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.

INITIAL PRESENTATION AND MANAGEMENT
SYMPTOMS AND SIGNS

The pathognomonic presentation of a primary testicular tumor is a painless testicular mass that may range in size from a few millimeters to several centimeters. However, the painless testicular mass occurs in only a minority of patients. The majority present with more diffuse testicular pain, swelling, hardness, or some combination of these findings. Because infectious epididymitis or orchitis, or a combination of the two, is more common, a trial of antibiotic therapy is often reported in questionable cases. Acute testicular pain, simulating testicular torsion, occurs less frequently and may represent intratumoral hemorrhage. If the testicular discomfort does not abate or findings do not revert to normal within 2 to 4 weeks, a testicular ultrasound is indicated. On ultrasound, the typical testicular tumor is intratesticular, and may produce one or more discrete hypoechoic masses or diffuse abnormalities with microcalcifications. The latter is more frequently found in seminoma. Delay in diagnosis, caused by either patient- or physician-related factors, or both, generally results in higher stage at presentation and presumably lower survival. These data on delay in diagnosis require that this highly curable neoplasm be properly managed at all stages.

DIAGNOSIS

A radical inguinal orchiectomy, using an inguinal incision with early high ligation of the spermatic cord at the deep inguinal ring, minimizes local tumor recurrence and aberrant lymphatic spread and is the only acceptable therapeutic and diagnostic procedure. The vasal and vascular components are doubly clamped and divided separately; their respective stumps are pushed into the retroperitoneal space to facilitate future removal of the gonadal vessels at the time of retroperitoneal lymph node dissection (RPLND). The testicle and spermatic cord are removed en bloc, avoiding any spillage, and meticulous hemostasis is achieved. The testis embryologically originates in the genital ridge, and descends during fetal life through the abdomen and inguinal canal into the scrotum. Therefore, the primary lymphatic and vascular drainage of the testis is to the retroperitoneal lymph nodes and the renal or great vessels, respectively. A transscrotal orchiectomy is contraindicated, because it permits the development of alternate lymphatic drainage pathways to the inguinal and pelvic lymph nodes, and leaves intact the spermatic cord from the external to the internal ring. In the rare situation when the diagnosis of a testicular tumor is in question, then an inguinal incision is required for an open biopsy. The testis can then be examined in situ in a sterile field and an appropriate biopsy taken with minimal risk of scrotal or inguinal contamination. Regardless of the preoperative diagnosis, all potential, primary testicular malignancies should be managed through an inguinal approach.

Extragonadal GCTs comprise fewer than 10% of all GCT presentations. The mediastinum and retroperitoneum are the most common primary sites. Pineal tumors, occurring most frequently in children, are usually GCT. Because of their unique access to the meninges, the metastatic pattern of pineal germ GCT includes intradural sites along the neuraxis and is infrequently systemic. The management of pineal GCT is discussed elsewhere in this text. In extremely rare circumstances, primary GCTs have been found in unusual sites such as the sacrum, thyroid, paranasal sinuses, and soft tissues of the head and neck. In patients with extragonadal presentations of GCT, a testicular ultrasound is required. The management of extragonadal and testicular GCT is the same, and primary site is an independent factor in current staging and risk classifications.

Testicular cancer is the most common solid tumor in men between the ages of 20 and 35 years. There are three modal peaks: infancy, ages 25 to 40, and about age 60.

A solid testicular mass in a man aged 50 or greater is usually a lymphoma. An estimated 6000 new cases and 350 deaths due to testicle cancer occured in the United States in 1995. The lifetime probability of developing a GCT is approximately 0.2% for an American Caucasian male. The incidence of testis cancer varies significantly according to geographic area. The reported incidence is highest in Scandinavia, Switzerland, Germany, and New Zealand; intermediate in the United States and Great Britain; and lowest in Africa and Asia. The worldwide incidence of testis GCT has more than doubled in the past 40 years.

EPIDEMIOLOGY

GCTs are seen principally in young Caucasians, rarely in African-Americans. The published ratio between Caucasian and African-American patients is approximately 4 to 5:1, although it was closer to 40:1 ratio in the US Military. In African-Americans, GCT behaves similarly to that of the general population, and the incidence of GCT in African-Americans has not increased over the past 40 years. Familial clustering has been observed, particularly among siblings.
The cause of GCT is unknown. Hypotheses implicating an endocrine-driven, pituitary stimulation of damaged germinal epithelium have not been proved. Instead, random genetic events occurring during the early stages of meiosis seem to be responsible for the malignant transformation of germ cells (see section on biology). A few congenital developmental defects predispose to the disease.

CRYPTORCHIDISM

The risk of GCT occurring in the cryptorchid testis is several times the risk in normally descended testes. Between 5% and 20% of patients with a history of cryptorchidism develop a tumor in the normally descended testis.An abdominal cryptorchid testis is more likely to develop GCT than an inguinal cryptorchid testis. The protective effect of orchiopexy is difficult to quantify, but most data suggest a reduced likelihood of GCT if orchiopexy is performed prior to puberty. If the testis is inguinal, hormonally functioning, and easily examined, surveillance is recommended. If the testis is not amenable to orchiopexy or cannot be adequately examined, orchiectomy is recommended.