ABSTRACT: Whether patients with clinical stage I nonseminomatous testicular germ-cell cancer (NSGCT) should be treated with orchiectomy and retroperitoneal lymph node dissection (RPLND) or orchiectomy and surveillance remains controversial. Proponents of the former approach cite the uncertainty and risks of monitoring young men who may harbor occult metastases, while proponents of the latter strategy contend that surgical staging overtreats 60% to 70% of men. Over the last few years, prognostic factors in the primary testicular tumor have helped clinicians make more rational decisions about whether RPLND or surveillance should follow initial orchiectomy. As of 1996, the most clinically useful prognostic factors are the percentage of embryonal carcinoma and the presence or absence of vascular invasion by tumor cells in the primary tumor. Ongoing work with flow cytometry, image analysis, proliferation markers, and oncogene and tumor-suppressor gene markers may allow us to further stratify patients as to their likelihood of occult metastases and permit rational "risk-adaptive" treatment. [ONCOLOGY 10(9):1359-1374, 1996]
It is estimated that in 1996, there will be 6,600 new cases of testicular cancer in the United State and 63% of these will be clinically localized at initial diagnosis. If half of the new cases are nonseminomas, approximately 2,050 cases of clinical stage I nonseminomatous germ-cell tumor (NSGCT) will be diagnosed.
Major controversy persists over the care of these patients. Inexact staging does not permit true stage I disease, ie, that confined to the testis, to be distinguished from occult stage II/III retroperitoneal or distant disease. Because up to 30% of men will have occult retroperitoneal disease that is not appreciated on initial staging studies, the standard of care in the United States continues to be orchiectomy followed by retroperitoneal lymph node dissection (RPLND) rather than by surveillance (observation). Based on the numbers above, some might argue that over 1,400 patients (2,050 × .7) per year are being subjected to an unnecessary major abdominal procedure. In fact, this has been the major argument given by those who favor surveillance as initial treatment for clinical stage I NSGCT.
Prognostic factors for testicular cancer patients have only become relevant over the last 20 years with the advent of cisplatin (Platinol)-based curative chemotherapy. Prior to this, the majority of patients died, and the value of prognostic markers was moot.
Over the last decade a number of primary tumor prognostic factors have been discovered that may be useful in stratifying clinical stage I patients as to their likelihood of harboring occult disease. Clinical use of these markers may help identify which patients are best managed by RPLND as opposed to observation or even primary chemotherapy. Use of these markers to guide therapy, termed "risk-adaptive" management, may allow for a more rational scientifically based decision in favor of RPLND or surveillance for individual patients.
The following sections will examine the value of individual histologic, clinical, and molecular and proliferative prognostic factors for stratifying the clinical stage I patient.
The utility of vascular invasion (VI) as a prognostic marker in clinical stage I NSGCT was first recognized in a 1983 surveillance study by Peckham et al. These authors noted that 6 of 8 patients who had VI and/or lymphatic invasion (LI) relapsed, as compared with only 5 of 19 patients without these features. However, not all early studies recognized the importance of VI. For example, in another study of 1,058 testicular cancer patients examined for prognostic factors in 1984, no mention of VI was made.
With studies conducted in the mid-1980s, however, the potential importance of VI became more obvious.[7-10] The studies by Fugime et al and Moriyama et al were limited by small numbers of patients, the inclusion of all stages of disease, and the failure to perform multivariate analysis. Javadpour and Young studied 165 NSGCT patients for prognostic factors and found VI to be correlated with clinical stage I staging error and recurrence after negative RPLND.
The main problem with these early studies, which still plagues some studies performed recently, is the failure to clearly define what constitutes VI. Some investigators have found it difficult to differentiate blood vessel from lymph vessel invasion[7-11] or simply failed to specify exactly what was included as VI.
• Multivariate and Surveillance Studies—Studies conducted in the late 1980s shed more light on the subject by carefully defining vascular and lymphatic invasion and by performing multivariate analyses on prognostic factors.[13-19] Hoskin et al were the first to carefully define VI as tumor within a luminal space lined by endothelium and containing a smooth muscle wall; LI was tumor in an endothelial-lined space but without a smooth muscle wall. These investigators also were the first to carry out multivariate analysis. In their multivariate prognostic factor study of clinical stage I nonseminomas, Dunphy et al even provided a photomicrograph to demonstrate the difference between VI and LI.
Table 1 summarizes those factors proven by multivariate statistical testing to have prognostic importance in clinical stage I NSGCT. Both Hoskin et al and Dunphy et al did not find VI to be significant on multivariate analysis; however, LI was felt to be important. In the multivariate analysis of Freedman et al, both VI and LI maintained significance. These three studies[13-15] used relapse on a surveillance protocol as an end point of the prognostic capability of VI.
In contrast, Fung et al and Moul et al used pathologic stage II disease at RPLND or later recurrence as end points, and noted that VI alone, but not LI, remained significant by multivariate testing. The largest study (279 patients) by Klepp et al, which also used positive RPLND and/or recurrence after RPLND as end points, did not examine VI and LI individually. However, both variables analyzed together were predictive in their multivariate analysis.
Table 2 lists surveillance studies that have commented on factors predictive of recurrence. Some studies evaluated VI and LI individually, whereas others combined VI and LI. Most of these surveillance studies did find VI to be important.
• Prospective Study—From the preceding discussion, it is clear that VI is an exceedingly important prognostic factor in clinical stage I nonseminoma with regard to predicting both recurrence on surveillance and occult disease found at RPLND. A study by Pont et al prospectively utilized VI to stratify patients between surveillance and primary chemotherapy. When this single prognostic factor was used, relapses occurred in only 3 (7.5%) of 40 patients, 1 in the surveillance arm and 2 in the chemotherapy arm.
These authors were very careful in defining VI as: "(1) compact aggregation of tumor cells within the lumen similar to or associated with a thrombotic occlusion and/or (2) definite endothelial destruction by tumor invasion. Isolated tumor cells or tumor cell aggregation in the vascular space without actual attachment to the wall cannot be accepted for vascular invasion, since they are possibly artifacts resulting from specimen processing. Lymphatic invasion is not evaluated since to our pathologists it appears impossible to define invasion into lymphatic spaces on a histological basis without misinterpreting artifacts."
• Areas of Controversy—Despite the critical importance of VI, there is still controversy, particularly over the use of VI alone, LI alone, the combination of VI and LI, and even, as Pont et al noted, the validity of diagnosing LI. Since the average small- or medium-sized hospital does not see an abundance of testicular cancer cases, and even many medical centers are hampered by a similar problem, it is essential to have an experienced reference pathologist review these cases. This point is illustrated in the Testicular Cancer Intergroup Study. The central laboratory detected VI in 179 (43%) of 414 specimens, whereas the local pathologist found VI in only 59 (14%) of 414 specimens. There were even more striking differences in recurrence rates comparing VI determined by local vs reference pathologists. When VI was assessed locally, recurrence rates were 35% and 19% in patients with and without VI. In contrast, these rates were 40% and 8%, respectively, when VI was assessed by the reference pathologist.
Because of differences in the definition of VI and the ability to detect it, Stephenson has pointed out that VI rates vary between 16% to 53% even among institutions that care for significant numbers of testicular cancer patients. These data further emphasize the need for an experienced reference pathologist to examine all testicular cancer orchiectomy specimens for VI.
• Neovascularization—A related concept to VI, neovascularization, has recently been described as a prognostic marker in clinical stage I NSGCT. When factor VIII staining was used to determine microvascular counts in 65 patients with clinical stage I disease, none of the patients with pathologic stage I disease had microvessel counts > 400 per high power field. Neovascularization did not remain a significant predictor of occult disease in multivariate analysis, however. Further prospective work with larger numbers of patients is needed to determine whether this prognostic marker has clinical value.
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