Disclosure The incidence of testicular tumors in the United States is approximately 5500 cases per year. Overall incidence of this disease worldwide ranges from 0.2-10.3 cases per 100,000 persons. Tumors may arise in persons of nearly any age group and may be of germ cell or non–germ cell origin. Of primary importance to determining prognosis are the tumor histology and tumor stage. This article addresses the demographics, histology, prognosis, and treatments of nonseminomatous germ cell tumors (NSGCTs). History of the Procedure: The treatment of testicular cancer has developed in earnest over the past half century. Before 1970, mortality rates from testicular tumors approached 50%, whereas recent studies have indicated a greater than 90% cure rate using multimodal therapy. Improved understanding of the histology, mechanisms of tumor spread, and tumor markers combined with the improved quality of radiographic imaging for accurate staging have greatly contributed to disease management. The combination of refinements in surgical intervention and the application of effective combination chemotherapy has emerged as a paradigm for the successful use of multimodal therapy for solid tumors. Problem: Testicular cancer has 3 main types, (1) germ cell tumors, (2) non–germ cell tumors, and (3) extragonadal tumors. Germ cell tumors are the most common and are classified as either a seminoma or a nonseminoma, based on their histology. While seminoma is the most common, NSGCTs are the second most common form of testicular cancer. This discussion explores the incidence, risk factors, diagnosis, treatment options, and prognosis of NSGCTs. Frequency: US incidence Testicular cancer is relatively uncommon, with only approximately 5500 new cases per year in the United States. Peak incidence occurs in men aged 20-34 years. It is the most common solid tumor of this otherwise young, healthy, and productive age group. Furthermore, despite improvements in survival rates since the introduction of platinum-based chemotherapy in the United States in the 1970s and 1980s, the incidence rate in the US white male population has risen 51% from 1973-1995 to 5.44 cases per 100,000 persons. The risk of NSGCTs also appears to have increased for more recent birth cohorts. Similarly, the incidence in the military population among active servicemen has almost doubled from 1988-1996. African American males have a lower incidence of this disease. International incidence The world's highest rates of testicular cancer are in Norway, Denmark, Germany, and Switzerland. The incidence in Switzerland in 1997 was 10.3 cases per 100,000 persons. Between 45% and 50% of these were NSGCTs. This population has also shown an alarming increase in incidence (>300%) since 1955. An increase in risk for birth cohorts, except for those born during World War II, has also been observed. Etiology: Factors that alter the differentiation of the primordial germ cell, resulting in the presence of an embryonal stem cell, can increase the risk of NSGCT. These factors include a history of testicular cancer in the contralateral testis, cryptorchidism, gonadal dysgenesis, exposure to prenatally high estradiol levels, exposure to chemical carcinogens, trauma, and orchitis. Furthermore, associations with childhood inguinal hernias and any cause of testicular atrophy have been observed. Recently, the findings of a 25-year follow-up study of 44,864 Swedish men suggests a possible association with elevated serum cholesterol levels (Wirehn, 2005). Further validation studies are required to evaluate these findings in other populations. Pathophysiology: NSGCTs refer to the germ cell tumors that have embryonal stem cells. These may differentiate into extraembryonic tissues or somatic elements. Most tumors are composed of a mixture of these elements. The 4 histologic classifications of NSGCTs are (1) embryonal carcinoma, (2) teratoma, (3) choriocarcinoma, and (4) yolk sac tumor. When a mixture of these tumors exists, the tumors are usually referred to as a mixed tumor. A tumor with both seminomatous and nonseminomatous elements is considered an NSGCT because the NSGCT component most accurately reflects the response to treatment and overall prognosis. Clinical: The classic presentation for testicular tumors is that of a healthy male in the third or fourth decade of life with a painless, swollen, hard testis. The presentation can vary with the amount of disease, clinical stage, and the presence of metastasis at the time of referral. Some patients present with a swollen painful mass in the scrotum that may be dismissed as infectious or inflammatory in nature. This dismissal results in an expensive delay in starting the treatment for NSGCT. In any situation in which the physical examination does not reveal findings of a palpably normal testicle, a scrotal ultrasound should be performed.
Obtain a complete history and perform a complete physical examination for all patients. In the history, specific questions should be asked regarding possible risk factors for testicular cancer. Questions about cryptorchidism, trauma, and mumps orchitis are useful. Likewise, the occupational, chemical exposure, and smoking history of the patient should be obtained. During the general physical examination, special attention should be given to the presence of gynecomastia (5% incidence). Supraclavicular adenopathy may be present in patients with advanced disease. Lung examination can reveal areas of decreased breath sounds in the presence of widespread lung metastases. Abdominal examination should be performed to assess for visceral or bulky lymphatic involvement. The contralateral testis must be examined for possible abnormalities. Finally, a neurological examination, in consideration of possible brain metastasis, is also important.
Relevant Anatomy: The testicles should be readily palpable in the scrotum upon physical examination. The contour of each testicle should be smooth and the consistency uniform. Any size discrepancy between the 2 testicles should be assessed and noted. Careful palpation should allow differentiation of the scrotal contents. The epididymis, attached to the posterior aspect of the testicle, can frequently be the site of induration or cysts, which may prompt a patient performing a self-examination to seek medical attention. These conditions should be identifiable during the physical examination. If any concern exists about the ability to perform an adequate evaluation, scrotal ultrasound must be used to aid in the diagnosis. Contraindications: Surgery is indicated for the initial treatment and is also the method of diagnosis. No contraindications exist to the performance of radical (inguinal) orchiectomy, other than potential anesthetic risks and uncontrolled bleeding diathesis. Preoperative clearance and preparation may be required for these inherently higher-risk patients, but radical orchiectomy should still be performed at the earliest opportunity. |
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Lab Studies:
Imaging Studies:
Other Tests:
Diagnostic Procedures:
Staging: The means of determining prognosis and optimal treatment is accomplished by staging the tumor. Staging is initially accomplished by clinical means, using results from a survey of serum tumor markers, the CT scan of the abdomen and pelvis, and chest radiography to determine the presence of any metastases.
Medical therapy: The primary treatment of testicular cancer is surgical, in the form of radical (or inguinal) orchiectomy, to determine the histologic type of the cancer and the local tumor stage. Chemotherapy is used as primary therapy in advanced disease and is used as adjuvant therapy in low-stage disease. A combination of agents typically used as first-line agents includes bleomycin, etoposide, and platinum (ie, the BEP regimen) and is typically administered in a 3-course cycle. Alternatively, some centers administer etoposide and platinum alone (ie, the EP regimen) in a 4-course cycle. Vinblastine, ifosfamide, and cisplatin have been described as salvage therapy for primary treatment failures. Because platinum is a highly effective treatment for NSGCT, high-dose therapy using carboplatin in combination with autologous bone marrow transplant has been used with success for the most refractory cases. Surgical therapy: Radical orchiectomy is performed when a testis tumor is appreciated upon examination or preoperative imaging studies. This is accomplished via an inguinal incision in order to not alter the lymphatic drainage pattern of the testicle (ie, drainage to the retroperitoneal lymph nodes) by violating the scrotal wall (ie, drainage to the superficial inguinal lymph nodes). Radical orchiectomy also allows ligation of the vas deferens and testicular vessels at the internal inguinal ring. The reason for this is should subsequent surgical removal of the spermatic cord and retroperitoneal lymph nodes be required (ie, for therapy or staging), the inguinal canal need not be explored again. After radical orchiectomy is performed and the tumor is identified as an NSGCT, clinical and/or surgical staging is mandatory. As previously discussed in Discussion of treatment options for clinical stage I NSGCT, primary RPLND is used to determine pathological staging and, in most of these patients, is curative therapy. Historically, a bilateral suprahilar approach was taken for RPLND. This approach was used for 2 reasons, (1) the knowledge of the primary landing sites of these tumors was not known and (2) salvage chemotherapy was not very effective. Today, platinum-based chemotherapy, even in the setting of relapse, carries a greater than 90% cure rate. Therefore, the operation has been refined to a more limited dissection with a secondary goal of reducing long-term adverse effects in these young men. The most common adverse effect described is a loss of antegrade ejaculation. Bilateral suprahilar RPLND has now evolved to a modified-template nerve-sparing dissection, depending on the side of the testis involved. For right-sided tumors, the dissection is limited by the medial aspect of the right ureter laterally, the right renal vessels superiorly, and the anterior aorta medially. The dissection down the aorta is taken to the root of the inferior mesenteric artery (IMA), and the dissection down the inferior vena cava is taken to the right iliac bifurcation. For left-sided tumors, the limits of dissection are the left ureter laterally, left renal vessels superiorly, and the anterior aspect of the vena cava medially. Inferiorly, dissection is taken to the root of the IMA and, laterally, down to the right iliac artery. The nerve-sparing aspect of the operation refers specifically to the isolation and preservation of postganglionic fibers from the lumbar spinal cord that arise from the right sympathetic trunk. These fibers enter the retroperitoneal space from behind the vena cava and travel through the interaortocaval and preaortic regions. Because much of the lymph node dissection occurs in this area, special care must be taken to preserve these nerves, which are essential for ejaculation. In a series of 2200 patients who underwent RPLND, all patients who had primary nerve-sparing RPLNDs for stage I disease who responded to the survey (402) reported normal ejaculation (100%). Of 98 patients who attempted conception, 82 (84%) were successful. The authors also reported an impressive 77% rate of normal ejaculation for patients who responded after postchemotherapy nerve-sparing RPLND. Preoperative details: Prior to radical orchiectomy, routine preoperative preparations should be taken and laboratory studies obtained as previously described. Prior to planned RPLND, some surgeons advocate that patients should start a low-fat diet 2 weeks before the operation to reduce the risk of chylous ascites, and they should continue this in the immediate postoperative period. On the day before RPLND, the patient should start a clear liquid diet and take a mechanical bowel preparation at home. Intraoperative details: For radical orchiectomy, an inguinal incision is made and the cord isolated and compressed with a vessel loop for vessel control prior to manipulating the testis. The testicle is maneuvered from the scrotum up into the inguinal canal to expose it in the inguinal incision. The gubernaculum is divided to free the testicle from the inner wall of the scrotum. Typically, the cord is dissected proximally to the level of the internal ring and divided between clamps. The proximal vessels and vas deferens are secured with nonabsorbable sutures in the event subsequent RPLND is to be performed. A prosthesis may be placed in the scrotum at the time of orchiectomy. Postoperative details: Limitations on physical activity are typically instituted to decrease the risks of pain, bleeding, or wound complications. If serum tumor marker values were elevated prior to orchiectomy, repeat measurements of serum marker levels should be obtained to assess if an appropriate postoperative decrease occurred. The results of these studies aid in determining further staging and therapy. Follow-up care: The median time to recurrence is 7 months, and 90% of patients who experience recurrence do so by 2 years. Hence, an intensive schedule of follow-up and imaging is required for the first 2 years. Surveillance schedules vary but should include, at a minimum, serum marker evaluations, chest radiographs, and contralateral testis examination every 1 month for the first year, every 2 months for the second year, every 3 months for the third year, and every 4-6 months for the fourth and fifth years. CT scans of the abdomen and pelvis should be performed every 3 months for the first year, every 3-4 months for the second year, and every 6 months for the third through fifth years. Physicians treating patients through the surveillance period have a responsibility to ensure patients are not lost to follow-up and that they comply with the regimen. If findings are negative after RPLND, follow-up may be less stringent. This should include serum marker evaluations, chest radiographs, and physical examinations every 3-4 months for the first 2 years and every 6 months for the third through fifth years. Recurrence in the retroperitoneum is rare in these patients. CT scanning is warranted periodically, at least 6 months postoperatively and annually for the next few years, particularly if the patient was considered high risk. For excellent patient education resources, visit eMedicine's Men's Health Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer of the Testicle and Testicular Self-Exam.
The long-term adverse effects of RPLND and chemotherapy must be considered and discussed with the patient, especially in the setting in which either modality can be considered primary therapy. In the hands of an experienced surgeon, the mortality rate associated with an RPLND should be approximately 0%. Significant recovery time is required before patients can return to work, primarily because of the length of the incision. The most commonly described long-term complication is the loss of antegrade ejaculation. When the patient has low-volume disease and a nerve-sparing procedure can be performed, ejaculation can be maintained in virtually all patients. However, in a patient with stage IIB cancer, a nerve-sparing procedure may compromise surgical cure, and a patient who wishes to preserve ejaculatory function may elect for primary chemotherapy, as mentioned above. In contrast, primary chemotherapy results in azoospermia in most patients for up to 24-36 months, and approximately 25% of patients at 2-5 years of follow-up have a persistent absence of sperm in their semen. With respect to concerns regarding postoperative sexual function (ie, libido), erectile function, and the potential for orgasm, sacrifice of the sympathetic nerves in the non–nerve-sparing RPLND does not appear to be contributory. Chemotherapy also carries an increased risk of secondary malignancies. The relative risk of leukemia, lymphoma, sarcoma, melanoma, and gastrointestinal tumors is increased, in the range of 1.7- to 8.8-times more common than without chemotherapy. A recent study of quality of life by Stava et al among people who survived cancer (including testicular cancer) revealed a 6.8% rate of hearing loss (although this was not specific to patients with testicular cancer). In a study from Norway, Mykletun et al report that, at a mean of 11 years of follow-up, people who survived testicular cancer had no clinically significant difference in quality of life when compared to age-matched controls. Overall, only minimal differences were seen in quality of life between different testicular cancer treatment modalities. The apparently excellent quality-of-life results of this study may offer some reassurance regarding the potential for complications and challenges to patients who must face the diagnosis and treatment of testicular cancer.
Patients with stage I disease typically achieve a 98% disease-free survival rate at 5 years. Patients with stage IIA and IIB disease typically achieve a 92% disease-free survival rate at 5.5 years. Patients with stage IIC disease can expect an approximately 92% overall survival rate at 5 years. Patients with stage III disease classified as good-risk have a 92% overall survival rate at 5 years. Intermediate-risk patients have an 80% overall survival rate at 5 years. Poor-risk patients have a 48% overall survival rate at 5 years.
Laparoscopic RPLND The long-term adverse effects of RPLND can be diminished with a more limited dissection in the appropriate patient. The short-term adverse effects of such an extensive dissection include a long postoperative hospital stay, significant pain, and a protracted period before the patient can resume normal work and leisure activities. Some of these disadvantages can be mitigated through the use of a relatively new surgical approach that uses several small incisions to admit an operative telescope and miniature surgical instruments to accomplish the same surgery as in the traditional, large, single-incision procedure. The advantages of laparoscopic surgery are observed primarily in the postoperative setting, with a shorter hospital stay, decreased pain, and more rapid convalescence. Several series on the application of laparoscopic RPLND in a patient with clinical stage I NSGCT have already been reported in the literature, with promising results. One such series reported on 73 laparoscopic RPLNDs for clinical stage I NSGCT. Twenty-six percent of the patients had pathological stage II disease, and they all received 2 cycles of adjuvant chemotherapy. All patients in stage I (mean follow-up of 43.3 mo) and in stage II (mean follow-up of 42.7 mo) were free of disease. Ejaculation was preserved in all 70 patients who had adequate follow-up time. The conversion rate from laparoscopic to open RPLND was only 2.7% (2 of 73 cases). The mean operative time was prolonged (297 min); however, the time improved dramatically with experience. Further experience with this novel and challenging technique is necessary to establish its role in the treatment of NSGCT. A second controversy relates to the role of RPLND post chemotherapy. In general, all patients with a residual retroperitoneal mass require RPLND. However, if the mass resolves completely or its volume is reduced by more than 90%, virtually all patients will have necrosis and fibrosis only and RPLND may be averted.
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