Early studies showed a lower risk of relapse when fewer than six nodes were involved and no node was 2 cm; and higher when 6 nodes or more were involved, any node was larger than 2 cm, or extranodal extension was present.
Surveillance is a treatment choice for compliant patients with fewer than six involved nodes and none larger than 2 cm. Surveillance requires close monitoring, and chemotherapy is reserved for patients who relapse. Patient compliance, psychologic factors, age, or other issues may make adjuvant chemotherapy the preferred choice in rare patients. Three or four cycles of cisplatin-based therapy will be required at relapse according to disease status at that time.

Adjuvant chemotherapy remains a strong consideration in patients when six nodes or more are involved, any node is larger than 2 cm, or there is extranodal extension. In the late 1970s, treatment programs based on cisplatin, vinblastine, and bleomycin were given as adjuvant therapy following RPLND, and nearly 100% of patients survived relapse free. Considerable treatment-related morbidity was associated with these regimens, prompting efforts to reduce toxicity. Two cycles of cisplatin-based chemotherapy are nearly always effective in preventing relapse. A randomized trial showed that observation with standard treatment at relapse and two cycles of adjuvant chemotherapy had equivalent survival. Etoposide has replaced vinblastine in adjuvant regimens. A recent study suggests that etoposide plus cisplatin alone is adequate, and that bleomycin is unnecessary as part of adjuvant therapy.

Disorders information

Observation

The driving forces for early observation studies in clinical stage I patients were the infertility resulting from RPLND (due to retrograde ejaculation) and the apparent absence of therapeutic benefit (i.e., orchiectomy was a curative procedure or systemic disease occurred in the absence of retroperitoneal disease). The ability of cisplatin-based chemotherapy to cure systemic disease directly permitted observation studies, because cure of low-burden disease was more than 95% and treatment of relapse would not compromise survival. Relapse occurs in 25% to 30% of patients who are observed. A higher likelihood of retroperitoneal or systemic relapse was associated with T2-4 tumors and lymphatic or vascular invasion in T1 tumors. Some studies suggested that a high percentage of embryonal carcinoma and other histologic features also predicted a higher likelihood of relapse. However, the correlation between lymphatic-vascular invasion and the presence of embryonal carcinoma is high, and general agreement on histologic criteria for relapse independent of vascular or lymphatic invasion does not exist. Therefore, vascular-lymphatic invasion is the critical pathologic predictor for relapse in tumors confined to the testis. The retroperitoneum is the site of relapse in approximately two thirds of patients; the lungs or markers alone, in approximately one third; and other visceral sites, much less frequently. There is a slightly higher likelihood that both chemotherapy and modified bilateral RPLND ( not nerve sparing) are needed in order to achieve the same cure rate.

Patients with clinical stage I nonseminomatous GCT with a T1 tumor without vascular-lymphatic invasion and serum tumor markers that are normal or declining at half-life should be offered both surgical and observation options. If RPLND is chosen, it should be of the nerve-sparing type, thereby preserving ejaculatory capacity in the majority of patients. Frequent CT scans of the abdomen are unnecessary once an RPLND has been performed. If surveillance is chosen, then a possibly unnecessary RPLND is avoided, limiting therapy to orchiectomy alone in at least 70% of the patients (i.e., those who never relapse). Patient compliance cannot be overemphasized. A physical examination, chest x-ray, and determinations of AFP and hCG levels are required at monthly intervals in the first year, every other month in the second year, quarterly in the third year, and less frequently thereafter. An abdominal CT scan is required quarterly in the first year, every 4 months in the second year, and every 6 months beginning in the third year. Visits and evaluations should be annual in the fifth year and beyond. In both situations, relapses are extremely uncommon after 2 years and have only very rarely been observed after 5 years, in contrast to seminoma.

Chemotherapy

There are few data regarding chemotherapy as initial treatment of clinical stage I disease when the risk of retroperitoneal disease is high. In three reports of patients receiving two cycles of cisplatin-based chemotherapy, fewer than 5% relapsed and about 1% died of GCT. Although this approach avoids RPLND and the duration of therapy is brief, a majority of these patients would be exposed to the transient (e.g., myelosuppression), permanent (e.g., neuropathy), and delayed (e.g., Raynaud’s phenomenon, acute leukemia) toxicities of chemotherapy. The data are not yet mature and follow-up is short; this approach should be considered investigational.

Rarely, patients with clinical stage I disease are found to have persistently elevated serum concentrations of AFP or hCG after orchiectomy. If these markers increase or plateau at an elevated level after a period of observation (4 weeks or less), metastatic disease is present. This group of patients should receive initial systemic chemotherapy, because the disease is often not limited to the retroperitoneum. An RPLND should be done only if clinical studies at the conclusion of therapy demonstrate new disease.

Antegrade ejaculation requires coordination of three separate events: (1) closure of the bladder neck, (2) seminal emission, and (3) ejaculation. The sympathetic fibers that mediate seminal emission emanate primarily from the T12 to L3 thoracolumbar spinal cord. In the midretroperitoneum, after leaving the sympathetic trunk, the fibers converge toward midline and form the hypogastric plexus near the aortic bifurcation. From the hypogastric plexus, sympathetic fibers travel via pelvic nerves to innervate the vas deferens, seminal vesicles, prostate, and bladder neck. Ejaculation is mediated by combined autonomic and somatic innervation originating at the sacral and lumbar spinal cord levels. Sympathetic stimulation tightens the bladder neck, while pudendal somatic innervation from S2 to S4 causes relaxation of the external urethral sphincter and rhythmic contraction of bulbourethral and perineal muscles. Preservation of ejaculatory capacity requires preservation of paravertebral sympathetic ganglia and their fibers that converge at the superior hypogastric plexus around the aortic bifurcation. Sympathetic chains and postganglionic sympathetic fibers can be prospectively identified, meticulously dissected, and preserved.

Nerve-sparing RPLND may be of two types: nerve dissecting or nerve avoiding. With nerve dissection, about 90% of patients will be left with normal ejaculatory status postoperatively. Despite pathologic stage II disease in patients selected for this procedure, recurrences in the retroperitoneum are rare. In addition, spontaneous recovery of ejaculation has been reported following a modified RPLND. Modified, nerve-avoiding RPLND templates were designed to avoid the contralateral sympathetic fibers responsible for ejaculation and were developed for use in clinical stage I or IIA disease. These template dissections do not attempt to identify specific nerve fibers. Instead, their design minimizes trauma to the hypogastric plexus by limiting the contralateral dissection to the level above the takeoff of inferior mesenteric artery. This method avoids transsection of the contralateral nerves and results in preservation of ejaculation rates ranging from 51% to 88%. These rates are higher for a right-sided, nerve-avoiding template dissection compared to modified, left-sided dissection. Preservation of ejaculation appears to be more successful when nerves are prospectively identified and spared, compared to modified template dissection, although duration of operation is usually longer for the former. Regardless of technique, retrograde ejaculation is a potential risk with any RPLND; therefore, preoperative sperm banking is recommended. alpha-Adrenergic drugs such as ephedrine, pseudoephedrine, and imipramine occasionally promote antegrade ejaculation in patients who are anejaculatory following RPLND. The low number of reported such cases suggests substantial case selection, and many patients will probably not respond to alpha-adrenergic stimulation. Transrectal electroejaculation provides an option for patients who fail sympathomimetic agents.

Cancer treatment information

MANAGEMENT OF CLINICAL STAGE I DISEASE
SEMINOMA

Radiation Therapy

The management of clinical stage I seminoma has not changed significantly in the last 20 years. Radiation therapy remains the treatment of choice. The ipsilateral hemiscrotum does not require therapy unless gross tumor spillage has taken place. Conventional fractionation for clinical stage I disease is 150 to 180 cGy/d for five sessions per week using high-energy linear accelerator beams to a total dose of 2500 to 3000 cGy. Elective, prophylactic radiation therapy to the mediastinum is contraindicated. The contralateral testis should be shielded during treatment. Proper shielding will result in an exposure 1% or less of the total dose. The relapse rate within the irradiated portal after adequate radiation therapy is negligible. The systemic relapse rate, usually presenting as a supraclavicular mass, ranges from 2% to 9%, and the death rate is under 2%. CT scanning of the abdomen and pelvis is required and has replaced intravenous pyelography. LAG may have two purposes. Small nodal metastases that distort architecture but do not increase nodal size may be identified, and the field size may be smaller than those planned on the basis of CT alone. The smaller field may reduce the long-term effects of abdominal radiotherapy. For left-side, primary testicular tumors, the left renal hilum must be encompassed. Treatment of pelvic lymph nodes is sometimes required for T4 primary tumors or for scrotal violations with tumor spillage. An involved spermatic cord margin at the internal ring may also require field extension.

Observation

Although the dose of radiation therapy is low and the cure rate exceptionally high, long-term sequelae include the potential for an increased incidence of gastrointestinal neoplasms (see later). As a consequence, studies have been performed investigating observation as the only management after orchiectomy, to be followed by chemotherapy at relapse. The relapse rate is approximately 15%, but the median time to relapse is about 12 months, longer than that observed for nonseminomatous GCT. Moreover, relapses have occurred at intervals more than 5 years from diagnosis, implying that abdominal CT scanning to detect late relapses must occur indefinitely in patients with seminoma. Therefore, in the United States, observation for clinical stage I seminoma is not considered routine.

NONSEMINOMATOUS GERM CELL TUMORS

Nonseminomatous GCT is relatively radioresistant. Therefore, radiation therapy plays no role in its initial management. If a patient has clinical stage I disease at the conclusion of initial staging, three management options remain, the choice of which depends on specific histologic features and status of serum tumor marker concentrations.
Retroperitoneal Lymph Node Dissection

Because of predictable lymphatic metastatic spread, the conventional approach to patients with clinical stage I nonseminomatous GCT has been the modified, bilateral RPLND. Adequate exposure for RPLND can be achieved through either a transthoracic or a transabdominal approach. The standard bilateral infrahilar RPLND template, which remains the standard against which therapeutic alternatives are judged, includes the paracaval, interaortocaval, preaortic, paraaortic, and common iliac lymph nodes bilaterally.

Despite refinement of radiologic imaging, 15% to 40% of patients are clinically understaged. Retroperitoneal metastases will be found in about 30% of patients judged preoperatively to be clinical stage I. Retroperitoneal relapse will occur in about 20% to 25% of patients on clinical stage I surveillance protocols, and teratoma or viable cancer will be found pathologically in 20% of patients with a normal postchemotherapy CT scan.

Infield recurrence is rare after a properly performed RPLND, which is a curative procedure in the majority of patients with N1 disease, with relapse rates less than 35% without adjuvant chemotherapy and essentially no relapses for higher stage nodal disease followed by two cycles of cisplatin-based chemotherapy. Surgical mortality is less than 1%. Major complications are unusual but can include pancreatitis, renal vascular or ureteral injuries, chylous ascites, aortic wall necrosis, bowel obstruction, pulmonary emboli, hemorrhage, and wound dehiscence. Minor complications include lymphocele, atelectasis, wound infection, and prolonged ileus.

Most patients undergoing bilateral RPLND experience retrograde ejaculation and subsequent infertility. An improved understanding of the neuroanatomy of seminal emission and ejaculation, the pattern of retroperitoneal metastasis for right- and left-sided tumors, and surgical mapping studies led to modification of infrahilar surgical boundaries and techniques. Two approaches have been used: (1) formal dissection and preservation of sympathetic fibers, and (2) modified template that avoids (but does not specifically identify) sympathetic fibers.

HISTOLOGY
CARCINOMA IN SITU

Carcinoma in situ (CIS) (intratubular germ cell neoplasia) precedes invasive testicular GCT in virtually all cases of typical and anaplastic seminoma and all nonseminomatous histologies in the adult. CIS is frequently present in retroperitoneal presentations and is rarely, if ever, present in mediastinal presentations. It has not been described in spermatocytic seminoma and rarely in tumors arising in prepubertal patients. Cytologically, CIS preceding seminoma and nonseminoma is identical. The median time for progression of CIS to invasive disease is 5 years. In the general population, the incidence of CIS is very low, while in men with impaired fertility, the incidence is about 0.5%. The incidence of CIS is 2% to 5% in both cryptorchid testes and the contralateral testis in patients with a documented prior testicular GCT.
SEMINOMA

Seminoma accounts for approximately 50% of all GCT and most frequently appears in the fourth decade of life. The typical or classic form consists of sheets 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 human chorionic gonadotropin (hCG) are present in 15% to 20% of tumors. The presence of syncytiotrophoblastic giant cells in an otherwise pure seminoma does not influence prognosis or treatment. Anaplastic seminoma is an older term used when three or more mitotic figures are seen per high-powered field, and it has no clinical or prognostic importance. Stage for stage, anaplastic seminoma is similar in response and prognosis to classic seminoma.

An atypical form of seminoma has been described with unusual immunohistochemical features. While the cells cytologically resemble classic seminoma, lymphocytic infiltrate and granulomatous reaction are absent, necrosis is more common, and the nuclear: cytoplasmic ratio is higher. These tumors must be distinguished morphologically from solid variants of embryonal carcinoma and yolk sac tumor. Atypical seminoma frequently shows cytoplasmic expression of low-molecular-weight keratin or the type 1 precursor to the blood group antigens, while typical seminoma stains negative. Electron microscopic studies have shown that the individual tumor cells acquire cytoplasmic cytokeratin intermediate filaments, suggesting epithelial differentiation. There has been no specific association of atypical seminoma with an adverse prognosis, and its management is currently the same as any other seminoma.

Spermatocytic seminoma is a rare histologic variant seen almost exclusively in men above the age of 45. The relationship of spermatocytic seminoma to other GCTs is not clear, because it is not associated with CIS or bilaterally, does not express placental alkaline phosphatase (PLAP) (see later), and has not been shown to have the same genetic abnormalities as other GCTs. Metastatic potential is minimal.