State Alan
D. Steinfeld,
success stories in cancer management are uncommon. The treatment of men with testicular tumors is a happy exception to this rule. Advances in diagnostic and staging procedures, in addition to innovations in radiation therapy, surgery, and chemotherapy, have made cure the expected outcome for most patients. This review focuses on areas of controversy that remain in the treatment of men with testicular tumors. Ongoing research that addresses these issues is critically evaluated. EAL
PATIENT
AT
RISK
Because of the relative scarcity of primary testicular tumors (only about 5,000 American men develop them each year), some physicians may not have a comfortable working knowledge of the factors that lead to their development. Such information is important in helping to define groups of men who may be appropriate for screening and in counseling individual patients. Recent advances in genetics have furthered our understanding of the cause of the germ cell tumors and have shed light on which patients are at risk. The division of germinal testicular tumors into seminoma and nonsem-
Index studies, Testis, Radiology
terms: State-of-art 847.1214 #{149} Testis, US studies, 847.1298 1990;
reviews neoplasms,
Tumors: Evaluation
inoma is classic (1,2) and, as will be seen, retains its value. Totipotential primordial germ cells, under proper oncogenic influence, are thought to develop into seminoma or embryonal cell carcinoma. The latter, with differentiation along somatic lines, can produce a teratoma, or, if trophoblastic differentiation occurs, choriocarcinoma (2,3). In an alternate scheme, seminoma develops into embryonal carcinoma, which in turn gives rise to teratoma or choriocarcinoma. While the exact pathway remains unclear, the importance of the host’s genetic influence on whether a tumor develops, and which particular subtype it is, is being clarified. Weissbach and Widman (4) analyzed the histologic characteristics of germ cell tumors occurring in members of the same family. The histologic characteristics of tumors in identical twin pairs were discordant only 20% of the time, while in other sibling pairs the rate rose to 67%. The difference between these values was significant at the .05 level. An ongoing study by the Imperial Cancer Research Fund Epidemiology and Clinical Trials Unit found six familial cases of testicular tumor among 200 cases registered (5). This number is far in excess of what would be expected and corroborates a lead from an earlier retrospective study (6). These studies support a familial tendency toward developing the disease.
Testis, MR 847.329.
#{149}
175:603-606
1 From the Division NYU Medical Center, NY 10016. Received requested January 3, January 16; accepted print requests to the RSNA, 1990
Art
MD
Testicular Germ Cell Review of Contemporary and Management’
THE
of the
of Radiation Oncology, 560 First Aye, New York, December 4, 1989; revision 1990; revision received January 17. Address reauthor.
SCREENING If a genetic predisposition toward developing a testicular tumor exists, can this information be used to develop an effective screening program? The population to be screened might include family members of men who have had testicular tumor, as well as those with other risk factors. Men with testicular maldescent or atrophy have long been noted to be at increased risk for developing
testicular cancer (7). However, the magnitude of this risk remains unclear. In 1979, Krabbe et al (8) found four cases of carcinoma in situ (CIS) among 50 men with a history of testicular maldescent. These 50 men were volunteers from a larger group of 180 who were asked to participate in the study. A recent larger study has shown the risk to be substantially smaller. Giwercman et al (9) found a 2% frequency of CIS among more than 200 men, aged 20-30 years, with a history of maldescent. Similarly, a cohort study of young men with prior maldescent found an approximately 2% risk of invasive cancer (10). For a screening program to be effective, several criteria have to be met. In addition to having a defined population to screen, methods must be used with sufficient sensitivity and specificity to detect tumors before they are clinically noticeable. The concept of the program must be acceptable to the population at risk. Finally, the program should permit discovery of disease when therapy would yield a result superior to that which would occur if the tumor were found clinically. At present, none of the available screening methods meets all of these criteria. Testicular biopsy permits efficient diagnosis of CIS because the changes are usually widely dispersed in the organ (11). Patient discomfort and the intense requirements of resources for surgical biopsy make it suboptimal as a screening tool for large numbers of patients. Other techniques are needed. Two tools under investigation for this purpose are ultrasound (US) and magnetic resonance (MR) imaging. Lenz et al (12) identified four echo patterns of testicular tissue in 379
Abbreviations: AFP = alpha fetoprotein, /3hCG = beta subunit of human chorionic gonadotropin, CIS = carcinoma in situ.
603
scans obtained from 192 men with a history of cryptorchidism. A markedly abnormal pattern (pattern 4) was found in only 12 testes. Biopsy was performed of 1 1 of these testes, and two cases of CIS were found. No instances of CIS were found among the other 186 biopsies done on 143 men with patterns 1, 2, or 3. This yield, and the lack of toxicity of the procedure, would seem to make US a good tool for screening patients at risk. MR imaging is also being tried as a means to detect early tumors based on differences in relaxation times rather than image abnormalities. Thomsen et al (13) compared MR images, relaxation time measurements, and spectroscopy findings in six men with biopsy-proved CIS and five normal subjects. None of the men with CIS showed any focal lesions on the images. However, both the Ti and T2 relaxation times for the testicles with CIS differed from those of the testides in normal subjects and the contralateral testicle in the patients. The cause of these differences, whether due to the presence of the malignancy or a coincidental factor, awaits elucidation. Should these findings be substantiated by others, MR imaging would be a powerful tool for noninvasive screening of patients. Participation in a screening program requires awareness, by the population at risk, of the nature and magnitude of the danger posed by the illness. This seems to be a problem with regard to testicular cancer. In a study of 1,364 ninth grade boys, Vaz et al (14) found that while 28% of their subjects had heard of testicular cancer, only 13% had ever heard of self-examination and none knew how to perform the procedure correctly. Seventy-five percent of the young men had seen physicians for physical examinations within the prior 15 months, with only 2% reporting that they had been taught how to examine their testicles. Pinch et al (15) found the situation among college men only slightly better. Only 23% of 159 freshman students knew how to perform the examination, and, of these, few performed it regularly. While these figures are disturbing, the relative rarity of the disease and the early stage at which most patients present make it difficult to advocate the expenditure of limited resources on efforts to alert individual patients on the need for, and methods of, testicular self-examination. Even though only about 10% of patients with germ cell testicular tumors have a history of maldescent (16), it does 604
Radiology
#{149}
seem appropriate for pediatricians and family physicians to teach highrisk patients about the procedure. EVALUATING Biochemical
THE
PATIENT
Tests
Rational treatment decisions can be made only when the exact nature and full extent of the tumor are appreciated. Evaluation must include biochemical and radiologic studies to supplement the complete history and physical examination. Proper staging of the malignancy remains an important antecedent to planning a course of therapy. The specific chemical markers produced by many germ cell tumors are useful in determining the histologic nature of the disease, evaluating the completeness of initial therapy, and detecting preclinical relapse. Alpha fetoprotein (AFP), described by Waldmann and Mclntire in 1974 (17), is present in embryonal carcinoma and endodermal sinus tumors. Because its half-life is approximately 6 days, sufficient time must be allowed for clearance of the circulating glycoprotein before residual disease can be declared present. Similarly, nonmalignant causes of AFP elevation, such as hepatocellular dysfunction, must be ruled out. AFP is not found in pure seminoma, so its presence in the serum indicates that nonseminomatous elements exist in the tumor. In comparison, the $ subunit of human chorionic gonadotropin (/3-hCG) is found in about 10% of patients with pure seminoma, due to the presence of syncytiotrophoblastlike cells. Since its half-life is about a day (18), it is important that assays for j3-hCC be done promptly, before the marker has a chance to drop to normal levels. Assay for AFP and fl-hCC must be considered a standard part of the evaluation of patients with suspected testicular cancer. Several other substances may play a role. Serum lactic dehydrogenase has been correlated with volume of disease in germ cell testicular tumors (19,20), but the numerous other causes of elevation of this enzyme make its use in clinical practice difficult. Similarly, while placental-like alkaline phosphatase is found in approximately 90% of patients with pure seminoma (21-23), its elevation in virtually anyone who smokes limits its usefulness. Other pregnancy related proteins (early pregnancy factor, Schwangerschaftsproteine-1) are still under study with regard to their clinical value.
Radiologic
Investigations
The chest.-There is a natural tendency to use new, sophisticated technology, often on the assumption that new is better. Following this line of reasoning, it has become commonplace to evaluate testicular cancer with computed tomography (CT) of the chest, in addition to posteroantenor and lateral plain radiography (24,25). However, the routine use of chest CT in all patients with testicular germ cell tumors is difficult to defend. Using conventional chest radiography alone, one expects that approximately 20%-30% of patients with nonseminomatous tumors will have mediastinal or pulmonary involvement at presentation. Whole lung tomography may demonstrate more areas of metastatic disease but rarely depicts new tumors in a patient with a normal chest radiograph (26). Chest CT has a small but definite advantage over whole lung tomography in evaluation of these patients. Husband et al (27) found five patients in whom occult pulmonary metastases were detected with CT, among a group of 62 patients evaluated with both chest CT and whole lung tomography. This superiority of CT over plain radiography is maintained in the surveillance of patients after treatment. Williams et al (28) used both modalities to follow up 147 patients with stage I nonseminomatous tumors. CT demonstrated chest relapse in 15 patients, while plain radiography demonstrated lesions in only eight of these patients. The value of chest CT does not seem to hold up for the evaluation of seminoma. Steinfeld and Macher (29) reviewed images of 93 patients with stage I or II seminoma. All patients had a normal chest radiograph, and 22 patients were also evaluated with whole lung tomography or chest CT. In no patient was occult lung or mediastinal disease found. Long-term follow-up produced no evidence of chest failure as the first or sole site of relapse. However, none of their patients with stage II disease had bulky (stage IIB) disease. It would seem, at least for patients with stage I or hA seminoma, that a plain chest radiograph is sufficient for initial staging. Similarly, chest radiography may be sufficient in following up patients with seminoma with initial smallvolume disease. Peckham and Brada (30) described 52 patients with stage I seminoma who received no adjuvant therapy after orchiectomy. With a June
1990
median follow-up period of 23 months, seven patients have relapsed, six with disease confined to the abdomen and one with abdominal and pulmonary lesions. While the method by which the lung lesions were found in that patient is not stated, the scarcity of the event argues against the routine use of chest CT as a tool for following up these patients. The abdomen.-The radiologic evaluation of the abdomen in patients with testicular germ cell tumors is essentially a search for retroperitoneal lymph nodes, the most common site of metastasis for this disease. The route of lymphatic drainage from the testicles to these nodes is well documented (31). Since direct testicular lymphangiography is quite painful, alternate methods are required. While many techniques are available to image the retroperitoneum (US, excretory urography, inferior vena cavography, gallium scanning, lymphoscintigraphy, radioimmunodetection, angiography, MR imaging), only lymphangiography and CT have been widely studied. In deciding which studies to perform, and in what order, the physician must be aware of the relative accuracies of the studies available and the impact that the information will have on treatment decisions. For example, it may be more important to know about small-volume disease in a patient who will be managed with observation only than in a patient who will definitely be treated. The sensitivity (chance of detecting a true-positive case, or one minus the false-negative rate), specificity (probability of finding a true-negative case, or one minus the false-positive rate), and accuracy (proportion of true-positive plus true-negative cases) of CT and lymphangiography in evaluating testicular cancer have recently been reviewed by Fung and Garnick (32). Despite the theoretical advantage of lymphangiography, based on its ability to show internal nodal architecture, the overall accuracy of the two procedures is comparable. Dunnick and Javadpour (33) and Marincek et al (34) have demonstrated sensitivity as high as 90% by combining both procedures. However, accuracy did not improve appreciably. In the absence of a clear superiority of one technique over another or convincing evidence that a combination of the procedures is superior, the problem of selecting between the two tests becomes a matter of secondary issues. Clearly, lymphangiograVolume
175
Number
#{149}
3
phy is the more morbid and invasive procedure. A reasonable approach might be to perform CT on all patients. Men with negative studies, who will not be getting elective treatment of the retroperitoneal nodes (either radiation or surgery), might appropriately undergo lymphangiography to increase the accuracy of assessment. Some radiation oncologists believe that a lymphangiogram is mandatory to guide adequate treatment of paraaortic nodes. Since the dose of radiation required to sterilize this disease is relatively low (as will be noted later), it is possible to use treatment fields based on the anatomy as shown by CT to properly cover the areas at risk. TREATMENT
AND
OUTCOME
Seminoma The routine cure of seminoma is a result of several factors. The disease is most often noted while still limited to the testicle (stage I). Its route of spread is predictable, with retroperitoneal lymph nodes the usual site of first metastasis (stage II). Sensitive radiologic methods exist to determine the extent of the disease. Finally, its exquisite sensitivity to radiation makes tumor control a virtual certainty. Consequently, 5-year survival rates for patients with stage I disease are generally better than 95%, with figures for stage II patients in the 85%-90% range (35-41). As a result of these successes, there has been interest in reducing the amount of treatment given, both in terms of extent of radiation and, to some extent, the dose employed. The traditional use of irradiation to retroperitoneal lymph nodes in stage I disease is being questioned by several surveillance programs. As mentioned earlier, Peckham and Brada (30) described 52 patients with stage I disease who were observed after orchiectomy. With a median follow-up of 23 months, seven (13%) have relapsed; in six cases retroperitoneal nodes were the site of metastases. At the time of the report, six patients were in remission after radiation or chemotherapy and one patient was still being treated. Viewed another way, 87% of their patients were spared apparently unnecessary treatment. Oliver (42) reported similar results in 26 patients with a median follow-up period of 18 months. Four patients relapsed, all of whom were salvaged with chemotherapy. The author noted that three of the four re-
lapses were difficult to diagnose. Nevertheless, adjuvant retroperitoneal irradiation, to a dose of 2,000-3,000 cGy, must still be considered the standard of care for patients with stage I seminoma. The concept of “less is better” has been extended to stage II seminoma as well. Thomas et al (39) and Willan and McGowan (43) reported 5-year survival rates of 100% and 82% in patients with stage IIA (nonpalpable abdominal) disease who did not receive mediastinal irradiation. Only two of the patients in the study by Willan and McGowan (43) developed disease in the mediastinum, and then as a component of more generalized disease. Hanks (44) has questioned the wisdom of accepting these two studies as a basis for changing the standard of care. Despite this warning, a recent national study has documented a decrease in the frequency with which patients with stage II disease receive mediastinal irradiation (45). In the absence of a prospective randomized trial (a recent attempt at such a trial by the Radiation Therapy Oncology Group failed due to lack of patient accrual), the physician should consider other factors (eg, patient reliability for follow-up) in deciding whether to give adjuvant treatment to the mediastinum. Patients with bulky abdominal disease (stage JIB) or with stage III disease are uncommon, particularly in recent series from the United States. Their treatment should be individualized, with strong consideration given to chemotherapy. Other
Germ
Cell
Tumors
Interest in maintaining excellent outcome results, while giving less therapy, is the hallmark of the current philosophies regarding treatment of nonseminomatous germ cell tumors. Standard care for patients with stage I nonseminomatous germ cell tumors has been, until recently, retroperitoneal lymph node dissection following radical inguinal orchiectomy. Using such an approach, Staubitz achieved an 86% 5-year survival for 65 patients with pathologic stage I disease (46). The advent of adjuvant chemotherapy, particularly regimens employing cisplatin, has dramatically improved the situation. Reports by Skinner (47), Donahue (48), and Fraley et al (49) document 3-5-year survival rates of virtually 100% in patients with stage I disease and 95% in patients with stage II disease, using Radiology
605
#{149}
adjuvant chemotherapy regimens, generally containing cisplatin. These superb results set the stage for attempts at diminishing the extent of initial therapy. One thrust of current research is to minimize side effects by changing or eliminating the standard retroperitoneal lymph node dissection. A less extensive dissection may decrease the frequency of bowel injury or loss of ejaculation, the latter of which can occur in up to 75% of patients. Rowland (50) recently summarized proposed changes in surgical technique. Surveillance studies of patients who have undergone orchiectomy are also underway. In some instances, initial chemotherapy is given (30), while in other approaches chemotherapy and surgery are used as salvage treatment (51,52). The optimal therapeutic approach will be the one that achieves the lowest morbidity while maintaining high cure rates. AND
7.
8.
9.
11 .
12.
2.
3. 4. 5.
6.
FJ, Moore RA. Tumors of the male Vol 32. Washington. DC: Armed
sex
Forces Institute of Pathology, 1952; 48-103. Collins DH, Pugh RCB. Classification and frequency of testicular tumors. Br J Urol 1964; 36(suppi):1-1 1. Melicow MM. Classification of tumors of testis. 3 mt Coil Surg 1956; 25:187-201. Weissbach L, Widman T. Familial tumor of the testis. Eur J Urol 1986; 12:104-108. Delozier-Blanchet CD, Walt H, Engel E, Vuagflat P. Cytogenetic studies of human testicular germ cell tumours. mt j Androl 1987; 10:69-77.
Oliver
RTD.
HLA
phenotype
and
#{149} Radiology
J Androl
1987;
10:173-180.
C. Jensen
cer: adolescent 15.
16. 17.
18.
20.
Peckham
M.
Eur J Cancer
22:647-653. Tucker DF, rum marker phosphatase-like
cell tumours 22.
23.
24.
25.
27.
28.
29.
30.
31.
and
attitudes.
Rowland
Marincek phography
cancer.
Acta Oncol
Clin
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ease.
36.
37.
38.
39.
40.
41.
RG, Donohue
JP.
Testicular
42.
1983; 56:243-246.
of treatment Oncol 1986;
Hanks
CE, Herring
of care
outcome
Oliver
and complications. 6:115-120.
DF, Kramer studies:
Oncol
Biol
RTD.
Patterns
of the
of the testis.
Phys
1981;
Limitations
as an option
I seminoma.
S.
results
in seminoma
veillance
stage
nation-
J
Int
Ra-
7:1413-1417.
to the use of surin the
management
Int J Androl
1987;
of
10:263-
268.
43.
Willan
BD, McGowan
DC.
testis: a 22 year experience therapy. Int J Radiation 11:1769-1775.
44.
1983; 9:949-950. Steinfeld AD, therapy Oncol
46.
47.
48. 49.
50.
51.
52.
of the
radiation
Biol Phys
Staubitz
JJ, Hanks evolution
Diamond
seminoma:
practice in the 1990; 2:14-17.
1985;
WJ.
Surgical
United
CE. Stage of radiation
States.
treatment
Clin
of nonsem-
inomatous germinal testis tumors. In: Johnson DE, Samuels ML, eds. Cancer of the genitourinary tract. New York: Raven, 1979; 135138. Skinner DC. Role of surgery in the management of nonseminomatous germ cell tumors of the testis. In: VanOosterom AT, Muggia FM, Cleton FJ, eds. Therapeutic progress in ovarian cancer, testicular cancer and the sarcomas. The Hague: Nijhoff, 1980; 159-172.
Donahue
JP.
Transabdominal
tomy. timore:
In: Donahue Williams
Fraley
EE, Markland
JP. ed. & Wilkins,
lymphadenecTestis tumors. Bal1983; 178-206.
C, Lange
PH.
Surgical
treatment of stage I and stage II nonseminomatous testicular cancer in adults. Urol Clin North Am 1977; 4:453-463. Rowland RC. Testicular germ-cell neoplasms: curative approaches. Hematol Oncol Clin North Am 1988; 2:467-484. Herr HW, Whitmore WF, Sogani PC, eta!. Selection of testicular tumor patients for omission of retroperitoneal lymph-node dissection. J Urol 1986; 135:500-503. Hoskin P. Dilly 5, Easton D. et al. Prognostic factors in stage I nonseminomatous germ cell tumors managed by orchiectomy and surveil-
lance: implications py. J Clin Oncol 53.
Seminoma with
Oncol
Hanks CE. Apples and oranges in seminoma: a comparison of U.S.A. and Canadian experience. Int J Radiation Oncol Biol Phys II testicular
1988; 80:1373-1382.
Jochelson MS. Garnick MB, Balikian JP, et al. The efficacy of routine whole lung tomography in germ cell tumors. Cancer 1984; 54:1007-1009. Husband JE, Peckman MJ, MacDonald JS, et al. The role of computed tomography in the management to testicular teratoma. Clin Radiol 1979; 30:243-252. Williams SD, Stablein DM, Einhorn LH, et al. Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 1987; 317:1433-1438. Steinfeld AD, Macher M. Radiologic staging of the chest in testicular seminoma. Urology (in press). Peckham MJ, Brada M. Surveillance following orchidectomy for stage I testicular cancer. Int J Androl 1987; 10:247-254. Ray B. Hajdu SI, Whitmore WF. Distribution of retroperitoneal lymph node metastases in testicular germinal tumors. Cancer 1974; 33:340-348. Fung CY, Garnick MB. Clinical stage I carcinoma of the testis: a review. J Clin Oncol 1988; 6:734-750.
Radiol
Hamilton C, Horwich A, Easton D, Peckham MJ. Radiotherapy for stage I seminoma tes-
diation
cancer:
innovation in diagnosis and treatment. Semin Urol 1988; 6:223-232. Loehrer PJ, Williams SD, Einhorn LH. Testicular cancer: the quest continues. J NatI
Urol
testicular cancer: stage metastatic dis-
Hunter M, Peschel RE. Testicular seminoma: results of the Yale University experience, 1964-1984. Cancer 1989; 64:1608-1611. Lederman CS, Herman TS, Jochelson M, et al. Radiation therapy of seminoma: 17-year experience at the Joint Center for Radiation Therapy. Radiother Oncol 1989; 14:203-208. Zwaveling A, Roepnarain S. Testicular tumors in the Netherlands. Cancer 1985; 55:1612-1617. Schultz HP, VonderMaase H, Rorth M, et al. Testicular seminoma in Denmark 1976-1980. Acta Radiol Oncol 1984; 23:263-270. Thomas CM, Rider WD, Dembo AJ, et al. Seminoma of the testis: results of treatment and patterns of failure after radiation therapy. Int J Radiation Oncol Biol Phys 1982; 8:165-174.
al practice
1986;
monoclonal
nonseminomatous detection of early
tis: results Radiother
45.
by H17E2
B, Brutschin P. Triller 3, et al. Lymand computed tomography in
staging limited
Oliver RTD, Travers P. et al. Sepotential of placental alkaline activity in testicular germ
evaluated
Inst
34.
3
9:474-479. A. Testicular the college male.
antibody assay. Br J Cancer 1985; 51:631-639. Horwich A, Tucker DF, Peckham MJ. Placental alkaline phosphatase as tumour marker in seminoma using the H17E2 monoclonal antibody assay. Br J Cancer 1985; 51:625-629. Muensch HA, Maslow WC, Azama G, et al. Placental-like alkaline phosphatase: re-evaluation of the tumor marker with exclusion of smokers. Cancer 1986; 58:1689-1694.
Cancer 26.
knowledge
Testicular
Dunnick NR, Javadpour N. Value of CT and lymphangiography: distinguishing retroperitoneal metastases from nonseminomatous testicular tumours. AJR 1981; 136:1093-1099.
A, et al.
1988; 27:439-453. Waldmann GA, Mclntire KR. The use of a radioimmunoassay for aiphafetoprotein in the diagnosis of malignancy. Cancer 1974; 34:1510-1515. Lange PH, Raghavan D. Clinical applications of tumor markers in testicular cancer. In: Donohue JP, ed. Testis tumors. Baltimore: Williams & Wilkins, 1983; 111-130. Lippert MC, Javadpour N. Lactic dehydrogenase in the monitoring and prognosis of testicular cancer. Cancer 1981; 48:2274-2278. Taylor RE, Duncan W, Horn DB. Lactic dehydrogenase as a marker for testicular germ-
cell tumors. 21.
KE, Giwercman
Adolesc Health Care 1988; Pinch WJ, Nilges A, Schnell self-examination: reaching Coil Health 1988; 37:131-132.
33.
35.
Giwercman A, Grindsted J, Hansen B, et al. Testicular cancer risk in boys with maldescended testis: a cohort study. J Urol 1987; 138:1214-1216. Berthelsen JG, Skakkebaek NE. Distribution of carcinoma-in-situ in testes from infertile men. mt J Androl 1981; 4:172-184. Lenz S. Giwercman A, Skakkebaek NE, et al. Ultrasound in detection of early neoplasia of the testis. mt J Androl 1987; 10:187-190.
14.
32.
606
in malig-
Magnetic resonance: in vivo tissue characterization of the testes in patients with carcinoma-in-situ of the testis and healthy subjects. Int J Androl 1987; 10:191-198. Vaz RM, Best DL, Davis SW. Testicular can-
clinico-
pathological behaviour of germ cell tumours: possible evidence for clonal evolution from seminomas to nonseminomas. mt J Androl 1987; 10:85-93.
Studies
Thomsen
References Dixon organs.
JB.
13.
19.
1.
JB, Hamilton
nant testis tumors. mu. mncidence and nature of tumors in ectopic testes. Surg Gynecol Obstet 1940; 71:731-743. Krabbe S. Berthelsen JG, Volsted P. et al. High incidence of undetected neoplasia in maldescended testes. Lancet 1979; 1:999-1000. Giwercman A, Berthelsen JG, Muller J, et al. Screening for carcinoma-in-situ of the testis.
mt 10.
NEXT...
The speed with which chemotherapeutic regimens for testicular germ cell tumors develop is almost dizzying and makes their discussion a difficult task. Recent publications (16,53) summarize this rapidly changing field. Further refinements are also to be expected in defining subgroups of patients who need more, or less, treatment based on, for example, marker status, DNA ploidy, or histologic subgroup. And finally, long-term follow-up evaluations, such as those conducted by the Patterns of Care Study, will provide accurate information on the price of success. U
Gilbert
Einhorn ticular 15.
LH. cancer.
for adjuvant chemothera1986; 4:1031-1036. Complicated Semin Oncol
problems in tes1988; 15(supp):9-
June
1990
D. Steinfeld,
success stories in cancer management are uncommon. The treatment of men with testicular tumors is a happy exception to this rule. Advances in diagnostic and staging procedures, in addition to innovations in radiation therapy, surgery, and chemotherapy, have made cure the expected outcome for most patients. This review focuses on areas of controversy that remain in the treatment of men with testicular tumors. Ongoing research that addresses these issues is critically evaluated. EAL
PATIENT
AT
RISK
Because of the relative scarcity of primary testicular tumors (only about 5,000 American men develop them each year), some physicians may not have a comfortable working knowledge of the factors that lead to their development. Such information is important in helping to define groups of men who may be appropriate for screening and in counseling individual patients. Recent advances in genetics have furthered our understanding of the cause of the germ cell tumors and have shed light on which patients are at risk. The division of germinal testicular tumors into seminoma and nonsem-
Index studies, Testis, Radiology
terms: State-of-art 847.1214 #{149} Testis, US studies, 847.1298 1990;
reviews neoplasms,
Tumors: Evaluation
inoma is classic (1,2) and, as will be seen, retains its value. Totipotential primordial germ cells, under proper oncogenic influence, are thought to develop into seminoma or embryonal cell carcinoma. The latter, with differentiation along somatic lines, can produce a teratoma, or, if trophoblastic differentiation occurs, choriocarcinoma (2,3). In an alternate scheme, seminoma develops into embryonal carcinoma, which in turn gives rise to teratoma or choriocarcinoma. While the exact pathway remains unclear, the importance of the host’s genetic influence on whether a tumor develops, and which particular subtype it is, is being clarified. Weissbach and Widman (4) analyzed the histologic characteristics of germ cell tumors occurring in members of the same family. The histologic characteristics of tumors in identical twin pairs were discordant only 20% of the time, while in other sibling pairs the rate rose to 67%. The difference between these values was significant at the .05 level. An ongoing study by the Imperial Cancer Research Fund Epidemiology and Clinical Trials Unit found six familial cases of testicular tumor among 200 cases registered (5). This number is far in excess of what would be expected and corroborates a lead from an earlier retrospective study (6). These studies support a familial tendency toward developing the disease.
Testis, MR 847.329.
#{149}
175:603-606
1 From the Division NYU Medical Center, NY 10016. Received requested January 3, January 16; accepted print requests to the RSNA, 1990
Art
MD
Testicular Germ Cell Review of Contemporary and Management’
THE
of the
of Radiation Oncology, 560 First Aye, New York, December 4, 1989; revision 1990; revision received January 17. Address reauthor.
SCREENING If a genetic predisposition toward developing a testicular tumor exists, can this information be used to develop an effective screening program? The population to be screened might include family members of men who have had testicular tumor, as well as those with other risk factors. Men with testicular maldescent or atrophy have long been noted to be at increased risk for developing
testicular cancer (7). However, the magnitude of this risk remains unclear. In 1979, Krabbe et al (8) found four cases of carcinoma in situ (CIS) among 50 men with a history of testicular maldescent. These 50 men were volunteers from a larger group of 180 who were asked to participate in the study. A recent larger study has shown the risk to be substantially smaller. Giwercman et al (9) found a 2% frequency of CIS among more than 200 men, aged 20-30 years, with a history of maldescent. Similarly, a cohort study of young men with prior maldescent found an approximately 2% risk of invasive cancer (10). For a screening program to be effective, several criteria have to be met. In addition to having a defined population to screen, methods must be used with sufficient sensitivity and specificity to detect tumors before they are clinically noticeable. The concept of the program must be acceptable to the population at risk. Finally, the program should permit discovery of disease when therapy would yield a result superior to that which would occur if the tumor were found clinically. At present, none of the available screening methods meets all of these criteria. Testicular biopsy permits efficient diagnosis of CIS because the changes are usually widely dispersed in the organ (11). Patient discomfort and the intense requirements of resources for surgical biopsy make it suboptimal as a screening tool for large numbers of patients. Other techniques are needed. Two tools under investigation for this purpose are ultrasound (US) and magnetic resonance (MR) imaging. Lenz et al (12) identified four echo patterns of testicular tissue in 379
Abbreviations: AFP = alpha fetoprotein, /3hCG = beta subunit of human chorionic gonadotropin, CIS = carcinoma in situ.
603
scans obtained from 192 men with a history of cryptorchidism. A markedly abnormal pattern (pattern 4) was found in only 12 testes. Biopsy was performed of 1 1 of these testes, and two cases of CIS were found. No instances of CIS were found among the other 186 biopsies done on 143 men with patterns 1, 2, or 3. This yield, and the lack of toxicity of the procedure, would seem to make US a good tool for screening patients at risk. MR imaging is also being tried as a means to detect early tumors based on differences in relaxation times rather than image abnormalities. Thomsen et al (13) compared MR images, relaxation time measurements, and spectroscopy findings in six men with biopsy-proved CIS and five normal subjects. None of the men with CIS showed any focal lesions on the images. However, both the Ti and T2 relaxation times for the testicles with CIS differed from those of the testides in normal subjects and the contralateral testicle in the patients. The cause of these differences, whether due to the presence of the malignancy or a coincidental factor, awaits elucidation. Should these findings be substantiated by others, MR imaging would be a powerful tool for noninvasive screening of patients. Participation in a screening program requires awareness, by the population at risk, of the nature and magnitude of the danger posed by the illness. This seems to be a problem with regard to testicular cancer. In a study of 1,364 ninth grade boys, Vaz et al (14) found that while 28% of their subjects had heard of testicular cancer, only 13% had ever heard of self-examination and none knew how to perform the procedure correctly. Seventy-five percent of the young men had seen physicians for physical examinations within the prior 15 months, with only 2% reporting that they had been taught how to examine their testicles. Pinch et al (15) found the situation among college men only slightly better. Only 23% of 159 freshman students knew how to perform the examination, and, of these, few performed it regularly. While these figures are disturbing, the relative rarity of the disease and the early stage at which most patients present make it difficult to advocate the expenditure of limited resources on efforts to alert individual patients on the need for, and methods of, testicular self-examination. Even though only about 10% of patients with germ cell testicular tumors have a history of maldescent (16), it does 604
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seem appropriate for pediatricians and family physicians to teach highrisk patients about the procedure. EVALUATING Biochemical
THE
PATIENT
Tests
Rational treatment decisions can be made only when the exact nature and full extent of the tumor are appreciated. Evaluation must include biochemical and radiologic studies to supplement the complete history and physical examination. Proper staging of the malignancy remains an important antecedent to planning a course of therapy. The specific chemical markers produced by many germ cell tumors are useful in determining the histologic nature of the disease, evaluating the completeness of initial therapy, and detecting preclinical relapse. Alpha fetoprotein (AFP), described by Waldmann and Mclntire in 1974 (17), is present in embryonal carcinoma and endodermal sinus tumors. Because its half-life is approximately 6 days, sufficient time must be allowed for clearance of the circulating glycoprotein before residual disease can be declared present. Similarly, nonmalignant causes of AFP elevation, such as hepatocellular dysfunction, must be ruled out. AFP is not found in pure seminoma, so its presence in the serum indicates that nonseminomatous elements exist in the tumor. In comparison, the $ subunit of human chorionic gonadotropin (/3-hCG) is found in about 10% of patients with pure seminoma, due to the presence of syncytiotrophoblastlike cells. Since its half-life is about a day (18), it is important that assays for j3-hCC be done promptly, before the marker has a chance to drop to normal levels. Assay for AFP and fl-hCC must be considered a standard part of the evaluation of patients with suspected testicular cancer. Several other substances may play a role. Serum lactic dehydrogenase has been correlated with volume of disease in germ cell testicular tumors (19,20), but the numerous other causes of elevation of this enzyme make its use in clinical practice difficult. Similarly, while placental-like alkaline phosphatase is found in approximately 90% of patients with pure seminoma (21-23), its elevation in virtually anyone who smokes limits its usefulness. Other pregnancy related proteins (early pregnancy factor, Schwangerschaftsproteine-1) are still under study with regard to their clinical value.
Radiologic
Investigations
The chest.-There is a natural tendency to use new, sophisticated technology, often on the assumption that new is better. Following this line of reasoning, it has become commonplace to evaluate testicular cancer with computed tomography (CT) of the chest, in addition to posteroantenor and lateral plain radiography (24,25). However, the routine use of chest CT in all patients with testicular germ cell tumors is difficult to defend. Using conventional chest radiography alone, one expects that approximately 20%-30% of patients with nonseminomatous tumors will have mediastinal or pulmonary involvement at presentation. Whole lung tomography may demonstrate more areas of metastatic disease but rarely depicts new tumors in a patient with a normal chest radiograph (26). Chest CT has a small but definite advantage over whole lung tomography in evaluation of these patients. Husband et al (27) found five patients in whom occult pulmonary metastases were detected with CT, among a group of 62 patients evaluated with both chest CT and whole lung tomography. This superiority of CT over plain radiography is maintained in the surveillance of patients after treatment. Williams et al (28) used both modalities to follow up 147 patients with stage I nonseminomatous tumors. CT demonstrated chest relapse in 15 patients, while plain radiography demonstrated lesions in only eight of these patients. The value of chest CT does not seem to hold up for the evaluation of seminoma. Steinfeld and Macher (29) reviewed images of 93 patients with stage I or II seminoma. All patients had a normal chest radiograph, and 22 patients were also evaluated with whole lung tomography or chest CT. In no patient was occult lung or mediastinal disease found. Long-term follow-up produced no evidence of chest failure as the first or sole site of relapse. However, none of their patients with stage II disease had bulky (stage IIB) disease. It would seem, at least for patients with stage I or hA seminoma, that a plain chest radiograph is sufficient for initial staging. Similarly, chest radiography may be sufficient in following up patients with seminoma with initial smallvolume disease. Peckham and Brada (30) described 52 patients with stage I seminoma who received no adjuvant therapy after orchiectomy. With a June
1990
median follow-up period of 23 months, seven patients have relapsed, six with disease confined to the abdomen and one with abdominal and pulmonary lesions. While the method by which the lung lesions were found in that patient is not stated, the scarcity of the event argues against the routine use of chest CT as a tool for following up these patients. The abdomen.-The radiologic evaluation of the abdomen in patients with testicular germ cell tumors is essentially a search for retroperitoneal lymph nodes, the most common site of metastasis for this disease. The route of lymphatic drainage from the testicles to these nodes is well documented (31). Since direct testicular lymphangiography is quite painful, alternate methods are required. While many techniques are available to image the retroperitoneum (US, excretory urography, inferior vena cavography, gallium scanning, lymphoscintigraphy, radioimmunodetection, angiography, MR imaging), only lymphangiography and CT have been widely studied. In deciding which studies to perform, and in what order, the physician must be aware of the relative accuracies of the studies available and the impact that the information will have on treatment decisions. For example, it may be more important to know about small-volume disease in a patient who will be managed with observation only than in a patient who will definitely be treated. The sensitivity (chance of detecting a true-positive case, or one minus the false-negative rate), specificity (probability of finding a true-negative case, or one minus the false-positive rate), and accuracy (proportion of true-positive plus true-negative cases) of CT and lymphangiography in evaluating testicular cancer have recently been reviewed by Fung and Garnick (32). Despite the theoretical advantage of lymphangiography, based on its ability to show internal nodal architecture, the overall accuracy of the two procedures is comparable. Dunnick and Javadpour (33) and Marincek et al (34) have demonstrated sensitivity as high as 90% by combining both procedures. However, accuracy did not improve appreciably. In the absence of a clear superiority of one technique over another or convincing evidence that a combination of the procedures is superior, the problem of selecting between the two tests becomes a matter of secondary issues. Clearly, lymphangiograVolume
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3
phy is the more morbid and invasive procedure. A reasonable approach might be to perform CT on all patients. Men with negative studies, who will not be getting elective treatment of the retroperitoneal nodes (either radiation or surgery), might appropriately undergo lymphangiography to increase the accuracy of assessment. Some radiation oncologists believe that a lymphangiogram is mandatory to guide adequate treatment of paraaortic nodes. Since the dose of radiation required to sterilize this disease is relatively low (as will be noted later), it is possible to use treatment fields based on the anatomy as shown by CT to properly cover the areas at risk. TREATMENT
AND
OUTCOME
Seminoma The routine cure of seminoma is a result of several factors. The disease is most often noted while still limited to the testicle (stage I). Its route of spread is predictable, with retroperitoneal lymph nodes the usual site of first metastasis (stage II). Sensitive radiologic methods exist to determine the extent of the disease. Finally, its exquisite sensitivity to radiation makes tumor control a virtual certainty. Consequently, 5-year survival rates for patients with stage I disease are generally better than 95%, with figures for stage II patients in the 85%-90% range (35-41). As a result of these successes, there has been interest in reducing the amount of treatment given, both in terms of extent of radiation and, to some extent, the dose employed. The traditional use of irradiation to retroperitoneal lymph nodes in stage I disease is being questioned by several surveillance programs. As mentioned earlier, Peckham and Brada (30) described 52 patients with stage I disease who were observed after orchiectomy. With a median follow-up of 23 months, seven (13%) have relapsed; in six cases retroperitoneal nodes were the site of metastases. At the time of the report, six patients were in remission after radiation or chemotherapy and one patient was still being treated. Viewed another way, 87% of their patients were spared apparently unnecessary treatment. Oliver (42) reported similar results in 26 patients with a median follow-up period of 18 months. Four patients relapsed, all of whom were salvaged with chemotherapy. The author noted that three of the four re-
lapses were difficult to diagnose. Nevertheless, adjuvant retroperitoneal irradiation, to a dose of 2,000-3,000 cGy, must still be considered the standard of care for patients with stage I seminoma. The concept of “less is better” has been extended to stage II seminoma as well. Thomas et al (39) and Willan and McGowan (43) reported 5-year survival rates of 100% and 82% in patients with stage IIA (nonpalpable abdominal) disease who did not receive mediastinal irradiation. Only two of the patients in the study by Willan and McGowan (43) developed disease in the mediastinum, and then as a component of more generalized disease. Hanks (44) has questioned the wisdom of accepting these two studies as a basis for changing the standard of care. Despite this warning, a recent national study has documented a decrease in the frequency with which patients with stage II disease receive mediastinal irradiation (45). In the absence of a prospective randomized trial (a recent attempt at such a trial by the Radiation Therapy Oncology Group failed due to lack of patient accrual), the physician should consider other factors (eg, patient reliability for follow-up) in deciding whether to give adjuvant treatment to the mediastinum. Patients with bulky abdominal disease (stage JIB) or with stage III disease are uncommon, particularly in recent series from the United States. Their treatment should be individualized, with strong consideration given to chemotherapy. Other
Germ
Cell
Tumors
Interest in maintaining excellent outcome results, while giving less therapy, is the hallmark of the current philosophies regarding treatment of nonseminomatous germ cell tumors. Standard care for patients with stage I nonseminomatous germ cell tumors has been, until recently, retroperitoneal lymph node dissection following radical inguinal orchiectomy. Using such an approach, Staubitz achieved an 86% 5-year survival for 65 patients with pathologic stage I disease (46). The advent of adjuvant chemotherapy, particularly regimens employing cisplatin, has dramatically improved the situation. Reports by Skinner (47), Donahue (48), and Fraley et al (49) document 3-5-year survival rates of virtually 100% in patients with stage I disease and 95% in patients with stage II disease, using Radiology
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adjuvant chemotherapy regimens, generally containing cisplatin. These superb results set the stage for attempts at diminishing the extent of initial therapy. One thrust of current research is to minimize side effects by changing or eliminating the standard retroperitoneal lymph node dissection. A less extensive dissection may decrease the frequency of bowel injury or loss of ejaculation, the latter of which can occur in up to 75% of patients. Rowland (50) recently summarized proposed changes in surgical technique. Surveillance studies of patients who have undergone orchiectomy are also underway. In some instances, initial chemotherapy is given (30), while in other approaches chemotherapy and surgery are used as salvage treatment (51,52). The optimal therapeutic approach will be the one that achieves the lowest morbidity while maintaining high cure rates. AND
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mt 10.
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The speed with which chemotherapeutic regimens for testicular germ cell tumors develop is almost dizzying and makes their discussion a difficult task. Recent publications (16,53) summarize this rapidly changing field. Further refinements are also to be expected in defining subgroups of patients who need more, or less, treatment based on, for example, marker status, DNA ploidy, or histologic subgroup. And finally, long-term follow-up evaluations, such as those conducted by the Patterns of Care Study, will provide accurate information on the price of success. U
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for adjuvant chemothera1986; 4:1031-1036. Complicated Semin Oncol
problems in tes1988; 15(supp):9-
June
1990
