ABSTRACT: Improvements in the clinical staging of testicular cancer may permit the identification of clinical stage I patients at low risk of harboring metastatic disease, who could be spared treatment and observed only. Both retrospective, single-institution studies and studies of unselected, consecutive patients have confirmed that vascular invasion, lymphatic invasion, and percentage of embryonal carcinoma are predictive of metastasis in patients with low-stage nonseminoma. Whether patients with these risk factors have a worse outcome if managed with surveillance, rather than with aggressive therapy, is unclear. Low MIB-1 staining (which identifies the Ki-67 antigen) in conjunction with a low percentage of embryonal carcinoma in the testicular specimen appears to be predictive of a low probability of metastasis. Computed tomography (CT) is a useful staging tool. A new prognostic classification system for seminomas and nonseminomas was recently developed by an international consensus conference. Laparoscopic retroperitoneal lymphadenectomy appears to be a feasible staging tool with acceptable short-term morbidity. Whether laparoscopic lymph node dissection is equivalent to the open procedure when used as a therapeutic modality is not yet known. At present, laparoscopy should be used only in selected patients in a study setting. Primary chemotherapy is not recommended currently because it has not yet been proven to be superior in patients with high-risk clinical stage I nonseminoma and can cause significant long-term sequelae.[ONCOLOGY 13(12):1689-1694, 1999]
The treatment of testicular cancer continues to evolve. Several treatment alternatives are available that afford an excellent chance for cure in patients with low-stage seminoma or nonseminoma. Current issues in low-stage disease relate to minimization of the morbidity of therapy and maximization of the patient’s psychological and physiologic well-being. In addition, cost constraints are important issues in low-stage testicular cancer.
With respect to good- or intermediate-risk patients with high-stage disease, minimization of treatment-related morbidity is being actively studied. Another very pertinent issue in high-stage disease is the treatment of patients with poor-risk features.
The current article is not meant to be an exhaustive review of clinical studies of staging, prognosis, and treatment. Rather, the intent is to update the clinician on recent advances in these three aspects of testis cancer management.
Patients with clinical stage I or II nonseminoma have approximately a 95% to 99% chance of being cured. These patients are treated primarily with either nerve-sparing retroperitoneal lymphadenectomy, surveillance, or primary chemotherapy. Reported outcomes using these treatment strategies in patients with clinical stage I or II nonseminoma are approximately equal, at least over the short term. Therefore, improvements in clinical staging are unlikely to change the prognosis of the patient but may, by identifying metastasis earlier, allow for selection of the single most effective method of management in an individual patient.
What, then, is to be gained from improvements in the clinical staging of these patients? Since approximately 70% of clinical stage I patients, in fact, do not develop metastatic disease, identification of this low-risk group of patients would allow such patients to be observed without any treatment.
Pro and con arguments can be made regarding the treatment-related morbidities of surgery, surveillance, and primary chemotherapy in patients with clinical stage I disease, but no clinician would be likely to oppose a strategy of observation alone if a group of clinical stage I patients with an extremely low risk of metastasis could be identified. Treatment-related morbidity would be minimized, costs would likely be decreased, and the anxiety patients experience over whether or not occult metastatic disease exists would also be lessened. Therefore, an excellent rationale exists for identifying patients at extremely low risk for metastasis.
Many excellent studies of staging have been performed in patients with low-stage testis cancer. Most of these studies have attempted to identify patients at high risk for metastatic disease in order to appropriately institute therapy earlier in the course of the disease.[1,2] Most of the studies were retrospective, single-institution studies, with a mixture of pathologic stage I and II patients that does not conform to the expected mixture of these two stages (ie, 70%, pathologic stage I; 30%, pathologic stage II). However, some very well-designed, well-conducted studies have addressed clinical staging issues in consecutive groups of patients, usually in multi-institution format. This article will review selected studies of the former type, as well as selected studies in consecutive patients.
• Single-Institution Studies—Among the most frequently studied parameters predictive of pathologic stage are histologic factors, such as the presence of vascular invasion and lymphatic invasion. [3,4] These and other studies, such as the study by Dunphy et al, also identified the presence of embryonal carcinoma as another factor associated with relapse if patients were managed on a surveillance protocol. In addition, studies performed by Freedman et al and Hoskin et al found the absence of yolk sac elements in the tumor to be associated with an increased risk of recurrence among patients managed by surveillance.
More recently, Moul et al showed that the combination of percentage embryonal carcinoma and vascular invasion was predictive of pathologic stage II disease in a group of 92 clinical stage I patients—all of whom underwent retroperitoneal lymphadenectomy. The presence of these two factors predicted stage 85.9% of the time in this selected population of patients.
Similarly, Wishnow et al demonstrated a greater likelihood of a higher pathologic stage if the orchiectomy specimen exhibited a high percentage of embryonal carcinoma and vascular invasion. In this study, a cohort of low-risk patients who had no vascular invasion, less than 80% embryonal carcinoma, and an alpha-fetoprotein level less than 80 ng/mL experienced no relapses when managed by surveillance.
In general, other single-institution studies have supported the prognostic importance of extent of embryonal carcinoma, vascular invasion, and lymphatic invasion.
• Studies in Consecutive Patients—Studies performed in consecutive, unselected patients have corroborated the predictive ability of these parameters. A prospective study of surveillance conducted by the Medical Research Council (MRC) in the United Kingdom showed that vascular invasion, lymphatic invasion, the presence of embryonal carcinoma, and the absence of yolk sac elements are predictive of recurrence. Patients with three or four of these risk factors had a relapse-free rate of 53%. This study confirmed the previous findings of the MRC in an independent data set.
A prospective, multicenter, Scandinavian study by Klepp et al showed the importance of vascular invasion as a predictor of metastasis. Similarly, Sesterhenn et al reviewed the histology of the orchiectomy specimens in the Testicular Cancer Intergroup study. Vascular invasion and percentage of embryonal carcinoma in the tumor were predictive of stage in these patients, who were managed by retroperitoneal lymph node dissection.
• Unanswered Questions—Thus, significant evidence confirms that vascular invasion, lymphatic invasion, and percentage of embryonal carcinoma are predictive of metastasis in patients with low-stage nonseminoma. What is unclear from these studies is whether or not patients with such risk factors necessarily have a poor outcome if they are managed aggressively at diagnosis with either retroperitoneal lymphadenectomy or chemotherapy, as compared with their outcome if they are managed by surveillance.
In other words, if secondary issues (eg, morbidity, psychological issues, or economic issues) are set aside, is it essential for increased survival that such patients be managed proactively when “high risk” is defined at orchiectomy? Does managing high-risk patients with surveillance necessarily lead to a lower chance for cure? Based on the evidence from several surveillance series, this does not seem to be the case.
Immunohistochemical and Flow Cytometric Parameters
Immunohistochemical and flow cytometric parameters also have been studied in an effort to improve clinical staging. In a retrospective analysis of a selected group of patients, DeReese et al found that proliferative parameters (as measured by flow cytometry) were predictive of pathologic stage II disease in patients managed with retroperitoneal lymphadenectomy. However, Moul et al found that such parameters were predictive in a univariate but not a multivariate analysis.
Albers et al subsequently studied these same parameters in a group of 105 consecutive patients. In a multivariate analysis, proliferative parameters (as defined by flow cytometry) were the most predictive of pathologic stage. In contrast, Fossa et al found that these proliferative parameters were not helpful in predicting metastasis.
Immunohistochemical parameters that correlate with cell division also have been assessed in an attempt to predict metastasis. Albers et al showed that low MIB-1 staining (which identifies the Ki-67 antigen) in conjunction with low volumes of embryonal carcinoma predicts those patients managed with retroperitoneal lymphadenectomy who are at a low probability of having pathologic stage II disease. This finding was subsequently confirmed in an independent group of German patients.
The use of other immunohistochemical markers, such as proliferative cell nuclear antigen (PCNA) and p53 staining, have been investigated in many other studies and have shown no definite ability to predict pathologic stage. Various investigators have examined the use of isochromosome 12P, a common chromosomal abnormality in testicular germ-cell tumors. These studies have shown no definite correlation between this chromosomal abnormality and metastasis. Biological markers, such as HST-1 and ras mutation, similarly have shown no definite usefulness in the prediction of metastasis in low-stage disease.
Computed tomographic (CT) criteria for the diagnosis of abnormal lymph nodes in the retroperitoneum are also evolving. Traditionally, lymph nodes £ 1 cm in diameter were considered to be normal in the staging of testicular cancer. Moul and Leibovitch et alfound that by decreasing the limits for the diagnosis of abnormal lymph nodes to below 1 cm, the sensitivity of clinical staging was improved.
In a subsequent study of consecutive patients, by combining such new CT-based criteria with MIB immunostaining and the volume of embryonal carcinoma in the testicular specimen, Leibovitch et al were able to identify a group of 41 patients felt to be at low risk for metastatic disease. Of these 41 patients, 40 actually proved to have pathologic stage I disease at retroperitoneal lymphadenectomy. This group of 41 patients constituted 45% of the overall population of clinical stage I patients in this study. In addition, this study was performed in a group of consecutive patients.
Therefore, several studies have identified new predictors of pathologic stage in patients with low-stage nonseminomatous testis cancer. Many of these studies have limitations, in that the populations studied were selected and the parameters used to predict metastasis may suffer from interobserver variability (eg, CT scan reading and immunohistochemical staining).
If the goal is to accurately define a paradigm that is more useful in the prediction of pathologic stage, a prospective study comparing consecutive, unselected patients managed by retroperitoneal lymphadenectomy vs surveillance is needed. The cooperative groups have been planning such a study for some time. Hopefully, this study will be approved shortly and will be completed expeditiously in a multi-institution, prospective format.
1. Reed G, Stenning SP, Cullen MH, et al: Medical Research Council
prospective study for surveillance for stage I testicular teratoma. J
Clin Oncol 10:1762-1768, 1992.
2. Cullen MH, Stenning SP, Parkinson MC, et al: Short course adjuvant
chemotherapy in high-risk stage I nonseminomatous germ cell tumors of
the testis: A Medical Research Council report. J Clin Oncol
3. Freedman LS, Parkinson MC, Jones WG, et al: Histopathology in the
prediction of relapse of patients with stage I testicular teratoma
treated by orchidectomy alone. Lancet 2:294, 1987.
4. Hoskin P, Dilly S, Easton D, et al: Prognostic factors in stage I
nonseminomatous germ cell testicular tumors managed by orchiectomy
and surveillance: Implications for adjuvant chemotherapy. J Clin
Oncol 4:1031-1036, 1986.
5. Dunphy CH, Ayala AG, Swanson DA, et al: Clinical stage I
nonseminomatous and mixed germ-cell tumors of the testis. Cancer
6. Moul JW, McCarthy WF, Fernandez EB, et al: Percentage of embryonal
carcinoma and of vascular invasion predict pathologic stage in
clinical stage I nonseminomatous testicular cancer. Cancer Res
7. Wishnow KI, Johnson DE, Swanson DA, et al: Identifying patients
with low-risk clinical stage nonseminomatous testicular tumors who
should be treated by surveillance. Urology 34:339, 1989.
8. Klepp O, Olssen AM, Henrikson H, et al: Prognostic factors in
clinical stage I nonseminomatous germ cell tumors of the testis:
Multivariate analysis of a prospective multicenter study. J Clin
Oncol 6:509-518, 1990.
9. Sesterhenn IA, Weiss RB, Mostofi FK, et al: Prognosis in other
clinical correlates of pathologic review in stage I and II testicular
carcinoma: A report from the Testicular Cancer Intergroup study. J
Clin Oncol 10:69-78, 1992.
10. DeReese WT, DeReese C, Ulbright TA, et al: Flow cytometric and
quantitative histologic parameters as prognostic indicators for
occult retroperitoneal disease in clinical stage I nonseminomatous
testicular germ cell tumors. Int J Cancer 57:1-6, 1994.
11. Moul JW, Foley JP, Hitchcock CL, et al: Flow cytometric and
quantitative histologic parameters to predict occult disease in
clinical stage I nonseminomatous testicular germ cell tumors. J Urol
12. Albers P, Ulbright TM, Albers J, et al: Tumor proliferative
activity is predictive of pathological stage in clinical stage I
nonseminomatous testicular germ cell tumors. J Urol 155:579-586, 1996.
13. Fossa S, Nesland JM, Waehre H, et al: DNA ploidy in the primary
testicular cancer. Br J Cancer 64:948, 1991.
14. Albers P, Miller GA, Orazi A, et al: Immunohistochemical
assessment of tumor proliferation and volume of embryonal carcinoma
identified patients with clinical stage A nonseminomatous testicular
germ cell tumor at low-risk for occult metastasis. Cancer 75:844, 1995.
15. Albers P, Bierhoff E, Neu D, et al: MIB-1 immunohistochemistry in
clinical stage I nonseminomatous testicular germ cell tumors predicts
patients at low risk for metastasis. Cancer 79:1710-1716, 1997.
16. Ulbright TM, Orazi A, DeReese W, et al: The correlation of p53
protein expression with proliferative activity in occult metastases
in clinical stage I nonseminomatous germ cell tumors of the testis.
Mod Pathol 7:64-68, 1994.
17. Bosl GJ, Dimitrovsky E, Reuter VE, et al: Isochromosome of
chromosome 12: Clinically useful marker for male germ cell tumors. J
Natl Cancer Inst 81:1874, 1989.
18. Moul JW: Proper staging techniques in testicular cancer. Tech
Urol 1:126-132, 1995.
19. Leibovitch I, Foster RS, Kopecky KK, et al: Improved accuracy of
CT based clinical staging in low-stage nonseminomatous germ cell
cancer using size criteria of retroperitoneal lymph nodes. J Urol
20. Leibovitch I, Foster RS, Kopecky KK, et al: Identification of
clinical stage A nonseminomatous testis cancer patients at extremely
low risk for metastatic disease: A combined approach using
quantitative immunohistochemical, histopathologic, and radiologic
assessment. J Clin Oncol 16:261-268, 1998.
21. Group IGCCC. International Germ Cell Consensus Classification: A
prognostic factor-based staging system for metastatic germ cell
cancers. J Clin Oncol 15:594-603, 1997.
22. Bajorin D, Mazumdar M, Meyers M, et al: Metastatic germ cell
tumors: Modeling for response to chemotherapy. J Clin Oncol
23. Donohue JP, Thornhill JA, Foster RS, et al: Primary
retroperitoneal lymph node dissection in clinical stage A
nonseminomatous germ cell testis cancer: A review of the Indiana
University experience (1965-1989). Br J Urol 71:326-335, 1993.
24. Donohue JP, Thornhill JA, Foster RS, et al: The role of
retroperitoneal lymphadenectomy in clinical stage B testis cancer:
The Indiana University experience (1965-1989). J Urol 153:85-89, 1995.
25. Gerber GS, Bissada NK, Hulbert JC, et al: Laparoscopic
retroperitoneal lymphadenectomy: Multi-institutional analysis. J Urol
26. Janetschek G, Hobisch A, Holtl L, et al: Retroperitoneal
lymphadenectomy for clinical stage I nonseminomatous testicular
tumor: Laparoscopy vs open surgery and impact of learning curve. J
Urol 156:89-94, 1996.
27. Rassweiler JJ, Seemann O, Henkel TO, et al: Laparoscopic
retroperitoneal lymph node dissection for nonseminomatous germ cell
tumors: Indications and limitations. J Urol 156:1108-1113, 1996.
28. Janetschek G, Hobisch A, Hittmair A, et al: Laparoscopic
retroperitoneal lymphadenectomy after chemotherapy for stage IIB
non-seminomatous testicular carcinoma. J Urol 161:477-481, 1999.
29. Baniel J, Foster RS, Einhorn LH, et al: Late relapse of clinical
stage I testicular cancer. J Urol 154:1370-1372, 1995.
30. Studer U, Fey M, Calderoni A, et al: Adjuvant chemotherapy after
orchidectomy in high-risk patients with clinical stage I
nonseminomatous testicular cancer. Eur Urol 23:444-449, 1993.
31. Pont J, Albrecht W, Postner G, et al: Adjuvant chemotherapy for
high-risk clinical stage I nonseminomatous testicular germ cell
cancer: Long-term results of a prospective trial. J Clin Oncol