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Germ Cell Tumors of the Testis
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Epidemiology and Risk Factors
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Malignant tumors of the testis are rare, with approximately 9 new cases per 100,000 males reported in the United States each year. Of all primary testicular tumors, 90–95% are germ cell tumors (seminoma and nonseminoma), while the remainders are nongerminal neoplasms (Leydig cell, Sertoli cell, gonadoblastoma). The lifetime probability of developing testicular cancer is 0.2% for a white male in the United States. Survival of patients with testicular cancer has improved dramatically in recent years, reflecting the development and refinement of effective combination chemotherapy. Of the 8480 new cases of testicular cancer in the United States in 2010, only 350 deaths are expected.
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The incidence of testicular cancer shows marked variation among different countries, races, and socioeconomic classes. Scandinavian countries report up to 6.7 new cases per 100,000 males annually; Japan reports 0.8 per 100,000 males. In the United States, the incidence of testicular cancer in blacks is approximately one-fourth that in whites. Within a given race, individuals in the higher socioeconomic classes have approximately twice the incidence of those in the lower classes.
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Testicular cancer is slightly more common on the right side than on the left, which parallels the increased incidence of cryptorchidism on the right side. Of primary testicular tumors, 1–2% are bilateral, and about 50% of these tumors occur in men with a history of unilateral or bilateral cryptorchidism. Primary bilateral tumors of the testis may happen synchronously or asynchronously but tend to be of the same histologic type. Seminoma is the most common germ cell tumor in bilateral primary testicular tumors, while malignant lymphoma is the most common bilateral tumor of the testis.
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Although the cause of testicular cancer is unknown, both congenital and acquired factors have been associated with tumor development. The strongest association has been with the cryptorchid testis. Approximately 7–10% of testicular tumors develop in patients who have a history of cryptorchidism; seminoma is the most common form of tumor these patients have. However, 5–10% of testicular tumors occur in the contralateral, normally descended testis. The relative risk of malignancy is highest for the intra-abdominal testis (1 in 20) and is significantly lower for the inguinal testis (1 in 80). Placement of the cryptorchid testis into the scrotum (orchiopexy) lowers the risk of malignancy if it is performed prior to the age of 13 (Pettersson et al, 2007).
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Exogenous estrogen administration to the mother during pregnancy has been associated with an increased relative risk for testicular tumors in the fetus, ranging from 2.8 to 5.3 over the expected incidence. Other acquired factors such as trauma and infection-related testicular atrophy have been associated with testicular tumors; however, a causal relationship has not been established.
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Numerous classification systems have been proposed for germ cell tumors of the testis. Classification by histologic type proves to be the most useful with respect to treatment. The two major divisions are seminoma and nonseminomatous germ cell tumors (NSGCTs), which include embryonal, teratoma, choriocarcinoma, and mixed tumors.
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Tumorigenic Hypothesis for Germ Cell Tumor Development
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During embryonal development, the totipotential germ cells can travel down normal differentiation pathways and become spermatocytes. However, if these totipotential germ cells travel down abnormal developmental pathways, seminoma or embryonal carcinomas (totipotential tumor cells) develop. If the embryonal cells undergo further differentiation along intraembryonic pathways, teratoma will result. If the embryonal cells undergo further differentiation along extraembryonic pathways, either choriocarcinoma or yolk sac tumors are formed (Figure 24–1). This model helps to explain why specific histologic patterns of testicular tumors produce certain tumor markers. Note that yolk sac tumors produce alpha-fetoprotein (AFP) just as the yolk sac produces AFP in normal development. Likewise, choriocarcinoma produces human chorionic gonadotropin (hCG) just as the normal placenta produces hCG.
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Three histologic subtypes of pure seminoma have been described. However, stage for stage, there is no prognostic significance to any of these subtypes. Classic seminoma accounts for 85% of all seminomas and is most common in the fourth decade of life. Grossly, coalescing gray nodules are observed. Microscopically, monotonous sheets of large cells with clear cytoplasm and densely staining nuclei are seen. It is noteworthy that syncytiotrophoblastic elements are seen in approximately 10–15% of cases, an incidence that corresponds approximately to the incidence of hCG production in seminomas.
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Anaplastic seminoma accounts for 5–10% of all seminomas. Diagnosis requires the presence of three or more mitoses per high-power field, and the cells demonstrate a higher degree of nuclear pleomorphism than the classic types. Anaplastic seminoma tends to present at a higher stage than the classic variety. When stage is taken into consideration, however, this subtype does not convey a worse prognosis.
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Spermatocytic seminoma accounts for 5–10% of all seminomas. Microscopically, cells vary in size and are characterized by densely staining cytoplasm and round nuclei that contain condensed chromatin. More than half of the patients with spermatocytic seminoma are older than 50 years.
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Embryonal Cell Carcinoma (20%)
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Two variants of embryonal cell carcinoma are common: the adult type and the infantile type or yolk sac tumor (also called endodermal sinus tumor). Histologic structure of the adult variant demonstrates marked pleomorphism and indistinct cellular borders. Mitotic figures and giant cells are common. Cells may be arranged in sheets, cords, glands, or papillary structures. Extensive hemorrhage and necrosis may be observed grossly.
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The infantile variant, or yolk sac tumor, is the most common testicular tumor of infants and children. When seen in adults, it usually occurs in mixed histologic types and possibly is responsible for AFP production in these tumors. Microscopically, cells demonstrate vacuolated cytoplasm secondary to fat and glycogen deposition and are arranged in a loose network with large intervening cystic spaces. Embryoid bodies are commonly seen and resemble 1- to 2-week-old embryos consisting of a cavity surrounded by syncytio- and cytotrophoblasts.
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Teratomas may be seen in both children and adults. They contain more than one germ cell layer in various stages of maturation and differentiation. Grossly, the tumor appears lobulated and contains variable-sized cysts filled with gelatinous or mucinous material. Mature teratoma may have elements resembling benign structures derived from ectoderm, mesoderm, and endoderm, while immature teratoma consists of undifferentiated primitive tissue. In contrast to its ovarian counterpart, the mature teratoma of the testis does not attain the same degree of differentiation as teratoma of the ovary. Microscopically, ectoderm may be represented by squamous epithelium or neural tissue; endoderm may be represented by intestinal, pancreatic, or respiratory tissue; and mesoderm may be represented by smooth or skeletal muscle, cartilage, or bone.
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Choriocarcinoma (<1%)
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Pure choriocarcinoma is rare. Lesions tend to be small within the testis and usually demonstrate central hemorrhage on gross inspection. Microscopically, syncytio- and cytotrophoblasts must be visualized. The syncytial elements are typically large, multinucleated cells with vacuolated, eosinophilic cytoplasm; the nuclei are large, hyperchromatic, and irregular. Cytotrophoblasts are uniform cells with distinct cell borders, clear cytoplasm, and a single nucleus.
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Clinically, choriocarcinomas behave in an aggressive fashion characterized by early hematogenous spread. Paradoxically, small intratesticular lesions can be associated with widespread metastatic disease.
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Mixed Cell Type (40%)
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Within the category of mixed cell types, most (up to 25% of all testicular tumors) are teratocarcinomas, which are a combination of teratoma and embryonal cell carcinoma. Up to 6% of all testicular tumors are of mixed cell type, with seminoma being one of the components. Treatment for these mixtures of seminoma and NSGCT is similar to that of NSGCT alone.
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In a series of 250 patients with unilateral testicular cancer, Berthelsen et al (1982) demonstrated the presence of carcinoma in situ (CIS) in 13 (5.2%) of the contralateral testes. This is approximately twice the overall incidence of bilateral testicular cancer. The presence of contralateral atrophy or ultrasonographic microlithiasis in patients with testicular tumors warrants contralateral biopsy. If diagnosed, CIS is usually treated by external beam radiation therapy.
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Patterns of Metastatic Spread
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With the exception of choriocarcinoma, which demonstrates early hematogenous spread, germ cell tumors of the testis typically spread in a stepwise lymphatic fashion. Lymph nodes of the testis extend from T1 to L4 but are concentrated at the level of the renal hilum because of their common embryologic origin with the kidney. The primary landing site for the right testis is the interaortocaval area at the level of the right renal hilum. Stepwise spread, in order, is to the precaval, preaortic, paracaval, right common iliac, and right external iliac lymph nodes. The primary landing site for the left testis is the para-aortic area at the level of the left renal hilum. Stepwise spread, in order, is to the preaortic, left common iliac, and left external iliac lymph nodes. In the absence of disease on the left side, no crossover metastases to the right side have ever been identified. However, right-to-left crossover metastases are common. These observations have resulted in modified surgical dissections to preserve ejaculation in selected patients (see Section “Treatment”).
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Certain factors may alter the primary drainage of a testis neoplasm. Invasion of the epididymis or spermatic cord may allow spread to the distal external iliac and obturator lymph nodes. Scrotal violation or invasion of the tunica albuginea may result in inguinal metastases. Although the retroperitoneum is the most commonly involved site in metastatic disease, visceral metastases may be seen in advanced disease. The sites involved in decreasing frequency include lung, liver, brain, bone, kidney, adrenal, gastrointestinal tract, and spleen. As mentioned previously, choriocarcinoma is the exception to the rule and is characterized by early hematogenous spread, especially to the lung. Choriocarcinoma has also a predilection for unusual sites of metastasis such as the spleen.
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Many clinical staging systems have been proposed for testicular cancer. However, most are variations of the original system proposed by Boden and Gibb (1951). In this system, a stage A lesion was confined to the testis, stage B demonstrated regional lymph node spread, and stage C was spread beyond retroperitoneal lymph nodes. Numerous clinical staging systems have also been suggested for seminoma. A stage I lesion is confined to the testis. Stage II has retroperitoneal nodal involvement (IIA is <2 cm, IIB is >2 cm). Stage III has supradiaphragmatic nodal involvement or visceral involvement. The TNM classification of American Joint Committee (2010) has attempted to standardize clinical stages as in Table 24–1.
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The most common symptom of testicular cancer is a painless enlargement of the testis. Enlargement is usually gradual, and a sensation of testicular heaviness is not unusual. The typical delay in treatment from initial recognition of the lesion by the patient to definitive therapy (orchiectomy) ranges from 3 to 6 months. The length of delay correlates with the incidence of metastases. The importance of patient awareness and self-examination is apparent. Acute testicular pain is seen in approximately 10% of cases and may be the result of intratesticular hemorrhage or infarction.
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Approximately 10% of patients present with symptoms related to metastatic disease. Back pain (retroperitoneal metastases involving nerve roots) is the most common symptom. Other symptoms include cough or dyspnea (pulmonary metastases); anorexia, nausea, or vomiting (retroduodenal metastases); bone pain (skeletal metastases); and lower extremity swelling (vena caval obstruction).
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Approximately 10% of patients are asymptomatic at presentation, and the tumor may be detected incidentally following trauma, or it may be detected by the patient's sexual partner.
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A testicular mass or diffuse enlargement is found in most cases. The mass is typically firm and nontender and the epididymis should be easily separable from it. A hydrocele may accompany the testicular tumor and help to camouflage it. Transillumination of the scrotum can help to distinguish between these entities.
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Palpation of the abdomen may reveal bulky retroperitoneal disease; assessment of supraclavicular, scalene, and inguinal nodes should be performed. Gynecomastia is present in 5% of all germ cell tumors but may be present in 30–50% of Sertoli and Leydig cell tumors. Its cause seems to be related to multiple complex hormonal interactions involving testosterone, estrone, estradiol, prolactin, and hCG. Hemoptysis may be seen in advanced pulmonary disease.
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Laboratory Findings and Tumor Markers
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Anemia may be detected in advanced disease. Liver function tests may be elevated in the presence of hepatic metastases. Renal function may be diminished (elevated serum creatinine) if ureteral obstruction secondary to bulky retroperitoneal disease is present. The assessment of renal function (creatinine clearance) is mandatory in patients with advanced disease who require chemotherapy.
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Several biochemical markers are of importance in the diagnosis and management of testicular carcinoma, including AFP, hCG, and lactic acid dehydrogenase (LDH). AFP is a glycoprotein with a molecular mass of 70,000 daltons and a half-life of 4–6 days. Although present in fetal serum in high levels, beyond the age of 1 year, it is present only in trace amounts. While present to varying degrees in many NSGCTs (Table 24–2), it is never found in seminomas.
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hCG is a glycoprotein with a molecular mass of 38,000 daltons and a half-life of 24 hours. It is composed of two subunits: alpha and beta. The alpha subunit is similar to the alpha subunits of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The beta subunit conveys the activity to each of these hormones and allows for a highly sensitive and specific radioimmunoassay in the determination of hCG levels. A normal man should not have significant levels of beta-hCG. While more commonly elevated in NSGCTs, hCG levels may be elevated in up to 7% of seminomas.
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LDH is a cellular enzyme with a molecular mass of 134,000 daltons that has five isoenzymes; it is normally found in muscle (smooth, cardiac, skeletal), liver, kidney, and brain. Elevation of total serum LDH and in particular isoenzyme-I was shown to correlate with tumor burden in NSGCTs. LDH may also be elevated in seminoma.
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Other markers have been described for testis cancer, including placental alkaline phosphatase (PLAP) and gamma-glutamyl transpeptidase (GGT). These markers, however, have not contributed as much to the management of patients as those mentioned previously.
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The primary testicular tumor can be rapidly and accurately assessed by scrotal ultrasonography. This technique can determine whether the mass is truly intratesticular, can be used to distinguish the tumor from epididymal pathology, and may also facilitate testicular examination in the presence of a hydrocele.
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Once the diagnosis of testicular cancer has been established by inguinal orchiectomy, careful clinical staging of disease is mandatory. Chest radiographs (posteroanterior and lateral) and computed tomography (CT scan) of the abdomen and pelvis are used to assess the two most common sites of metastatic spread, namely, the lungs and retroperitoneum. The role of CT scanning of the chest remains controversial because of its decreased specificity. Of note is the fact that routine chest x-rays (CXR) detect 85–90% of pulmonary metastases. Pedal lymphangiography (LAG) is rarely used owing to its invasiveness as well as low specificity, although it may be warranted in patients undergoing a surveillance protocol (see Section “Treatment”).
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Differential Diagnosis
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An incorrect diagnosis is made at the initial examination in up to 25% of patients with testicular tumors and may result in delay in treatment or a suboptimal surgical approach (scrotal incision) for exploration. Epididymitis or epididymoorchitis is the most common misdiagnosis in patients with testis cancer. Early epididymitis should reveal an enlarged, tender epididymis that is clearly separable from the testis. In advanced stages, the inflammation may spread to the testis and result in an enlarged, tender, and indurated testis and epididymis. A history of acute onset of symptoms including fever, urethral discharge, and irritative voiding symptoms may make the diagnosis of epididymitis more likely. Ultrasonography may identify the enlarged epididymis as the cause of the scrotal mass.
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Hydrocele is the second most common misdiagnosis. Transillumination of the scrotum may readily distinguish between a translucent, fluid-filled hydrocele, and a solid testicular tumor. Since 5–10% of testicular tumors may be associated with hydroceles, if the testis cannot be adequately examined, a scrotal ultrasound examination is mandatory. Aspiration of the hydrocele should be avoided because positive cytologic results have been reported in hydroceles associated with testicular tumors.
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Other diagnoses to be considered include spermatocele, a cystic mass most commonly found extending from the head of the epididymis; hematocele associated with trauma; granulomatous orchitis, most commonly resulting from tuberculosis and associated with beading of the vas deferens; and varicocele, which is engorgement of the pampiniform plexus of veins in the spermatic cord and should disappear when the patient is in the supine position.
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Although most intratesticular masses are malignant, one benign lesion, an epidermoid cyst, may be seen on rare occasions. Usually, these cysts are very small benign nodules located just underneath the tunica albuginea; however, on occasion, they can be large. The diagnosis is usually made following inguinal orchiectomy; as frozen sections, the larger lesions are often difficult to distinguish from teratoma.
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Inguinal exploration with cross-clamping of the spermatic cord vasculature and delivery of the testis into the field is the mainstay of exploration for a possible testis tumor. If cancer cannot be excluded by examination of the testis, radical orchiectomy is warranted. Scrotal approaches and open testicular biopsies should be avoided. Further therapy depends on the histologic characteristics of the tumor as well as the clinical stage.
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Seminoma is exquisitely radiosensitive. About 95% of all stage I seminomas are cured with radical orchiectomy and retroperitoneal irradiation (usually 2500–3000 cGy). This low dose of radiation is usually well tolerated, with minimal gastrointestinal side effects. Because radiation therapy is associated with some morbidity and secondary malignancy risk, there is an increasing interest in surveillance in stage I seminoma. Because of the slow growth rate of seminoma, surveillance must be performed for up to 10 years and typically consists of a history and physical exam and tumor markers every 3–4 months for years 1–3, every 6 months for years 4–7, and then annually up to 10 years. Imaging while on surveillance includes abdominal and pelvic CT at each visit and CXR at alternate visits. Alternatively, single-agent carboplatin has been used in low-stage seminoma (NCCN, 2010).
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Low-volume retroperitoneal disease can also be treated effectively with retroperitoneal irradiation with an average 5-year survival rate of 87%. Prophylactic mediastinal radiation is no longer employed because this may cause considerable myelosuppression and thus compromise the patient's ability to receive chemotherapy if required. Chemotherapy should be used as salvage therapy for patients who relapse following irradiation.
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Patients with bulky seminoma and any seminoma associated with an elevated AFP should receive primary chemotherapy. Seminomas are also sensitive to platinum-based regimens, as are their NSGCT counterparts. Good-risk patients (see later) receive four cycles of etoposide and cisplatin (EP) or three cycles of cisplatin, etoposide, and bleomycin (PEB). Intermediate-risk patients receive four cycles of PEB.
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Ninety percent of patients with advanced disease achieve a complete response with chemotherapy. Residual retroperitoneal masses following chemotherapy are often fibrosis (90%) unless the mass is well circumscribed and in excess of 3 cm, under which circumstances approximately 40% of patients harbor residual seminoma. A positron emission tomography (PET scan) should be performed in patients with a residual mass and if positive, surgical resection is warranted. In such cases, surgical excision is warranted.
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Low-Stage Nonseminomatous Germ Cell Tumors
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Standard treatment for stage I disease in the United States has included retroperitoneal lymph node dissection (RPLND). However, because three-fourths of patients with clinical stage I disease are cured by orchiectomy alone and the morbidity of RPLND is not negligible, other alternatives have been explored. These options include surveillance and open nerve-sparing RPLND.
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Surveillance in stage I NSGCT was proposed because, as mentioned previously, 75% of patients with clinical stage I disease have, in fact, pathologic stage I disease. In addition, infertility related to disruption of sympathetic nerve fibers is common following RPLND. Clinical staging has been markedly improved in the presence of CT scanning and LAG. And finally, effective chemotherapy regimens have been developed for relapse. Patients are considered candidates for surveillance if the tumor is an NSGCT confined within the tunica albuginea, the tumor does not demonstrate vascular invasion, tumor markers normalize after orchiectomy, radiographic imaging shows no evidence of disease (CXR, CT), and the patient is considered reliable.
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Surveillance should be considered an active process on the part of both the physician and the patient. Patients are followed every 1–2 months for the first 2 years, every 3 months in year 3, every 4 months in year 4, and every 6 months in year 5. Tumor markers and CXR are obtained at each visit, and CT scans are obtained every 2–3 months in year 1, every 3–4 months in year 2, every 4 months in year 3, every 6 months in year 4, and once a year in year 5. Most relapses occur, however, within the first 8–10 months. With rare exceptions, patients who relapse can be cured by chemotherapy or surgery, or both.
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Retroperitoneal lymph node dissection has been the preferred treatment of low-stage NSGCTs in the United States until recently. A thoracoabdominal or midline transabdominal approach may be used, and all nodal tissue between the ureters from the renal vessels to the bifurcation of the common iliac vessels is removed. Patients with negative nodes or N1 disease do not require adjuvant therapy, whereas the recommendation for those with N2 disease is to receive two cycles of chemotherapy because their relapse rate approaches 50%.
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While effective in surgically staging and potentially curing a subset of patients, RPLND is associated with significant morbidity, especially with respect to fertility in young men. With a standard RPLND, sympathetic nerve fibers are disrupted, resulting in loss of seminal emission. Currently, a modified RPLND can be performed that preserves ejaculation in up to 90% of patients. By modifying the dissection below the level of the inferior mesenteric artery to include only the nodal tissue ipsilateral to the tumor, important sympathetic fibers from the contralateral side are preserved, thus maintaining emission.
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An alternative approach to patients with clinical stage I disease and vascular invasion in the primary is two cycles of chemotherapy. While obviating the need for surgery, such an approach is associated with neurotoxicity and fertility issues for these young patients.
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High-Stage Nonseminomatous Germ Cell Tumors
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Patients with bulky retroperitoneal disease (>3-cm nodes or three or more 1-cm cuts on CT scan) or metastatic NSGCT are treated with primary platinum-based combination chemotherapy following orchiectomy. Good-risk patients are treated with either four cycles of EP or three cycles of PEB. Intermediate- and poor-risk patients receive four cycles of PEB. If tumor markers normalize and a residual mass is apparent on imaging studies, resection of that mass is mandatory, because 20% of the time it will harbor residual cancer, 40% of the time it will be teratoma, and 40% of the time it will be fibrosis (Figure 24–2). In patients with residual cancer in the resected tissue, the histologic picture is usually embryonal cell carcinoma, but malignant teratoma is seen in <5% of cases. Malignant teratoma is unresponsive to chemotherapy, and only 15% of patients survive following surgical resection. If tumor markers fail to normalize following primary chemotherapy, salvage chemotherapy is required (cisplatin, etoposide, bleomycin, ifosfamide). Even if patients attain a complete response after chemotherapy (normal tumor markers, no mass on CT scan or CXR), some investigators advocate an RPLND because viable germ cell tumor may be seen in up to 10% of cases.
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Although the treatment plan described cures up to 70% of patients with high-volume disease, there are patients who fail to respond. Also, the potential complications from chemotherapy including sepsis, neuropathy, renal toxicity, and death must be considered. It is thus apparent that it is important to be able to discriminate between patients who are likely to respond to standard chemotherapy (good risk) and those who may require more aggressive regimens (intermediate or high risk). Table 24–3 stratifies patients with advanced testicular cancer into risk groups based upon the primary tumor site, location of metastases, and serum tumor markers. The rate of decline of serum tumor markers during chemotherapy has also been used to predict response in patients with advanced disease.
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All patients with testicular cancer require regular follow-up care. As discussed previously, patients on a surveillance protocol require vigorous follow-up. For those who have undergone surgery (RPLND) or radiotherapy, in general, they are followed at 3-month intervals for the first 2 years, then every 6 months until 5 years, and then yearly. Follow-up visits should include careful examination of the remaining testis, the abdomen, and the lymph node areas. Laboratory investigation should include AFP, hCG, and LDH levels. A CXR and an abdominal film (if an LAG was performed) should also be included at each visit. Abdominal CT scans are used less frequently as risk of relapse in the retroperitoneum is low following RPLND.
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Survival in testicular cancer has improved dramatically over the past several years, reflecting the continuing improvement and refinement in combination chemotherapy. For seminoma treated by orchiectomy and radiotherapy, the 5-year disease-free survival rate is 98% for stage I and 92–94% for stage II-A in several recent series. Higher stage disease treated by orchiectomy and primary chemotherapy has a 5-year disease-free survival rate of 35–75%, yet the lower value comes from older series in which more crude chemotherapy regimens were employed.
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Survival in patients with NSGCTs treated by orchiectomy and RPLND for stage I disease ranges from 96% to 100%. For low-volume stage II disease treated with chemotherapy plus surgery, >90% 5-year disease-free survival rates are attainable. Patients with bulky retroperitoneal or disseminated disease treated with primary chemotherapy followed by surgery have a 5-year disease-free survival rate of 55–80%.
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Epidemiology and Risk Factors
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Carcinoma of the penis accounts for <1% of cancers among males in the United States, with approximately one to two new cases being reported per 100,000 men. There is marked variation in incidence with geographic location. In areas such as Africa and regions of South America, penile carcinoma may compose 10–20% of all malignant lesions. Penile carcinoma occurs most commonly in the sixth decade of life, although rare case reports have included children.
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The one etiologic factor most commonly associated with penile carcinoma is poor hygiene. The disease is virtually unheard of in males circumcised near birth. One theory postulates that smegma accumulation under the phimotic foreskin results in chronic inflammation leading to carcinoma. A viral cause has also been suggested as a result of the association of this tumor with cervical carcinoma.
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Precancerous Dermatologic Lesions
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Leukoplakia is a rare condition that most commonly occurs in diabetic patients. A white plaque typically involving the meatus is seen. Histologic examination reveals acanthosis, hyperkeratosis, and parakeratosis. This lesion may precede or occur simultaneously with penile carcinoma.
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Balanitis xerotica obliterans is a white patch originating on the prepuce or glans and usually involving the meatus. The condition is most commonly observed in middle-aged diabetic patients. Microscopic examination reveals atrophic epidermis and abnormalities in collagen deposition.
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Giant condylomata acuminata are cauliflower-like lesions arising from the prepuce or glans. The cause is believed to be viral (human papillomavirus). These lesions may be difficult to distinguish from well-differentiated squamous cell carcinoma.
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Carcinoma In Situ (Bowen Disease, Erythroplasia of Queyrat)
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Bowen disease is a squamous cell carcinoma in situ typically involving the penile shaft. The lesion appears as a red plaque with encrustations.
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Erythroplasia of Queyrat is a velvety, red lesion with ulcerations that usually involve the glans. Microscopic examination shows typical, hyperplastic cells in a disordered array with vacuolated cytoplasm and mitotic figures.
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Invasive Carcinoma of the Penis
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Squamous cell carcinoma composes most penile cancers. It most commonly originates on the glans, with the next most common sites, in order, being the prepuce and shaft. The appearance may be papillary or ulcerative.
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Verrucous carcinoma is a variant of squamous cell carcinoma composing 5–16% of penile carcinomas. This lesion is papillary in appearance, and on histologic examination, it is noted to have a well-demarcated deep margin unlike the infiltrating margin of the typical squamous cell carcinoma.
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Invasive carcinoma of the penis begins as an ulcerative or papillary lesion, which may gradually grow to involve the entire glans or shaft of the penis. Buck's fascia represents a barrier to corporal invasion and hematogenous spread. Primary dissemination is via lymphatic channels to the femoral and iliac nodes. The prepuce and shaft skin drain into the superficial inguinal nodes (superficial to fascia lata), while the glans and corporal bodies drain to both superficial and deep inguinal nodes (deep to fascia lata). There are many cross-communications so that penile lymphatic drainage is bilateral to both inguinal areas. Drainage from the inguinal nodes is to the pelvic nodes. Involvement of the femoral nodes may result in skin necrosis and infection or femoral vessel erosion and hemorrhage. Distant metastases are clinically apparent in <10% of cases and may involve lung, liver, bone, or brain.
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The staging system used most commonly in the United States was proposed by Jackson (1966), and the stages are as follows: In stage I, the tumor is confined to the glans or prepuce. Stage II involves the penile shaft. Stage III has operable inguinal node metastasis. In stage IV, the tumor extends beyond the penile shaft, with inoperable inguinal or distant metastases. The TNM classification of the American Joint Committee (1996) is given in Table 24–4.
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The most common complaint at presentation is the lesion itself. It may appear as an area of induration or erythema, an ulceration, a small nodule, or an exophytic growth. Phimosis may obscure the lesion and result in a delay in seeking medical attention. In fact, 15–50% of patients delay for at least 1 year in seeking medical attention. Other symptoms include pain, discharge, irritative voiding symptoms, and bleeding.
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Lesions are typically confined to the penis at presentation. The primary lesion should be characterized with respect to size, location, and potential corporal body involvement. Careful palpation of the inguinal area is mandatory because >50% of patients present with enlarged inguinal nodes. This enlargement may be secondary to inflammation or metastatic spread.
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Laboratory evaluation is typically normal. Anemia and leukocytosis may be present in patients with long-standing disease or extensive local infection. Hypercalcemia in the absence of osseous metastases may be seen in 20% of patients and appears to correlate with volume of disease.
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Metastatic workup should include CXR, bone scan, and CT scan of the abdomen and pelvis. Disseminated disease is present in <10% of patients at presentation.
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Differential Diagnosis
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In addition to the dermatologic lesions discussed previously, carcinoma of the penis must be differentiated from several infectious lesions. Syphilitic chancre may present as a painless ulceration. Serologic and dark field examination should establish the diagnosis. Chancroid typically appears as a painful ulceration of the penis. Selective cultures for Haemophilus ducreyi should identify the cause. Condylomata acuminata appear as exophytic, soft, “grape cluster” lesions anywhere on the penile shaft or glans. Biopsy can distinguish this lesion from carcinoma if any doubt exists.
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Biopsy of the primary lesion is mandatory to establish the diagnosis of malignancy. Treatment varies depending on the pathology as well as the location of the lesion. CIS may be treated conservatively in reliable patients. Fluorouracil cream application or neodymium:YAG laser treatment is effective for CIS and is preserving of the penis. Patients must come for frequent follow-up examinations to monitor response.
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The goal of treatment in invasive penile carcinoma is complete excision with adequate margins. For lesions involving the prepuce, this may be accomplished by simple circumcision. For lesions involving the glans or distal shaft, partial penectomy with a 2-cm margin to decrease local recurrence has traditionally been suggested. Less aggressive surgical resections such as Mohs micrographic surgery and local excisions directed at penile preservation yet attaining a negative surgical margin have gained popularity. For lesions involving the proximal shaft or when partial penectomy results in a penile stump of insufficient length for sexual function or directing the urinary stream, total penectomy with perineal urethrostomy has been recommended.
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As discussed previously, penile carcinoma spreads primarily to the inguinal lymph nodes. However, enlargement of inguinal nodes at presentation does not necessarily imply metastatic disease. In fact, up to 50% of the time this enlargement is caused by inflammation. Thus, patients who present with enlarged inguinal nodes should undergo treatment of the primary lesion followed by a 4- to 6-week course of oral broad-spectrum antibiotics. Persistent adenopathy following antibiotic treatment should be considered to be metastatic disease, and sequential bilateral ilioinguinal node dissections should be performed. If lymphadenopathy resolves with antibiotics, observation in low-stage primary tumors (Tis, T1) is warranted. However, if lymphadenopathy resolves in higher stage tumors, more limited lymph node samplings should be considered, such as the sentinel node biopsy described by Cabanas (1977) or a modified (limited) dissection as suggested by Catalona (1988) (Figure 24–3). If positive nodes are encountered, bilateral ilioinguinal node dissection should be performed. A decision tree for penile carcinoma is presented in Figure 24–4. Patients who initially have clinically negative nodes but in whom clinically palpable nodes later develop should undergo a unilateral ilioinguinal node dissection.
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Patients who have inoperable disease and bulky inguinal metastases are treated with chemotherapy (cisplatin and 5-fluorouracil). In some cases, regional radiotherapy can provide significant palliation by delaying ulceration and infectious complications and alleviating pain.
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Four chemotherapeutic agents demonstrate activity against penile carcinoma: bleomycin, methotrexate, cisplatin, and 5-fluorouracil. However, no long term responders have been reported.
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Survival in penile carcinoma correlates with the presence or absence of nodal disease. Five-year survival rates for patients with node-negative disease range from 65% to 90%. For patients with positive inguinal nodes, this rate decreases to 30–50% and with positive iliac nodes decreases to <20%. In the presence of soft tissue or bony metastases, no 5-year survivors have been reported.
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Squamous cell carcinoma accounts for 98% of penile cancers. Sporadic cases of melanoma, basal cell carcinoma, and Paget disease have been reported. The incidence of Kaposi sarcoma of the penis is increasing with the increasing prevalence of the human immunodeficiency virus. It appears as a painful papule on the glans or shaft with bluish-purple discoloration. These lesions tend to be radiosensitive.