Testis Cancer: Germ Cell Tumors Testis tumors make up approximately two percent of all malignant cancers in men and account for up to ten percent of all malignant disease occurring within the male genitourinary system. More importantly, testis tumors are the most common malignant disease, excluding leukemia, developing in men between 20 and 34 years of age. Most of these tumors occur in three age groups - infancy, late adolescence and early adulthood. The cause of testis tumors is unknown. It occurs with an incidence of 2 to 3 per 100,000 males per year with some geographic variance, most notably in Denmark where the incidence has been reported as high as 6 per 100,000 per year. There is a higher incidence of testis cancer in undescended testicles. Testis tumors are rare in the black population regardless of which geographic black population is studied, i.e. African-Americans or Native Black Africans. A less dramatic lower incidence occurs as well in the Oriental race. In this country there are approximately 6,000 cases of testis cancer per year. Over the past twenty years a tremendous amount of knowledge has evolved due to the advances in basic science and pharmaceutical research, clinical pathology, advanced radiologic and diagnostic testing, tumor markers, and surgical skills. The use of testis tumor markers allows us to more accurately stage testis cancer and thus develop more logical treatment plans. Two decades ago testis tumors were the most common solid tumor cause of death in young males. Today surgery and chemotherapy for testis cancer is generally highly effective and achieves some of the highest successes in the field of oncology. Although tremendous progress has been made in the diagnosis and treatment of testis tumors, much work remains to be done....the patient with advanced testis cancer continues to present a formidable challenge. More recently the treatment plan has focused on reducing the amount of treatment without compromising the cure rate. As with other pendulum swings in medicine, "one size will probably not fit all". Q: What are the signs/symptoms of testis cancer? Dr. Green: Normally, the patient will present with a painless swelling or lump, or heavy feeling in the testis/scrotum. Epididymitis and epididymo-orchitis (inflammation of the attachment to the testis and testis) are the most frequently mistaken diagnosis for testis cancer. A non-tender heavy, enlarging hard testis mass is classic, but not always present. Associated testis pain occurs in approximately 40% of patients. Gynecomastia (enlarged breast) occurs in 2-4% of patients). In 5 to 10% of patients symptoms result from metastasis, e.g., back pain, vague abdominal pain. Q: Do all cases of testis cancer have symptoms or signs? Dr. Green: Unfortunately not. In a small group of patients, symptoms are absent or so minor as not to call the patient's attention to the testis cancer. Q: I've heard that a lot of testis cancer is detected late ....is that true? Dr. Green: Unfortunately, yes. One of the most tragic clinical features of testis cancer is the delay in diagnosis from the time of initial recognition to the time of treatment. This delay is often due to the insidious presentation and lack of overt signs. This delay not uncommonly exceeds six months. Ten percent of patients present with symptoms of metastasis when first seen and up to thirty-five percent of patients have evidence of metastatic disease when first seen. Q: How does one diagnose testis cancer? Dr. Green: (1) physical examination, which includes inspection and gentle bimanual palpation of the testes beginning with the normal testis first; any area of irregularity or firmness should be considered a tumor until proven otherwise, (2) the blood test (tumor markers) Alpha-1 fetoprotein and beta human chorionic gonadotropin, (3) testicular ultrasound, (4) testis removal and rarely biopsy (surgery). NB: The diagnosis of testis cancer may be suspected clinically but can only be proven by examination of excised tissue. Q: Are all testis cancers the same? Dr. Green: No, testis cancers are divided into two classes; germinal and non-germinal tumors. This article is concerned with germ cell tumors only. Germ cell tumors are those which are derived from germinal epithelium versus those which are of gonadal stroma origin. Tumors of germ cell origin comprise about 95% of all testis cancer. Germ cell tumors are further divided into five basic groups: 1) seminoma, which is the most common testis tumor, occurring in approximately 40% of the population; 2) embryonal carcinoma with or without seminoma, which occurs in about 25% of the group; 3) teratoma with or without seminoma, which occurs in about 7% of the group; 4) teratocarcinoma including teratoma with embryonal carcinoma, choriocarcinoma, or both with or without seminoma occurring in about 25% of the group; and 5) choriocarcinoma with or without seminoma or embryonal carcinoma or both account for the remaining 1-3%. Q: How does one treat testis cancer? Dr. Green: In order to properly treat testis cancer after making the diagnosis, the patient must be staged, i.e., determine the extent of the cancer: e.g., is it localized to the testis or has it spread beyond the testis? Currently at least six methods of staging are used in the United States. For our purpose, the following staging system will be used: - Stage I: tumor is confined to the testis, there is no evidence of spread beyond the confines of the testis.
- Stage II A: regional lymph node involvement less than 10 cm.
- Stage II B: regional lymph node involvement greater than 10 cm.
- Stage III: extensive lymph node involvement extending above the diaphragm, e.g., mediastinal or supraclavicular nodes.
- Stage IV: extralymphatic spread to solid visceral organs, brain, or bone.
Q: How do you stage testis cancer?
Dr. Green: Once the histologic diagnosis is secure, staging of the tumor is critical and includes the following: - chest x-ray or computerized axial tomography (CT) of the chest
- CT of the retroperitoneum and pelvis
- possible lymphangiography
- serum markers, alpha fetoprotein and beta human chorionic gonadotropin, must be determined prior to and after orchiectomy (testis removal).
Q: What is "lymphangiography" and are there other staging tests?
Dr. Green: Oh yes, lymphangiography ...."a forgotten diagnostic tool" and a "lost art" in some facilities. Lymphangiography is a radiologic technique whereby a lymphatic channel is canulated in the foot and injected with an iodinated contrast liquid under low pressure over approximately 1 1/2 hours. This allows for complete opacification of the lymphatic drainage system to the level of the thoracic duct. Criteria exist for interpretation of lymphangiography. This tool is rarely used today due to the technological advancement of CT imaging and the high false positive and negative rates with lymphangiography, as well as greater potential for complications as compared to CT. However, since CT scan, especially in the very thin young patient, often produces false negative results, lymphangiography combined with plain x-ray and CT probably offers the greatest staging accuracy especially for seminoma patients because most will not undergo lymph node dissection. Yes, there are other staging tests but are used only selectively when indicated, e.g., an intravenous pyelogram (IVP) is probably important only in the presence of a suspected large retroperitoneal mass. A liver scan is of little value unless a suspicious lesion is found on CT scan. Bone scans are rarely positive unless disseminated disease is present, and are probably necessary only in patients with advanced disease. A brain scan is indicated only when diffuse metastatic disease is present or when focal neurologic signs are present. Lactic Acid Dehydrogenase (LAD) may be helpful in monitoring germ cell tumors. Placental Alkaline Phosphatase (PAP) may be helpful in monitoring seminoma. Q: How accurate is clinical staging? Dr. Green: Once again, clinical staging attempts to define the extent of disease at the time of diagnosis. The accuracy of clinical assessment is imperative if the physician is to be able to make a logical decision as to therapy. Such knowledge allows the orderly decision of algorithms for appropriate treatment as well as reasonable expectations for prognosis. With the advent of alternative treatment protocols, "surveillance", for patients with clinical low-stage testicular cancer, the impact of staging and its accuracy assumes ever greater importance. Q: How do you treat testis cancer (germ cell)? Dr. Green: Treatment depends upon many factors, paramount of which are histologic group, i.e., seminoma versus non-seminoma germ cell tumors (NSGCT) and the stage of the cancer. Let us begin with seminoma; Remember, a radical orchiectomy through an inguinal approach is the initial diagnostic modality and treatment for all testis cancers. Seminoma: Stage I: the risk of retroperitoneal metastases in patients without clinical evidence of spread is less than that of NSGCT. In contrast, for NSGCT the risk is 30-40% versus 20% for seminoma. This has prompted consideration for "surveillance" therapy, i.e. patients are observed closely and monitored with physical examinations and ancillary testing at intervals of two to six months and receive additional therapy, radiation or chemotherapy, only if they relapse; the type of therapy depends on the location of the relapse, e.g., retroperitoneum or distant metastasis. The traditional or standard post-orchiectomy therapy has been low dose radiotherapy to the ipsilateral lymph nodes and the retroperitoneal lymph nodes to the diaphragm. The cure rate is approximately 99%, albeit not without some toxicity and long-term radiotherapy complications. Although surveillance has demonstrated efficacy as an alternative to standard radiation treatment, the series are small short-termed, and require a large commitment of resources from the healthcare system. Stage II A: the area of greatest controversy and uncertainty. Primary standard radiation therapy produces cure in approximately 70% of patients. The controversy exists regarding the use of supra-diaphragmatic therapy because of the small although real isolated recurrences in the supra-diaphragmatic areas. Clearly, no proof exists for one stance over the other. Until this controversy is resolved our recommendations are based on volume of tumor and are as follows: 1 . Patients with tumor masses less than 5 cm - No supra-diaphragmatic radiation. 2. Patients with tumor masses greater than 5 cm and up to 10 cm may benefit from supra-diaphragmatic radiotherapy and still have a prospect for effective chemotherapy in the rare case of tumor recurrence. Stage II B: These patients have large, bulky, often palpable masses in the retroperitoneum. The cure rate for radiation alone is between 50-70%, below that achieved with NSCGT. Because the amount of radiation required to treat this large volume of cancer would compromise further chemotherapy, chemotherapy should probably be the primary treatment of choice (TOC) in patients with large retroperitoneal metastasis with possible cytoreductive surgery. Stage III and IV: Since this represents extensive lymphatic or disseminated metastatic disease, chemotherapy is the TOC. Q: What role does surgery play in the treatment of seminomas? Dr. Green: Let's repeat ....the initial diagnosis is obtained from surgical removal of the testis. Due to the excellent response to radiotherapy and the dramatic effectiveness of chemotherapy for treatment failures, surgery is seldom indicated in patients with Stage I or II A cancer. Patients with Stage II B or III tumor may sometimes benefit from adjuvant surgery. As less toxic chemotherapeutic regimens are identified, the role of chemotherapy will probably increase, whereas that of radiotherapy will correspondingly decrease. Nonetheless, it must be remembered that these tumors are exquisitely radiation sensitive and early stage tumors are best treated with that modality. The role of surgery is diminishing and surgery is indicated only in rare cases. Let us now address the non-seminomatous germ cell tumors (NSGCT): Non-seminoma germ cell tumors (NSGCT) Q: How do you treat NSGCT? Dr. Green:
1) For Stage I tumors, removal of the testis through the inguinal area remains the TOC for pathologic diagnosis as well as local treatment. Morbidity is minimal and mortality should be virtually zero while allowing for 100% local control. Transcrotal biopsy is to be condemned. 2) Without evidence of metastasis, patients can be treated either with prophylactic lymphadenectomy or "surveillance". 3) If there is evidence of limited lymph node metastasis in the retroperitoneum, the TOC is: - retroperitoneal lymphadenectomy plus or minus chemotherapy or
- chemotherapy plus or minus salvage lymphadenectomy; primary chemotherapy should not be used if there are teratomatous elements in the primary tumor
- metastatic disease - TOC is chemotherapy
- for residual tumor following chemotherapy-surgical resection is usually performed; exceptions are patients with greater than 90% shrinkage, normalization of markers, and absence of teratomatous elements.
Q: What is the prognosis for testis cancer? Dr. Green: In general, 90 to 100% of patients with localized tumors can be cured and up to 70% with metastatic disease can be cured. Q: What are some complications of retroperitoneal lymphadenectomy? Dr. Green: There are several potential complications; the most notable is infertility secondary to denervation of the L1, 2 sympathetic nerve supply to the ampullae of the seminal vesicles and vas deferens, however, using nerve-sparing operations somewhat reduced in scope to modified unilateral dissection or bilateral dissections with preservation of the sympathetic nerves, ejaculation can be preserved in 50 to 90%. Q: What are the clinical short comings of "surveillance therapy"? Dr. Green: Up to 25% relapse rate which is even greater if there is embryonal carcinoma, invasion of the epididymis or vascular invasion. Q: Do children get testis cancer? Dr. Green: Testis cancer in the pediatric age group is rare, affecting one per 1 million Caucasian-American boys up to age 15. They account for only 1% of all childhood malignancies. Q: What are the most common types of testis tumors for adults and children? Dr. Green: For adults - Seminoma (40%)
For children - Yolk sac (72%) Q: Is it true that testis tumors occur on one side more than the other? Dr. Green: Yes, there appears to be a slight but definite predilection for testis tumors to involve the right side. Q: Can testis tumors occur in both testes? Dr. Green: Yes again, although rare, approximately 2% of cases (either simultaneous or sequential). The most common bilateral testis tumor is malignant lymphoma accounting for approximately 50% of the cases. Q: Do undescended testes have a higher incidence of subsequent development of testis cancers? Dr. Green: Yes, a patient with a cryptorchid testis has a 10 to 40 fold increase in the incidence of malignant degeneration of the testicle when compared to patients with normal testicular descent. Early orchiopexy (prior to six) may prevent subsequent tumor formation. Summary: Testicular cancer represents the most common malignancy in men in the age group from 15-35 and is the second most common malignancy from age 35-39. Testicular cancer has become one of the most curable solid neoplasms in the 1990s. Dramatic improvements in survival, with almost a total reversal from a 10 percent survival in the 1970s to a 90 plus percent survival in the 1990s, have resulted from the combination of effective diagnostic techniques, improvement in serum tumor markers, effective multi-drug chemotherapeutic regimens, and modifications of surgical techniques. All of these advances have led to a decline in morbidity and mortality. In the 1990s, overall survival for all stages of testicular cancer should be well above 80 percent and should approach 100 percent for patients with low-stage disease. Despite these remarkable advances, a high index of suspicion with increase in patient's "testes self-examination" leading to an earlier diagnosis of the primary lesion still remains the most important factor in further improving the overall survival rate in these patients. A word to the wise... "keep your eye on the ball". | 
