ABSTRACT: The management of germ cell tumors has advanced dramatically, with cure rates approaching 90% to 95%. Treatment of stage I/A seminomas generally includes orchiectomy and adjuvant radiotherapy. Treatment of stage I/A nonseminomatous germ cell tumors involves orchiectomy followed by retroperitoneal lymph node dissection or active surveillance. One of the major advances has been the introduction of cisplatin(Drug information on cisplatin)-based chemotherapy for metastatic disease and the development of a system of risk attribution. The logical management of any patient with curable disease is to provide curative therapy and then follow the patient in a structured manner, to diagnose and treat any complications in a timely manner.
In the second half of the past century, dramatic improvements were made in the management of advanced cancers of the genitourinary tract, with particular progress in the management of germ cell tumors. The management of metastatic testicular germ cell tumors has become one of the paradigms of successful treatment, reflecting advances in chemotherapy and an improved understanding of the principles of tumor biology and of the importance of multidisciplinary management. Nevertheless, with increasing experience, we have come to recognize that these approaches to treatment have some flaws, and that we must be careful if we are to maintain the high cure rates that have been achieved.
An increased understanding of risk factors has allowed us to tailor our treatment to the level of risk. We have come to realize that some of our treatment strategies are associated with significant late effects, and we have attempted to avoid these by modifying some treatment approaches. However, such attempts to improve treatment outcomes have failed, largely because of a reduction in the initial cure rate. This serves to illustrate a critically important principle- when effective treatment is available, modifications must be introduced in a thoughtful and structured manner to ensure that there are no hidden costs associated with the innovations under consideration (Table 1).
Most germ cell tumors arise from tissues derived from primordial cells that originate within the genital ridges and usually migrate in the midline to the testicles, and less frequently, to the retroperitoneum, mediastinum, and pineal region. These cells are capable of differentiating along two major histogenetic lines, forming seminomas and nonseminomatous germ cell tumors (NSGCT).[1,2] All of these tumors have a common germ cell origin and, in the testicles, arise from precursor cells described histologically as carcinoma in situ. Less than 5% of testicular cancers are lymphomas and other non-germ cell tumors.[ 1,4] The ability to differentiate along different pathways is of particular importance with regard to late relapse (see below).
The most common type of seminoma is the classical variant, composed of uniform, round, or polygonal cells with abundant cytoplasm and a centrally placed nucleolus. Less common spermatocytic and anaplastic variants have been described, although it should be noted that the anaplastic variant sometimes represents a misdiagnosed NSGCT. Seminomas are characterized by the presence of syncytiotrophoblastic giant cells in about 30% of cases, and these may produce a marker protein, human chorionic gonadotropin (HCG).
We have identified a subgroup of seminomas, morphologically resembling a solid variant of yolk sac carcinoma that is associated with a worse prognosis when treated with conventional radiotherapy or standard chemotherapy regimens. Studies are in progress to define whether the biochemical determinants of outcome identified in the molecular revolution may explain the differences in the natural history of these tumors- for example, aberrations in expression of c-kit, other oncogenes, or tumor-suppressor genes.
Nonseminomatous Germ Cell Tumors
The group of NSGCTs includes several histologic subtypes: embryonal carcinoma, mature and immature teratoma, endodermal sinus tumor, and choriocarcinoma. Frequently, NSGCT may consist of elements of undifferentiated cancer, trophoblastic tissue, and varying components of somatic differentiation, such as cartilage, glandular tissue, or hair.[1,2] Another tumor marker, alpha-fetoprotein (AFP) is classically produced by endodermal sinus tumor, although it is also associated with embryonal carcinoma. The presence of AFP in the circulation signifies the presence of nonseminomatous elements, even if pure seminoma has been diagnosed in the primary tumor. This constitutes an indication to manage the patient for a nonseminomatous germ cell malignancy.
Testicular seminomas and NSGCTs share many features in common[ 1,2]: (1) Both occur predominantly in males aged 18 to 35 years; (2) both usually follow an orderly pattern of spread, from the testis to the surrounding supportive tissues and/or up the spermatic cord, to regional and distant lymphatic channels, and sometimes to visceral sites via blood-borne metastasis; (3) both are characterized by the elaboration of tumor markers and by common etiologic associations, including a characteristic marker of the short arm of chromosome 12,[6,7] testicular maldescent, carcinoma in situ of the testis, and a less clearly explained association with the syndrome of multiple atypical nevi; (4) both histologic patterns have been associated with a susceptibility gene localized to chromosome Xq27; and (5) both are highly sensitive to the effects of chemotherapy.[10,11]
However, important differences exist between testicular seminomas and NSGCT, including a somewhat older age range for patients with seminoma, a slightly higher prevalence of second primary tumors among males with seminoma, different patterns of metastasis, and a substantial radiosensitivity in seminoma vs marked radioresistance in NSGCTs. Although the data are relatively preliminary, it appears that the c-kit ligand is expressed more heavily in seminomas than in NSGCTs,[12,13] and this leads to the potential for an increased chance of clinical improvement in response to modulators of these ligands, such as imatinib(Drug information on imatinib) mesylate (Gleevec) or more specific developmental compounds, when used for seminoma as opposed to NSGCT.
When presenting at extragonadal sites, the biology of these tumor types is less similar: The seminomatous tumors tend to retain sensitivity to treatment with chemotherapy or radiotherapy, and patients with these tumors are relatively easily cured. By contrast, the extragonadal NSGCTs are associated with much higher relapse rates and inferior cure rates.[14-16] The reasons for these differences are unknown, as the testicular and extragonadal tumors share virtually identical histologies and etiologic associations and similar patterns of spread.
Primary testicular cancer commonly presents as a painless enlargement of the testis, often noted on self-examination. There may be local pain, which is often associated with hemorrhage within the tumor. Occasionally, a large tumor will drag on the spermatic cord, causing referred pain in the region of the flank, which, therefore, does not necessarily indicate the presence of retroperitoneal lymph node metastases. Unless the patient has previously undergone surgery for testicular maldescent or scrotal violation as part of the initial management of the primary tumor (a cardinal error), inguinal lymph nodes are usually not involved. Drainage of the testis is typically to the lymph nodes at the level of the ipsilateral renal hilum.
The symptoms of metastatic germ cell tumors are protean and depend on the sites of involvement.[20,21] Most commonly, the retroperitoneal lymph nodes are involved early, which can be associated with lumbar backache or central/lower abdominal pain. Occasionally, renal colic is due to obstruction of the ureters by advanced lymph node metastases. Pulmonary metastases may be asymptomatic or, if extensive, may be associated with dyspnea, cough, hemoptysis, or chest pain. Brain metastases, although uncommon, may manifest as headache, confusion, dementia, or focal neurologic syndromes, and occasionally may be detected in the routine staging workup.[ 22,23] Liver or bone involvement is now distinctly uncommon at presentation but may be associated with relapse. When these features are seen at presentation, choriocarcinoma should be considered as the most likely histologic subtype. It should be kept in mind, however, that seminoma will sometimes metastasize to bone.
Germ cell tumors may be associated with nonspecific or constitutional symptoms, including weakness, sweats, fevers, malaise, and asthenia, especially in the case of advanced disease. Gynecomastia may indicate the presence of testicular cancer, especially in patients with a dominant element of choriocarcinoma either in a primary tumor, metastatic deposits, or both.
Extragonadal germ cell tumors manifest symptoms similar to those described above, although they are more heavily influenced by the site of origin. For example, pineal germ cell tumors may be associated with headache, confusion, visual changes, stroke-like syndromes, and Parinaud's syndrome. The presentation of retroperitoneal germ cell tumors is identical to that of testicular tumors with retroperitoneal metastases, with the exception of an obvious testicular primary. Mediastinal germ cell tumors are commonly associated with dyspnea, cough, chest, or back pain, and occasionally with superior vena cava syndrome. Mediastinal NSGCTs are commonly associated with metastases at presentation, and the symptoms reflect the sites of those metastases (Table 2).[24,25]
The efficacy of treatment is routinely monitored by clinical assessment, using physical examination and appropriate imaging studies. Plain radiographs and computerized axial tomographic (CT) scans are the standard modalities, with CT having almost completely replaced lymphangiography.[ 26] For brain metastases, magnetic resonance imaging (MRI) is superior to CT scanning, but the role of MRI in the assessment of other sites of systemic disease remains controversial. Although preliminary evidence supports the use of positronemission tomography (PET) in assessing the presence of viable cancer in residual deposits after chemotherapy for germ cell tumors, this technology has not yet secured a defined place in management, given conflicting reports regarding specificity and sensitivity.
The circulating tumor markers AFP and HCG should also be measured as part of the initial diagnostic work-up and when monitoring therapy. The first specimens should be obtained prior to primary surgery. AFP has a normal half-life in the circulation of 5 to 7 days, and HCG has a half-life of 24 to 36 hours. Prolongation of a circulating marker's half-life after orchiectomy usually denotes occult metastatic disease, and indicates the need for further investigation and treatment.
In patients with metastatic disease, the absolute levels of tumor markers constitute independent prognostic determinants. During chemotherapy, there may be a transient release of markers from dying cancer cells, causing a transient elevation of blood levels before they begin to decline according to normal half-life gradients. Thus, serial measurements should be taken to determine whether the patient is responding adequately to treatment. If these repeated measurements are not taken during the period of chemotherapy, tumor marker release will not be identified and the half-life calculation will be incorrect, suggesting a prolonged tumor marker decline (incorrectly implying the presence of resistant disease).