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Bilateral Testicular Germ Cell Tumors: A Report of 20 Cases
0022-5347 /87 /1375-0C73$G2.00 /0 Vol,
THE JCHJRI'>JAL OF UROLOG'l
Copyright© 1987 by T:1-e \¥illian1s & \Vilkins Co.
Printed in
BILATERAL TESTICULAR GERM CELL TUlVIORS: CASES K. SCHEIBER, D. ACKERMANN
AND
REPORT
20
U. E. STUDER
From the Department of Urology, University of Berne, Berne, Switzerland, and Institute of Urology, University of Innsbruck, Innsbruck, Austria
ABSTRACT
Of 412 patients with unilateral testicular cancer 20 (4.3 per cent) suffered a second primary germ cell tumor: 1 had a simultaneous bilateral tumor and in the remaining 19 the second tumor was diagnosed after an interval of 2 months to 32 years. Patients wit~ clinical stage~ III and IV disease were found only in the group with a second tumor. In 5 patients ~no:1"n nsk factor~ for t~e development of testicular tumors were found and in 2 prior testicular b10psies show~d carcmoma m situ. Effective chemotherapy was used more often in the treatment of the second pnmary tumor. Of the 20 patients 18 (90 per cent) are free of disease after a me~n observation ~f ?·7 yea~s. A long followup of testicular cancer patients with sonographic evaluat10n of the remammg testis as well as periodic self-examination by the patient is required. J. Urol., 138: 73-76, 1987 In 1853 Bidard reported a biopsy proved case of bilateral germ cell tumor.' Although this condition is rare it long has been recognized that men with testicular germ cell tumors have an increased risk for a second tumor developing in the contralateral testiso An incidence of l to 5. 7 per cent for bilateral testicular tumors has been reported. 2 - 9 Because of improved therapeutic procedures, particularly chemotherapy, the prognosis in patients with malignant testicular tumors has im proved. Similarly, patients with metastatic lesions can_ expect long survival. As a consequence the problem of a second tumor in the contralateral testicle is becoming increasingly more important. Data concerning 20 patients from 2 university hospitals are presented and the literature is reviewed.
RESULTS
Incidence. In 20 of the 412 patients (4.3 per cent) a second contralateral primary testicular cancer was diagnosed. In 1 patient bilateral tumor with a different histological composition The median age of the developed simultaneously (table patients at presentation with the initial tumor was 29 years (range 19 to 41 years). The second tumor in the contralateral testis was diagnosed at a mean patient age of 35 years (range 25 to 58 years). Histological findings. Of 20 patients 7 (35 per cent) had identical histological findings in both testicular tumors. Bilateral seminoma was found in 5 patients and embryonal carcinoma was noted in 2. In 10 of the 20 patients (50 per cent) histological study of the initial tumor showed seminoma, while 9 patients (45 per cent) had seminoma in the contralateral testis. One initial and 3 second tumors were mixed. Of the 10 patients with seminoma initially 5 had identical histological findings in the subsequent tumor and 4 of 10 patients with nonseminomatous tumors suffered a seminoma in the contralateral testis (table 2). Stage of initial and secondary tumors. In both groups stage I disease occurred with equal frequency. Four patients with stages III and IV disease were found in the group with a secondary tumor only (table Interval between initial and secondary tumors. One patient had synchronous bilateral tumors, a seminoma on the left side and a teratocarcinoma in the right testicle. In the remaining 19 patients the second primary tumor was diagnosed after an interval of 2 months to 32 years (median 73 months)o The contralateral tumor occurred within the first 2 years in 7 patients (37 per cent), within 5 years in 12 (63 per cent) and after more than 10 years in 3. The interval between the first symptoms and initial consultation was known in 16 patients. The interval to the diagnosis of the initial tumor was 6 weeks to 1 year (mean 4.4 months) and the interval to diagnosis of the second tumor was 2 days to 5 months (mean 5.2 weeks). Risk factors. Known risk factors for the development of testicular tumors were found in 5 patients. One patient underwent unilateral orchiopexy for cryptorchidism when he was 14 years old. Embryonal carcinoma occurred in the same testicle 13 years later (initial tumor). Three patients had been investigated several years earlier for impaired fertility and in 2 testicular biopsies showed atypical spermatogonia or carcinoma in situ. One patient suffered bilateral testicular tumor 1 and 3 years after diagnosis of carcinoma in situ, and in 1 bilateral
PATIENTS AND METHODS
Between 1969 and 1985 we treated 412 patients with testicular !!erm cell tumors. A total of 20 patients (4.3 per cent) with bilat:ral tumors has been evaluated in detail. We used the World Health Organization international histological classification and the Royal Marsden staging system: stage I-no evidence of disease outside the testis, stage II-infradiaphragmatic node involvement (stage HA-maximum diameter of metastases less than 2 cnL, stage HE-maximum diameter 2 to 5 cm. and stage IIC-maximum diameter greater than 5 stage III-supradiaphragmatic and infradiaphragmatic lymph node involvement (aodominal nodes A, Band C as for stage II, mediastinal nodes noted as M + and neck nodes noted as N +), and sta!!e IV -extension of tumor to extralymphatic sites B and C for abdominal nodes as for stages II and III, lung involvement noted as LI-less than 3 metastases, L2-more than 3 metastases less than 2 cm. in maximum diameter and L3-more than 3 metastases greater than 2 cm. in maximum diameter, hepatic involvement noted as H+ and involvement of other sites, for example bone and brain, as specified) .10· 11 During the 16-year study interval treatment of th~ 20 p~tients was inconsistent because of the progress achieved m chemotherapy, as well as some differences between thera?y schedules at both of our hospitals. However, generally, radiation therapy was given to patients with low stage seminoma, while nonseminoma patients underwent lymphadenectomy. Chemotherapy was used widely to treat advanced disease as well as the second tumor. Accepted for publication January 29, 1987. 73
74
SCHEIBER, ACKERMANN AND STUDER TABLE
1. Characteristics
Primary Tumor Pt.-Age
Histological Status
Secondary Tumor Interval
Stage
Therapy
Followup (yrs.)
Histological Status
Stage
Therapy
MH~26 BJ-25
Seminoma Teratoma
Unknown Tll
Radiation Radiation
32 yrs. 14 yrs.
Embryonal Ca Seminoma
TxIIIb,M,N TlI
Chemotherapy Radiation
Died of disease Free of disease
WW-32
Embryonal Ca
Tll
Radiation
6 yrs.
Embryonal Ca
TlIIIaM,N
Radiation
MR-19
Teratoca.
Tll
Radiation
9 yrs.
Seminoma
T3I
Radiation
Free of disease (13) Free of disease
BB-27
T3IIc
Chemotherapy
7 yrs.
Chemotherapy
Free of disease
Tll
Radiation
4 yrs.
Embryonal Ca, yolk sac tumor Seminoma
TlIIIb,M,N
SL-32
Chorioca., teratoma, seminoma Seminoma
Tll
EA-41
Seminoma
T4aI
Radiation
11 yrs.
Seminoma
T3I
HR-23
Seminoma
Tll
Radiation
2 yrs.
Teratoca.
TlI
(10)
(6)
GC-29
UW-26
Seminoma
Embryonal Ca
TlIIb
T3IIb
Chorioca., teratoma
Tll
KF-34
Seminoma
T3I
KJ-20
Teratoma
T3I
BB-20
Radiation
2 yrs.
Lymphadenectomy, chemotherapy Lymphadenectomy, chemotherapy Radiation
2½ yrs.
(8)
Embryonal Ca, seminoma
TlIIa
Embryonal Ca
T3I
Lymphadenectomy Primary none, treatment of iliac relapse by chemotherapy and lymphadenectomy Lymphadenectomy, chemotherapy Lymphadenectomy, chemotherapy Chemotherapy
Free of disease (8)
Free of disease (1½)
Free of disease (10)
Free of disease (9)
Free of disease (8)
5 yrs.
Embryonal Ca, yolk sac tumor
T4aIVcL1H
5 yrs.
Seminoma
T3I
Radiation
Free of disease
7 yrs.
Embryonal Ca, seminoma
Tll
Chemotherapy
Free of disease
Seminoma
T2I
Chemotherapy
Free of disease (5)
(4)
SH-39
Teratoma
T3IIb
SW-26
Seminoma
TlIIb
KF-31
WH-35
Chorioca., embryonal Ca, teratoma
T3I
Seminoma
T3I
Lymphadenectomy, chemotherapy Radiation
2 yrs.
(2)
Simultaneously teratoca.
Lymphadenectomy, chemotherapy Radiation
11 mos.
2 yrs.
TlIIb
Embryonal Ca
KM-32
Seminoma
T3I
Radiation
1 yrs.
Seminoma, teratoma (mature) Seminoma
BH-28
Embryonal Ca
Tll
Lymphadenectomy
3 yrs.
Seminoma
None
2 mos.
T2I
Tll
TlI
T3I
No treatment (moribund) Lymphadenectomy, chemotherapy Chemotherapy, adrenalectomy (metastases) No treatment (wait and see) Chemotherapy
Died of primary tumor Free of disease
No treatment (wait and see) Radiation
Free of disease
(7)
Free of disease (4)
Free of disease (1)
Free of disease (3)
LE-33
Seminoma
T3I
Seminoma
Tll
(1)
Free of disease (2)
TABLE 2.
Histological status of initial and secondary tumors Secondary Tumor
3. Clinical stage of primary and secondary cancers
Stage
Primary Tumor Seminoma Nonseminoma
TABLE
Seminoma
Nonseminoma
5 4
5 6
testicular tumor developed 5 and 14 years later. One patient had an atrophic testis after an inguinal hernioplasty in early childhood. Treatment. The therapy of the patients is shown in table 1. In general, patients with seminoma had radiation therapy. Of 6 patients with nonseminomatous tumors and without clinical
I II III IV Unknown
Primary Tumor (No.)
Secondary Tumor (No.)
14
14
5
2 3
1
evidence of retroperitoneal lymph node metastases 5 also were treated by radiation therapy. In these cases radiation therapy had been given more than 10 years ago. Patients with nonseminomatous tumors usually underwent retroperitoneal lymph
75
BILATERAL TESTICULAR GERM CELL TUMORS
node dissection and/ or chemotherapy according to the stage of disease. Chemotherapy was used more often to treat the second primary tumor, either as adjuvant therapy in patients who previously had undergone retroperitoneal lymphadenectomy, or for curative purposes when lymph node and/or distant metastases were present. One initial tumor and 7 secondary tumors were treated by chemotherapy alone. Outcome-prognosis. Of 20 patients 18 (90 per cent) who had been treated for bilateral testicular cancer were free of disease after a mean of 5.7 years (range 1 to 13 years). One patient died 9 months after diagnosis of the second primary embryonal carcinoma (stage III) with high levels. of tumor markers. The second tumor was diagnosed 32 years after the first tumor. Ope patient had brain metastases 2 years after initially inadequate treatment of nonseminomatous metastatic testicular cancer. At that time an enlargement of the contralateral testis was fqund but because of the poor general condition no castration was performed. At autopsy a stage pT2 seminoma was found in the contralateral testicle. DISCUSSION
It is well recognized that a history of testicular cancer predisposes to a second malignancy in the contralateral testis. As a result of increased survival after testicular cancer it is likely that urologists will be confronted more frequently with secondary contralateral testicular cancer and its treatment. Indeed, Aristizabel and associates reviewed the literature and found an incidence of 1.56 per cent. 12 A summary of cases of bilateral tumor since 1980 reveals a slightly increased incidence of 3.2 per cent. 2·3,5-9,13 In our series the frequency of bilateral testfr:ular tumors is 4.3 per cent. This increasing incidence probably relates to the developments in the treatment of testicular tumor during the last decade, with a high number (70 to 90 per cent) of patients surviving from the first testicular malignancy. Compared to the normal healthy male population the reported risk of a second tumor developing is increased by a factor of 500 to 700.7,12 . An increased incidence of bilateral tumor in patients who have had an undescended testis on one or both sides has been reported. 4·7· 14 Only 1 of our patients had had an undescended testis in the past. Three patients previously were investigated for decreased fertility and atypical germ cells were observed in testicular biopsies in 2 of them 1 and 3, and 5 and 14 years, respectively, before the development of testicular tumors. This finding is in agreement with that of others who showed that infertile men with in situ testicular carcinoma had a high risk for i~vasive germ cell tumors. 15-17 The use of biopsies for the early detection of germ· cell tumors in patients with previous testicular cancer also has been proposed. In most series histological examination generally revealed bilateral seminoma. Pui:,h, 14 and Sokal and associates 7 con eluded that the likelihood of a second tumor developing is slightly higher in seminoma patients. However, we did not find any correlation. Kristianslund and associates found that 94 per cent of the patients with initial seminomas had the same histological findings in the second tumor, while only 45 per cent of nonseminoma patients had a seminoma in the contralateral testis. 6 We found no difference between seminoma and nonseminoma patients when the histological findings of both tumors were compared. Of 10 patients with seminom:a and 10 with nonseminomatous tumor 5 and 6, respectively, had the same histological findings in both testicular tumors. Only 4 of the total 40 testicular cancers showed mixed histological findings. In regard to the interval between the incidence of first and second tumors, approximately a third of our patients suffered the second testicular cancer within 2 years, while in a third the diagnosis was confirmed at 2 to 5 years. Previously described intervals between the first and second malignancy vary widely but about 50 per cent of all successive testicular tumors appear
to develop within 5 years of the first tumor diagnosis. 2·3·5·7·12 However, since the second tumor must be considered as a new primary tumor a contralateral tumor can occur even after a decade or more has passed. To date there have been 2 reports on the occurrence of a second testicular tumor 23 and 25 years after the first tumor. 12· 18 We report on a patient with an interval of 32 years between tumors. Our data reveal that a long followup of patients with testicular cancer is required, with detailed counseling concerning the possible occurrence of a second tumor. Periodic self-examination by the patient and repeated sonographic evaluation of the remaining testis also are recommended. This method may explain the shorter mean time to the diagnosis of the second testicular tumor (5.2 weeks) compared to the first tumor (4.4 months) in our patients. Therefore, more patients would be expected to present with a low stage second tumor. However, surprisingly, cases of stages III and IV disease were found only in conjunction with the second testicular cancer. This observation may be explained partly by patient selection. Patients who presented initially with stages III and IV disease have had a poorer prognosis and, therefore, a decreased chance of survival with a consequently lower risk for a second tumor to develop. Widely used irradiation and i:etroperitoneal lymph node dissectton of the initial tumor alter the ly~phogenic pathways of metastatic spread. After retroperitoneal lymph node dissection extensive collateral circulation, new lymphatic connections and lympho-venous shunting have been described. 19 This new lymphatic environment may increase the chance of rapid distal metastases and it could be another reason for our observation of 4 of 20 patients with ~tages II( a:q.d IV disease despite a second primary with a short history and with local stage Tl disease in some cases. Treatment possibilities of the second tumor are compromised distinctly by previous therapy of the initial tumor. Radiation therapy of the second tumor is li~itep. by the previously used dosage. Since most patients underwent retroperitoneal lymphadenectomy and/or x-ray treatment along the retroperitoneal lymphatic pathways because of the fi:rst testicular malignancy, a second retroperitoneal lymphadenectomy or x-ray treatment virtually is impossible. Because of this fact, only 4 of 9 patients with a· seminoma as the secondary testicular cancer received radiation therapy. Therefore, regardless ofhistological findings, combined chemotherapy usually is the treatment of choice. Chemotherapy was given n9t only in the presence of biopsy proved metastases but also as an adjuvant therapy (2 cycles) after orchiectomy because of the second testicular cancer. Five patients with clinical stage I· secondary tumors had a short course of chemotherapy and they are alive. It is not known if a wait-and-watch policy after the diagnosis of a low stage second testicular cancer can be adopted. Our experience with 3 patients is.too limited to answer this question. One patient had a relapse in an iliac lymph node 1 year later and was salvaged by chemotherapy. Two patients had no evidence of disease after 1 year of observation. Owing to the changes in the retroperitoneal lymphatic pathways after treatment of the first testicular cancer and based on our findings that 4 patients had an advanced tumor stage at diagnosis of the second cancer, our policy is to be restrictive with a waitand-watch attitude after a second testicular cancer. In our series only 2 patients died: 1 of inadequate treatment of the initial tumor and 1 shortly after diagnosis of the second testicular cancer. No chemotherapy was possible because of the poor condition of the patient. Of 20 patients 18 were alive a mean of 5.6 years after the second testicular cancer, which indicates a high cure rate of this disease. Patients with 2 consecutive testicular malignancies also have a good chance for survival. 0
REFERENCES 1. Bidard, M.: Cancer du testicule. Bull. Soc. Anat. Paris, 28: 345,
1853.
76
SCHEIBER, ACKERMANN AND STUDER
2. Dieckmann, K.-P., Boeckmann, W., Brosig, W., Jonas, D. and Bauer, H.-W.: Bilaterale testikuliire Keimzelltumoren. Bericht iiber 9 Fiille und Literaturiibersicht. Akt. Urol., 1 7: 25, 1986. 3. Ehrengut, W., Schwartau, M. and Hubmann, R.: Testiculiire Vorerkrankungen bei Patienten mit Hodentumoren unter besonderer Beriicksichtigung der Mumpsorchitis. Urologe A, 19: 283, 1980. 4. Hamilton, J. B. and Gilbert, J. B.: Studies in malignant tumors of the testis: IV. Bilateral testicular cancer. Incidence nature and bearing upon management of the patients with a single testicular cancer. Cancer Res., 2: 125, 1942. 5. Hoekstra, H.J., Sleyfer, D. T., Wobbes, T. and Schraffordt Koops, H.: Bilateral primary germ cell tumors of testis. Urology, 19: 152, 1982. 6. Kristianslund, S., Fossa, S. D. and Kjellevold, K.: Bilateral malignant testicular germ cell cancer. Brit. J. Urol., 58: 60, 1986. 7. Sokal, M., Peckham, M. J. and Hendry, W. F.: Bilateral germ cell tumours of the testis. Brit. J. Urol., 52: 158, 1980. 8. Studer, U. E., Eilinger, H. and Haueter, M.: Patienten mit erhiihtem Risiko zur Entwicklung eines Hodentumors. Therapiewoche, 32: 520, 1982. 9. Ware, S. M., Heyman, J., Al-Askari, S. and Morales, P.: Bilateral testicular germ cell malignancy. Urology, 19: 366, 1982. 10. Mostofi, F. K. and Sobin, L. H.: Histological typing of testis tumours. In: International Histological Classification of Tumours. Geneva: World Health Organization No. 16, 1977. 11. Peckham, M. J.: Investigation and staging: general aspects and staging classification. In: The Management of Testicular Tumours. Edited by M. Peckham. London: Edward Arnold, chapt. 7, p. 89, 1981. 12. Aristizabal, S., Davis, J. R., Miller, R. C., Moore, M. J. and Boone, M. L. M.: Bilateral primary germ cell testicular tumors: report of four cases and review of the literature. Cancer, 42: 591, 1978. 13. Hartung, R., Ringert, R.-H. and Brehmer, B.: Zur Problematik beidseitiger Hodentumoren. Verhand. Dtsch. Gesell. Urol., 34: 406, 1982. 14. Pugh, R. C. B.: Testicular tumours-the panel classification. In: Pathology of the Testis. London: Blackwell Scientific, pp. 144146, 1976. 15. Niiesch-Bachmann, I. H. and Hedinger, C.: Atypische Spermato-
gonien als Priikanzerose. Schweiz. Med. Wschr., 107: 795, 1977. 16. Skakkebaek, N. E., Berthelsen, J. G. and Visfeldt, J.: Clinical aspects of testicular carcinoma-in-situ. Int. J. Androl., suppl. 4, 4: 153, 1981. 17. Skakkebaek, N. E.: Carcinoma in situ of the testis: frequency and relationship to invasive germ cell tumours in infertile men. Histopathology, 2: 157, 1978. 18. Collins, D. H. and Pugh, R. C. B.: Classification and frequency of testicular tumours. Brit. J. Urol., suppl., 36: 1, 1964. 19. Zattoni, F., Wajsman, Z., Beckley, S. A., Lanteri, V. and Pontes, J. E.: Treatment of sequential bilateral germ cell tumors of the testis following interval retroperitoneal lymph node dissection. J. Urol., 130: 142, 1983.
EDITORIAL COMMENT Several points deserve emphasis about this timely topic. The prognosis of patients with malignant germ cell tumors has improved to the extent that they can be expected to live long enough to exhibit a second testis tumor more often than seen in the past. The often quoted 1 per cent incidence of a second primary in these patients more likely is 2 to 4 times that in the present generation. In some patients the interval between tumors is longer than 10 years but most (63 per cent in this study) will present within 5 years. This finding underscores the need for patient self-examination instruction, interval scrotal ultrasound examinations and long-term followup. The discussion of treatment possibilities of the second tumor is worthwhile. It is influenced by the treatment used for the first tumor, as well as by clinical stage and histological findings. As a general comment, systemic platinum-based chemotherapy in a primary or adjuvant treatment mode is more attractive ifthere is reason to believe the lymphatic drainage pathways of metastatic spread have been altered by earlier treatment of the initial tumor. The prognosis for these patients remains good if they are treated promptly and followed carefully.
John P. Donohue Department of Urology Indiana University Medical Center Indianapolis, Indiana
THE JCHJRI'>JAL OF UROLOG'l
Copyright© 1987 by T:1-e \¥illian1s & \Vilkins Co.
Printed in
BILATERAL TESTICULAR GERM CELL TUlVIORS: CASES K. SCHEIBER, D. ACKERMANN
AND
REPORT
20
U. E. STUDER
From the Department of Urology, University of Berne, Berne, Switzerland, and Institute of Urology, University of Innsbruck, Innsbruck, Austria
ABSTRACT
Of 412 patients with unilateral testicular cancer 20 (4.3 per cent) suffered a second primary germ cell tumor: 1 had a simultaneous bilateral tumor and in the remaining 19 the second tumor was diagnosed after an interval of 2 months to 32 years. Patients wit~ clinical stage~ III and IV disease were found only in the group with a second tumor. In 5 patients ~no:1"n nsk factor~ for t~e development of testicular tumors were found and in 2 prior testicular b10psies show~d carcmoma m situ. Effective chemotherapy was used more often in the treatment of the second pnmary tumor. Of the 20 patients 18 (90 per cent) are free of disease after a me~n observation ~f ?·7 yea~s. A long followup of testicular cancer patients with sonographic evaluat10n of the remammg testis as well as periodic self-examination by the patient is required. J. Urol., 138: 73-76, 1987 In 1853 Bidard reported a biopsy proved case of bilateral germ cell tumor.' Although this condition is rare it long has been recognized that men with testicular germ cell tumors have an increased risk for a second tumor developing in the contralateral testiso An incidence of l to 5. 7 per cent for bilateral testicular tumors has been reported. 2 - 9 Because of improved therapeutic procedures, particularly chemotherapy, the prognosis in patients with malignant testicular tumors has im proved. Similarly, patients with metastatic lesions can_ expect long survival. As a consequence the problem of a second tumor in the contralateral testicle is becoming increasingly more important. Data concerning 20 patients from 2 university hospitals are presented and the literature is reviewed.
RESULTS
Incidence. In 20 of the 412 patients (4.3 per cent) a second contralateral primary testicular cancer was diagnosed. In 1 patient bilateral tumor with a different histological composition The median age of the developed simultaneously (table patients at presentation with the initial tumor was 29 years (range 19 to 41 years). The second tumor in the contralateral testis was diagnosed at a mean patient age of 35 years (range 25 to 58 years). Histological findings. Of 20 patients 7 (35 per cent) had identical histological findings in both testicular tumors. Bilateral seminoma was found in 5 patients and embryonal carcinoma was noted in 2. In 10 of the 20 patients (50 per cent) histological study of the initial tumor showed seminoma, while 9 patients (45 per cent) had seminoma in the contralateral testis. One initial and 3 second tumors were mixed. Of the 10 patients with seminoma initially 5 had identical histological findings in the subsequent tumor and 4 of 10 patients with nonseminomatous tumors suffered a seminoma in the contralateral testis (table 2). Stage of initial and secondary tumors. In both groups stage I disease occurred with equal frequency. Four patients with stages III and IV disease were found in the group with a secondary tumor only (table Interval between initial and secondary tumors. One patient had synchronous bilateral tumors, a seminoma on the left side and a teratocarcinoma in the right testicle. In the remaining 19 patients the second primary tumor was diagnosed after an interval of 2 months to 32 years (median 73 months)o The contralateral tumor occurred within the first 2 years in 7 patients (37 per cent), within 5 years in 12 (63 per cent) and after more than 10 years in 3. The interval between the first symptoms and initial consultation was known in 16 patients. The interval to the diagnosis of the initial tumor was 6 weeks to 1 year (mean 4.4 months) and the interval to diagnosis of the second tumor was 2 days to 5 months (mean 5.2 weeks). Risk factors. Known risk factors for the development of testicular tumors were found in 5 patients. One patient underwent unilateral orchiopexy for cryptorchidism when he was 14 years old. Embryonal carcinoma occurred in the same testicle 13 years later (initial tumor). Three patients had been investigated several years earlier for impaired fertility and in 2 testicular biopsies showed atypical spermatogonia or carcinoma in situ. One patient suffered bilateral testicular tumor 1 and 3 years after diagnosis of carcinoma in situ, and in 1 bilateral
PATIENTS AND METHODS
Between 1969 and 1985 we treated 412 patients with testicular !!erm cell tumors. A total of 20 patients (4.3 per cent) with bilat:ral tumors has been evaluated in detail. We used the World Health Organization international histological classification and the Royal Marsden staging system: stage I-no evidence of disease outside the testis, stage II-infradiaphragmatic node involvement (stage HA-maximum diameter of metastases less than 2 cnL, stage HE-maximum diameter 2 to 5 cm. and stage IIC-maximum diameter greater than 5 stage III-supradiaphragmatic and infradiaphragmatic lymph node involvement (aodominal nodes A, Band C as for stage II, mediastinal nodes noted as M + and neck nodes noted as N +), and sta!!e IV -extension of tumor to extralymphatic sites B and C for abdominal nodes as for stages II and III, lung involvement noted as LI-less than 3 metastases, L2-more than 3 metastases less than 2 cm. in maximum diameter and L3-more than 3 metastases greater than 2 cm. in maximum diameter, hepatic involvement noted as H+ and involvement of other sites, for example bone and brain, as specified) .10· 11 During the 16-year study interval treatment of th~ 20 p~tients was inconsistent because of the progress achieved m chemotherapy, as well as some differences between thera?y schedules at both of our hospitals. However, generally, radiation therapy was given to patients with low stage seminoma, while nonseminoma patients underwent lymphadenectomy. Chemotherapy was used widely to treat advanced disease as well as the second tumor. Accepted for publication January 29, 1987. 73
74
SCHEIBER, ACKERMANN AND STUDER TABLE
1. Characteristics
Primary Tumor Pt.-Age
Histological Status
Secondary Tumor Interval
Stage
Therapy
Followup (yrs.)
Histological Status
Stage
Therapy
MH~26 BJ-25
Seminoma Teratoma
Unknown Tll
Radiation Radiation
32 yrs. 14 yrs.
Embryonal Ca Seminoma
TxIIIb,M,N TlI
Chemotherapy Radiation
Died of disease Free of disease
WW-32
Embryonal Ca
Tll
Radiation
6 yrs.
Embryonal Ca
TlIIIaM,N
Radiation
MR-19
Teratoca.
Tll
Radiation
9 yrs.
Seminoma
T3I
Radiation
Free of disease (13) Free of disease
BB-27
T3IIc
Chemotherapy
7 yrs.
Chemotherapy
Free of disease
Tll
Radiation
4 yrs.
Embryonal Ca, yolk sac tumor Seminoma
TlIIIb,M,N
SL-32
Chorioca., teratoma, seminoma Seminoma
Tll
EA-41
Seminoma
T4aI
Radiation
11 yrs.
Seminoma
T3I
HR-23
Seminoma
Tll
Radiation
2 yrs.
Teratoca.
TlI
(10)
(6)
GC-29
UW-26
Seminoma
Embryonal Ca
TlIIb
T3IIb
Chorioca., teratoma
Tll
KF-34
Seminoma
T3I
KJ-20
Teratoma
T3I
BB-20
Radiation
2 yrs.
Lymphadenectomy, chemotherapy Lymphadenectomy, chemotherapy Radiation
2½ yrs.
(8)
Embryonal Ca, seminoma
TlIIa
Embryonal Ca
T3I
Lymphadenectomy Primary none, treatment of iliac relapse by chemotherapy and lymphadenectomy Lymphadenectomy, chemotherapy Lymphadenectomy, chemotherapy Chemotherapy
Free of disease (8)
Free of disease (1½)
Free of disease (10)
Free of disease (9)
Free of disease (8)
5 yrs.
Embryonal Ca, yolk sac tumor
T4aIVcL1H
5 yrs.
Seminoma
T3I
Radiation
Free of disease
7 yrs.
Embryonal Ca, seminoma
Tll
Chemotherapy
Free of disease
Seminoma
T2I
Chemotherapy
Free of disease (5)
(4)
SH-39
Teratoma
T3IIb
SW-26
Seminoma
TlIIb
KF-31
WH-35
Chorioca., embryonal Ca, teratoma
T3I
Seminoma
T3I
Lymphadenectomy, chemotherapy Radiation
2 yrs.
(2)
Simultaneously teratoca.
Lymphadenectomy, chemotherapy Radiation
11 mos.
2 yrs.
TlIIb
Embryonal Ca
KM-32
Seminoma
T3I
Radiation
1 yrs.
Seminoma, teratoma (mature) Seminoma
BH-28
Embryonal Ca
Tll
Lymphadenectomy
3 yrs.
Seminoma
None
2 mos.
T2I
Tll
TlI
T3I
No treatment (moribund) Lymphadenectomy, chemotherapy Chemotherapy, adrenalectomy (metastases) No treatment (wait and see) Chemotherapy
Died of primary tumor Free of disease
No treatment (wait and see) Radiation
Free of disease
(7)
Free of disease (4)
Free of disease (1)
Free of disease (3)
LE-33
Seminoma
T3I
Seminoma
Tll
(1)
Free of disease (2)
TABLE 2.
Histological status of initial and secondary tumors Secondary Tumor
3. Clinical stage of primary and secondary cancers
Stage
Primary Tumor Seminoma Nonseminoma
TABLE
Seminoma
Nonseminoma
5 4
5 6
testicular tumor developed 5 and 14 years later. One patient had an atrophic testis after an inguinal hernioplasty in early childhood. Treatment. The therapy of the patients is shown in table 1. In general, patients with seminoma had radiation therapy. Of 6 patients with nonseminomatous tumors and without clinical
I II III IV Unknown
Primary Tumor (No.)
Secondary Tumor (No.)
14
14
5
2 3
1
evidence of retroperitoneal lymph node metastases 5 also were treated by radiation therapy. In these cases radiation therapy had been given more than 10 years ago. Patients with nonseminomatous tumors usually underwent retroperitoneal lymph
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BILATERAL TESTICULAR GERM CELL TUMORS
node dissection and/ or chemotherapy according to the stage of disease. Chemotherapy was used more often to treat the second primary tumor, either as adjuvant therapy in patients who previously had undergone retroperitoneal lymphadenectomy, or for curative purposes when lymph node and/or distant metastases were present. One initial tumor and 7 secondary tumors were treated by chemotherapy alone. Outcome-prognosis. Of 20 patients 18 (90 per cent) who had been treated for bilateral testicular cancer were free of disease after a mean of 5.7 years (range 1 to 13 years). One patient died 9 months after diagnosis of the second primary embryonal carcinoma (stage III) with high levels. of tumor markers. The second tumor was diagnosed 32 years after the first tumor. Ope patient had brain metastases 2 years after initially inadequate treatment of nonseminomatous metastatic testicular cancer. At that time an enlargement of the contralateral testis was fqund but because of the poor general condition no castration was performed. At autopsy a stage pT2 seminoma was found in the contralateral testicle. DISCUSSION
It is well recognized that a history of testicular cancer predisposes to a second malignancy in the contralateral testis. As a result of increased survival after testicular cancer it is likely that urologists will be confronted more frequently with secondary contralateral testicular cancer and its treatment. Indeed, Aristizabel and associates reviewed the literature and found an incidence of 1.56 per cent. 12 A summary of cases of bilateral tumor since 1980 reveals a slightly increased incidence of 3.2 per cent. 2·3,5-9,13 In our series the frequency of bilateral testfr:ular tumors is 4.3 per cent. This increasing incidence probably relates to the developments in the treatment of testicular tumor during the last decade, with a high number (70 to 90 per cent) of patients surviving from the first testicular malignancy. Compared to the normal healthy male population the reported risk of a second tumor developing is increased by a factor of 500 to 700.7,12 . An increased incidence of bilateral tumor in patients who have had an undescended testis on one or both sides has been reported. 4·7· 14 Only 1 of our patients had had an undescended testis in the past. Three patients previously were investigated for decreased fertility and atypical germ cells were observed in testicular biopsies in 2 of them 1 and 3, and 5 and 14 years, respectively, before the development of testicular tumors. This finding is in agreement with that of others who showed that infertile men with in situ testicular carcinoma had a high risk for i~vasive germ cell tumors. 15-17 The use of biopsies for the early detection of germ· cell tumors in patients with previous testicular cancer also has been proposed. In most series histological examination generally revealed bilateral seminoma. Pui:,h, 14 and Sokal and associates 7 con eluded that the likelihood of a second tumor developing is slightly higher in seminoma patients. However, we did not find any correlation. Kristianslund and associates found that 94 per cent of the patients with initial seminomas had the same histological findings in the second tumor, while only 45 per cent of nonseminoma patients had a seminoma in the contralateral testis. 6 We found no difference between seminoma and nonseminoma patients when the histological findings of both tumors were compared. Of 10 patients with seminom:a and 10 with nonseminomatous tumor 5 and 6, respectively, had the same histological findings in both testicular tumors. Only 4 of the total 40 testicular cancers showed mixed histological findings. In regard to the interval between the incidence of first and second tumors, approximately a third of our patients suffered the second testicular cancer within 2 years, while in a third the diagnosis was confirmed at 2 to 5 years. Previously described intervals between the first and second malignancy vary widely but about 50 per cent of all successive testicular tumors appear
to develop within 5 years of the first tumor diagnosis. 2·3·5·7·12 However, since the second tumor must be considered as a new primary tumor a contralateral tumor can occur even after a decade or more has passed. To date there have been 2 reports on the occurrence of a second testicular tumor 23 and 25 years after the first tumor. 12· 18 We report on a patient with an interval of 32 years between tumors. Our data reveal that a long followup of patients with testicular cancer is required, with detailed counseling concerning the possible occurrence of a second tumor. Periodic self-examination by the patient and repeated sonographic evaluation of the remaining testis also are recommended. This method may explain the shorter mean time to the diagnosis of the second testicular tumor (5.2 weeks) compared to the first tumor (4.4 months) in our patients. Therefore, more patients would be expected to present with a low stage second tumor. However, surprisingly, cases of stages III and IV disease were found only in conjunction with the second testicular cancer. This observation may be explained partly by patient selection. Patients who presented initially with stages III and IV disease have had a poorer prognosis and, therefore, a decreased chance of survival with a consequently lower risk for a second tumor to develop. Widely used irradiation and i:etroperitoneal lymph node dissectton of the initial tumor alter the ly~phogenic pathways of metastatic spread. After retroperitoneal lymph node dissection extensive collateral circulation, new lymphatic connections and lympho-venous shunting have been described. 19 This new lymphatic environment may increase the chance of rapid distal metastases and it could be another reason for our observation of 4 of 20 patients with ~tages II( a:q.d IV disease despite a second primary with a short history and with local stage Tl disease in some cases. Treatment possibilities of the second tumor are compromised distinctly by previous therapy of the initial tumor. Radiation therapy of the second tumor is li~itep. by the previously used dosage. Since most patients underwent retroperitoneal lymphadenectomy and/or x-ray treatment along the retroperitoneal lymphatic pathways because of the fi:rst testicular malignancy, a second retroperitoneal lymphadenectomy or x-ray treatment virtually is impossible. Because of this fact, only 4 of 9 patients with a· seminoma as the secondary testicular cancer received radiation therapy. Therefore, regardless ofhistological findings, combined chemotherapy usually is the treatment of choice. Chemotherapy was given n9t only in the presence of biopsy proved metastases but also as an adjuvant therapy (2 cycles) after orchiectomy because of the second testicular cancer. Five patients with clinical stage I· secondary tumors had a short course of chemotherapy and they are alive. It is not known if a wait-and-watch policy after the diagnosis of a low stage second testicular cancer can be adopted. Our experience with 3 patients is.too limited to answer this question. One patient had a relapse in an iliac lymph node 1 year later and was salvaged by chemotherapy. Two patients had no evidence of disease after 1 year of observation. Owing to the changes in the retroperitoneal lymphatic pathways after treatment of the first testicular cancer and based on our findings that 4 patients had an advanced tumor stage at diagnosis of the second cancer, our policy is to be restrictive with a waitand-watch attitude after a second testicular cancer. In our series only 2 patients died: 1 of inadequate treatment of the initial tumor and 1 shortly after diagnosis of the second testicular cancer. No chemotherapy was possible because of the poor condition of the patient. Of 20 patients 18 were alive a mean of 5.6 years after the second testicular cancer, which indicates a high cure rate of this disease. Patients with 2 consecutive testicular malignancies also have a good chance for survival. 0
REFERENCES 1. Bidard, M.: Cancer du testicule. Bull. Soc. Anat. Paris, 28: 345,
1853.
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SCHEIBER, ACKERMANN AND STUDER
2. Dieckmann, K.-P., Boeckmann, W., Brosig, W., Jonas, D. and Bauer, H.-W.: Bilaterale testikuliire Keimzelltumoren. Bericht iiber 9 Fiille und Literaturiibersicht. Akt. Urol., 1 7: 25, 1986. 3. Ehrengut, W., Schwartau, M. and Hubmann, R.: Testiculiire Vorerkrankungen bei Patienten mit Hodentumoren unter besonderer Beriicksichtigung der Mumpsorchitis. Urologe A, 19: 283, 1980. 4. Hamilton, J. B. and Gilbert, J. B.: Studies in malignant tumors of the testis: IV. Bilateral testicular cancer. Incidence nature and bearing upon management of the patients with a single testicular cancer. Cancer Res., 2: 125, 1942. 5. Hoekstra, H.J., Sleyfer, D. T., Wobbes, T. and Schraffordt Koops, H.: Bilateral primary germ cell tumors of testis. Urology, 19: 152, 1982. 6. Kristianslund, S., Fossa, S. D. and Kjellevold, K.: Bilateral malignant testicular germ cell cancer. Brit. J. Urol., 58: 60, 1986. 7. Sokal, M., Peckham, M. J. and Hendry, W. F.: Bilateral germ cell tumours of the testis. Brit. J. Urol., 52: 158, 1980. 8. Studer, U. E., Eilinger, H. and Haueter, M.: Patienten mit erhiihtem Risiko zur Entwicklung eines Hodentumors. Therapiewoche, 32: 520, 1982. 9. Ware, S. M., Heyman, J., Al-Askari, S. and Morales, P.: Bilateral testicular germ cell malignancy. Urology, 19: 366, 1982. 10. Mostofi, F. K. and Sobin, L. H.: Histological typing of testis tumours. In: International Histological Classification of Tumours. Geneva: World Health Organization No. 16, 1977. 11. Peckham, M. J.: Investigation and staging: general aspects and staging classification. In: The Management of Testicular Tumours. Edited by M. Peckham. London: Edward Arnold, chapt. 7, p. 89, 1981. 12. Aristizabal, S., Davis, J. R., Miller, R. C., Moore, M. J. and Boone, M. L. M.: Bilateral primary germ cell testicular tumors: report of four cases and review of the literature. Cancer, 42: 591, 1978. 13. Hartung, R., Ringert, R.-H. and Brehmer, B.: Zur Problematik beidseitiger Hodentumoren. Verhand. Dtsch. Gesell. Urol., 34: 406, 1982. 14. Pugh, R. C. B.: Testicular tumours-the panel classification. In: Pathology of the Testis. London: Blackwell Scientific, pp. 144146, 1976. 15. Niiesch-Bachmann, I. H. and Hedinger, C.: Atypische Spermato-
gonien als Priikanzerose. Schweiz. Med. Wschr., 107: 795, 1977. 16. Skakkebaek, N. E., Berthelsen, J. G. and Visfeldt, J.: Clinical aspects of testicular carcinoma-in-situ. Int. J. Androl., suppl. 4, 4: 153, 1981. 17. Skakkebaek, N. E.: Carcinoma in situ of the testis: frequency and relationship to invasive germ cell tumours in infertile men. Histopathology, 2: 157, 1978. 18. Collins, D. H. and Pugh, R. C. B.: Classification and frequency of testicular tumours. Brit. J. Urol., suppl., 36: 1, 1964. 19. Zattoni, F., Wajsman, Z., Beckley, S. A., Lanteri, V. and Pontes, J. E.: Treatment of sequential bilateral germ cell tumors of the testis following interval retroperitoneal lymph node dissection. J. Urol., 130: 142, 1983.
EDITORIAL COMMENT Several points deserve emphasis about this timely topic. The prognosis of patients with malignant germ cell tumors has improved to the extent that they can be expected to live long enough to exhibit a second testis tumor more often than seen in the past. The often quoted 1 per cent incidence of a second primary in these patients more likely is 2 to 4 times that in the present generation. In some patients the interval between tumors is longer than 10 years but most (63 per cent in this study) will present within 5 years. This finding underscores the need for patient self-examination instruction, interval scrotal ultrasound examinations and long-term followup. The discussion of treatment possibilities of the second tumor is worthwhile. It is influenced by the treatment used for the first tumor, as well as by clinical stage and histological findings. As a general comment, systemic platinum-based chemotherapy in a primary or adjuvant treatment mode is more attractive ifthere is reason to believe the lymphatic drainage pathways of metastatic spread have been altered by earlier treatment of the initial tumor. The prognosis for these patients remains good if they are treated promptly and followed carefully.
John P. Donohue Department of Urology Indiana University Medical Center Indianapolis, Indiana