may cause significant toxicities, patients are stratified into "good-risk" and "poor-risk" groups according to

pretreatment clinical features. For good-risk patients, the goal is to achieve maximum efficacy with minimal toxicity. For poor-risk patients, the goal is to identify more effective therapy with tolerable toxicity.

The International Germ Cell Cancer Consensus Group developed criteria to assign patients to three risk groups (good, intermediate, poor) (Table 2). The marker cut-offs have been incorporated into the revised TNM (primary tumor, regional nodes, metastasis) staging of GCT. Hence, TNM stage groupings are now based on both anatomy (site and extent of disease) and biology (marker status and histology). Seminoma is either good or intermediate risk, based on the absence or presence of nonpulmonary visceral metastases. No poor-risk category exists for seminoma. Marker levels play no role in defining risk for seminoma. Nonseminomas have good-, intermediate-, and poor-risk categories based on the site of the primary tumor, the presence or absence of nonpulmonary visceral metastases, and marker levels.

Table 2 IGCCCG Risk Classification for Advanced Germ Cell Tumors

Risk Nonseminoma Seminoma Good Gonadal or retroperitoneal primary site Any primary site Absent nonpulmonary visceral metastases AFP <> Beta-hCG <> LDH <> Absent nonpulmonary visceral metastases Any LDH, hCG Intermediate Gonadal or retroperitoneal primary site Any primary site Absent nonpulmonary visceral metastases AFP 1000–10,000 ng/mL Beta-hCG 5000–50,000 mIU/mL LDH 1.5–10 x ULN Presence of nonpulmonary visceral metastases Any LDH, hCG Poor Mediastinal primary site Presence of nonpulmonary visceral metastases AFP >=10,000 ng/ML Beta-hCG > 50,000 mIU/mL LDH > 10 x ULN No patients classified as poor prognosis

For ~90% of patients with good-risk GCTs, four cycles of etoposide plus cisplatin (EP) or three cycles of BEP produce durable complete responses, with minimal acute and chronic toxicity. Pulmonary toxicity is absent when bleomycin is not used and is rare when therapy is limited to 9 weeks; myelosuppression with neutropenic fever is less frequent; and the treatment mortality rate is negligible. About 75% of intermediate-risk patients and 45% of poor-risk patients achieve durable complete remission with four cycles of BEP, and no regimen has proved superior. More effective therapy is needed.

Postchemotherapy Surgery

Resection of residual metastases after the completion of chemotherapy is an integral part of therapy. If the initial histology is nonseminoma and the marker values have normalized, all sites of residual disease should be resected. In general, residual retroperitoneal disease requires a modified bilateral RPLND. Thoracotomy (unilateral or bilateral) and neck dissection are less frequently required to remove residual mediastinal, pulmonary parenchymal, or cervical nodal disease. Viable tumor (seminoma, embryonal carcinoma, yolk sac tumor, or choriocarcinoma) will be present in 15%, mature teratoma in 40%, and necrotic debris and fibrosis in 45% of resected specimens. The frequency of teratoma or viable disease is highest in residual mediastinal tumors. If necrotic debris or mature teratoma is present, no further chemotherapy is necessary. If viable tumor is present but is completely excised, two additional cycles of chemotherapy are given.

If the initial histology is pure seminoma, mature teratoma is rarely present, and the most frequent finding is necrotic debris. For residual retroperitoneal disease, a complete RPLND is technically difficult owing to extensive postchemotherapy fibrosis. Observation is recommended when no radiographic abnormality exists on CT scan. Positive findings on a positron emission tomography (PET) scan correlate with viable seminoma in residua, and mandate surgical excision or biopsy.

Salvage Chemotherapy

Of patients with advanced GCT, 20–30% fail to achieve a durable complete response to first-line chemotherapy. A combination of cisplatin, ifosfamide, and vinblastine (VeIP) will cure about 25% of patients as a second-line therapy. Substitution of paclitaxel for vinblastine may be more effective in this setting. Patients are more likely to achieve a durable complete response if they had a testicular primary tumor and relapsed from a prior complete remission to first-line cisplatin-containing chemotherapy. In contrast, if the patient failed to achieve a complete response or has a primary mediastinal nonseminoma, then standard-dose salvage therapy is rarely beneficial. Treatment options for such patients include dose-intensive treatment, experimental therapies, and surgical resection.

Chemotherapy consisting of dose-intensive, high-dose carboplatin (>= 1500 mg/m²) plus etoposide (>= 1200 mg/m²), with or without cyclophosphamide, or ifosfamide, with peripheral blood stem cell support, induces a complete response in 25–40% of patients who have progressed after ifosfamide-containing salvage chemotherapy. About one-half of the complete responses will be durable. High-dose therapy is the treatment of choice and standard of care for this patient population. Paclitaxel is also active in previously treated patients and shows promise in high-dose combination programs. Cure is still possible in some relapsed patients.

Extragonadal GCT and Midline Carcinoma of Uncertain Histogenesis

The prognosis and management of patients with extragonadal GCT depends on the tumor histology and site of origin. All patients with a diagnosis of extragonadal GCT should have a testicular ultrasound examination. Nearly all patients with retroperitoneal or mediastinal seminoma achieve a durable complete response to BEP or EP. The clinical features of patients with primary retroperitoneal nonseminoma GCT are similar to those of patients with a primary of testis origin, and careful evaluation will find evidence of a primary testicular GCT in about two-thirds of cases. In contrast, a primary mediastinal nonseminomatous GCT is associated with a poor prognosis; one-third of patients are cured with standard therapy (four cycles of BEP). Patients with newly diagnosed mediastinal nonseminoma are considered to have poor-risk disease and should be considered for clinical trials testing regimens of possibly greater efficacy. In addition, mediastinal nonseminoma is associated with hematologic disorders, including acute myelogenous leukemia, myelodysplastic syndrome, and essential thrombocytosis unrelated to previous chemotherapy. These hematologic disorders are very refractory to treatment. Nonseminoma of any primary site may change into other malignant histologies such as embryonal rhabdomyosarcoma or adenocarcinoma. This is called malignant transformation. i(12p) has been identified in the transformed cell type, indicating GCT clonal origin.

A group of patients with poorly differentiated tumors of unknown histogenesis, midline in distribution, and not associated with secretion of AFP or hCG has been described; a few (10–20%) are cured by standard cisplatin-containing chemotherapy. i(12p) is present in ~25% of such tumors (the fraction that are cisplatin-responsive), confirming their origin from primitive germ cells. This finding is also predictive of the response to cisplatin-based chemotherapy and resulting long-term survival. These tumors are heterogeneous; neuroepithelial tumors and lymphoma may also present in this fashion.

Fertility

Infertility is an important consequence of the treatment of GCTs. Preexisting infertility or impaired fertility is often present. Azoospermia and/or oligospermia are present at diagnosis in at least 50% of patients with testicular GCTs. Ejaculatory dysfunction is associated with RPLND, and germ cell damage may result from cisplatin-containing chemotherapy. Nerve-sparing techniques to preserve the retroperitoneal sympathetic nerves have made retrograde ejaculation less likely in the subgroups of patients who are candidates for this operation. Spermatogenesis does recur in some patients after chemotherapy. However, because of the significant risk of impaired reproductive capacity, semen analysis and cryopreservation of sperm in a sperm bank should be recommended to all patients before treatment.