Original Paper Urol Int 1992;48:162-166
a Department of Urology, Armed Forces Hospital Hamburg, b Department of Microscopical Anatomy, University of Hamburg, FRG
Key Words Testicular tumor Carcinoma in situ Prevalence Therapy Biopsies
Further Practical Experiences in the Recognition and Management of Carcinoma in situ of the Testis
Abstract 99 biopsies from the contralateral testis in patients with unilateral germ cell tumor were investigated using the semithin section technique. Four cases (4%) revealed a carcinoma in situ (CIS) pattern. Two patients underwent a local radiation (20 Gy), 2 patients received combination chemotherapy (cisplatin, etoposide and bleomycin; PEB). No tumor cells were found in control biopsies 4-8 months after therapy. Both biopsy specimens taken from radiated patients lacked also germ cells. In contrast, 1 patient who was treated with PEB and also another 1 presenting with a teratocarcinoma of apparently retro peritoneal origin and unilateral CIS revealed germ cells after chemotherapy. The present data suggest radiation therapy to be the first line treatment for CIS-bearing testes. In order to get informations about the distribution of CIS cells in the affected testes, one or two biopsies were additionally taken from macroscopically unsuspicious tissue surrounding various solid germ cell tumors (74 patients). 56 cases (76%) revealed CIS. Even considering the possi bility of missing CIS, a screening biopsy is actually the only method for detect ing early manifestations of germ cell tumors and should be performed rou tinely in contralateral testes of patients with germ cell tumors.
Introduction The diagnosis of carcinoma in situ (CIS) is based on the histological evaluation of testicular biopsies [1, 2]. This first stage of germ cell tumor development in the male is characterized by the proliferation of intratubular cells. CIS may occur (1) in one testis representing a pri mary tumor; (2) in testicular tissue adjacent to solid germ
A brief report has been published previously in poster form (42. Kongress der Deutschen Gesellschaft für Urologie, Hamburg 1990).
Received: May 22, 1991 Accepted: Junc5, 1991
cell tumors, and (3) in the contralateral testis of patients with solid germ cell tumors representing a second tumor. The clinical significance of diagnosing CIS is evident: an adequate treatment prevents the development of a solid germ cell tumor. Ablatio testis, radiation and che motherapy are at disposal for treatment. There are controversal discussions about the most effective therapy and in particular concerning the value of
Dr. F.bcrhard Mumperow Städtisches Krankenhaus Köln-Holwcidc. Urologie Neufclder Strasse 32 D-W-5000 Köln 80 (FRG)
© 1992 S. Karger AG. Basel 0042-1138/92/0482-0162 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/25/2018 11:23:20 PM
E. Mumperowa H. Lauke'0 A.F. HoIsteinb M. Hartmanna
Fig. 1. Semithin section. Seminiferous tubule exhibiting sper matogenesis adjacent to a tubule with tumor cells (T). Note the thick ened lamina propria. X 320.
Patients and Methods From 99 patients with malignant germ cell tumors, contralateral biopsies were taken (March 1989 to December 1990). Small pieces of tissue (about 3 X 2 mm) were transscrotally removed opposite the epididymis, fixed immediately in 5.5% glutaraldehyde and investi gated by the semithin sectioning technique [6]. In 4 cases (4%) the histological examination revealed CIS: large cells with large nuclei and dark cytoplasm due to considerable amounts of glycogen staining intensively blue with toluidine/pyronin. These tumor cells were predominantly found in a row along the basal membrane but also in the inner compartment of the tubule. Occasionally, single CIS cells lay within the spermatogenetic epithe lium. Most of the affected tubules exhibited Sertoli and tumor cells and a thickened lamina propria. Other tubules showed normal sper matogenesis (fig. I).
The treatment of contralateral CIS depended on therapeutical requirements of the primary tumor (table l ). In clinical stage I (according to the European Organization for Research and Treatment of Cancer; EORTC), 2 patients received a total course of 20 Gy to the tumor bearing testis. In advanced stages (EORTC Ila and III), 2 patients received 2 and 4 courses of chemo therapy, respectively (cisplatin, etoposide and bleomycin; PEB). No tumor cells were found in control biopsies performed several months after therapy (table l). The biopsies revealed a 'Sertoli cell only’ syndrome, except 1 case where also germ cells were found. This biopsy was obtained from 1 patient who was treated with PEB. A special therapeutical proceeding required a case of ‘primary’ retro peritoneal teratocarcinoma (EORTC lie). Bilateral biopsies were taken, and histological evaluation revealed CIS of the left testis. The solid tumor was treated with 4 courses of PEB, and orchiectomy of the CIS-bearing testis was subsequently performed. The histological investigation after therapy showed an impaired spermatogenesis, tumor cells were not found. There was no anamnestical evidence of diminished testicular volume (less than 12 ml), maldescensus testes or azoospermia in the group of patients revealing a contralateral CIS. However, 2 patients refused a spermiogram (table 2). Three patients presenting a mature teratoma were not included in the study. Ipsilateral and contralateral biopsies were devoid of CIS. From 74 orchiectomized testes, one or two biopsies were taken from macroscopically normal tissue surrounding various solid germ cell tumors (table 3). These simulated biopsies were classified as ‘near’ (< I cm) or ‘distant’ (> 1 cm) from the visible tumor margin.
163
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screening biopsies of contralateral testes [3,4], In order to collect more informations about the incidence of CIS. a multicenter study was recently started by Dieckmann [5], In the present study, own clinical experiences in diag nosis and therapy of CIS are described. Prospective inves tigations of testicular tissue adjacent to solid germ cell tumors yielded data of the incidence and distribution of CIS.
Table 1. Histological and clinical data of 5 patients with germ cell tumors exhibiting CIS in the contralateral (in one) testis
Patient No.
Histology
Stage EORTC
Therapy
Biopsy (time) after therapy
1 2
III I
4 X PEB 20 Gy
Negative (7 months) Negative (5 months)
3
Teratocarcinoma Seminoma/embryonal carcinoma Teratocarcinoma
I la
2 X PEB
4
Seminoma
I
20 Gy
Negative (7 months) spermiogcncsis + Negative (8 months)
5
Teratocarcinoma (retroperitoneal)
lie
4 X PEB
Table 2. Findings in patients exhibiting contralateral CIS testis Patient No.
Testicular volume > 12 ml
Maldescensus testis
Spermiogram
1 2 3 4 5a
Yes Yes Yes Yes Yes
No No No No No
13.6 106/ml 22.8 106/ml Refused 34.7 106/ml Refused
Biopsy Single biopsy II
co CO
CIS in one testis.
Two different biopsies (n = 41 )
CIS
%
near(n= 14) distant (n = 19)
7 15
50 79
near distant
30 26
73 63
Biopsies were taken near or distant from the tumor.
Table 3. Histological features of the germ cell tumors in whom biopsies were taken from adjacent testicular tissue (n = 74)
Seminoma Nonscminoma/mixed tumor
Table 4. Incidence and localization of CIS testis in ipsilateral biopsies
c
a
Negative (4 months) spermiogcncsis +
Table 5. Incidence and localization of CIS testis in the total num ber of ipsilateral biopsies
n
%
Biopsy (n= 115)
CIS
%
20 54
27 73
Near (n = 55) Distant (n = 60)
38 41
69 68
Biopsies were taken near or distant from the tumor.
164
Discussion The incidence of contralateral CIS found in this study (4%) is consistent with findings of others [7, 8; Dieck mann, pers. commun.]. The diagnoses were based on the evaluation of semithin sections. Even single tumor cells within the spermatogenetic epithelium could be identi fied histologically by using epon-embedded material [6]. Various other methods are available to find CIS [2, 6, 9, 10], Frequently, paraffin sections of formalin or Bouin solution-fixed specimens are used for the histological
Mumperow/Lauke/Holstein/Hartmann
CIS of the Testis
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/25/2018 11:23:20 PM
56 (76%) of the testes revealed CIS additionally to the solid germ cell tumor. These data have to be pointed out in detail: at the begin ning of the study, only a single biopsy was arbitrarily taken (n = 24) and classified; later on, two local different biopsies were taken (n = 4 1), except for cases with large tumors where a small rim of testicular tissue only allowed a biopsy classified as ‘near’ (n = 9). These cases often showed hyalinized tubules without CIS. In 33 cases where 1 biopsy was taken (table 4) the histological investigation revealed CIS to be more frequent in specimens ‘distant’ the solid tumor. In 41 cases where two biopsies were taken (table 4), the data showed a different proportion (63 % ‘distant’ and 73 % ‘near’ the solid tumor). The total number of 115 biopsies (table 5) yielded a nearly bal anced proportion of CIS in biopsy specimens taken ‘near’ (69%) or ‘distant’ (68 %) the solid tumor.
tinely performed [3, 4], For obvious reasons, little is known about the distribution of tumor cells inside a testis in the earliest detectable stage of tumor development (ex clusively CIS) [3], Data about the incidence and distribu tion of CIS are predominantly received by investigating testicular tissue adjacent to solid germ cell tumors [4], In these ‘model systems’, the incidence of CIS was reported to be 63-98% [2], In the present study, testicular tissue adjacent to solid germ cell tumors was prospectively investigated by simu lated biopsies taken near or distant the tumor. Small locally precise biopsies were performed in order to adapt the procedure to a situation similar to screening biopsies. CIS was found in 76% of the biopsies. Presumably, inves tigation of the whole testis yielded a higher number of positive results. These results indicate that CIS was apparently present in the testis in a disseminated pattern. The total number of 115 biopsies (table 5) performed in testicular tissue adjacent to solid germ cell tumors yielded a nearly bal anced proportion of CIS in biopsy specimens taken ‘near’ (69%) o r‘distant’ (68%) the solid tumor. These results are consistent with histological findings showing that CIS is related to anatomical structures: the testicular lobules. Frequently, testicular lobules with normal spermatogene sis were found next to lobules exhibiting CIS-bcaring sem iniferous tubules. No decreasing incidence of CIS was found from close to the solid tumor to more distant areas as reported recently [ 17], Random biopsies yield possible false-negative results (24% in the present study), especially in cases where CIS is present in only a few testicular lobules [4]. Follow-up studies of negative cases have to be done. However, there is a high chance to find CIS in a testicu lar biopsy (76% in this study) presenting actually the only reliable method for detecting a tumor in the beginning of malignant development. For early germ cell tumors (CIS), radiation seems to be an effective therapy. Contralateral biopsies should be performed routinely in patients with germ cell tumors.
165
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/25/2018 11:23:20 PM
evaluation of CIS cells and the immunohistochemical demonstration of placental-like alkaline phosphatase in CIS cells [2], The choice of therapy had to consider firstly the differ ent requirements of the solid primary tumor. However, none of the biopsies revealed tumor cells after therapy (ra diation or chemotherapy, respectively). Contralateral germ cell tumors have been reported despite interval che motherapy [1 1], obviously without relevance to the thera peutic scheme. There are also reports on residual or per sistent CIS in a biopsy taken more than 1 year after che motherapy [12, 13], In this study, germ cells were found in biopsies of patients who were treated with chemotherapy. These germ cells (spermatogonia) possibly escaped from the influence of the chemotherapeutic drugs because their cell cycle between two periods of active proliferation was lon ger than the period of chemotherapy administration. Intratubular tumor cells appear to have also relatively low levels of mitotic divisions considering the clinical obser vation of long intervals between CIS and the development of a solid tumor [14], Comprehensive follow-up studies are needed to clarify whether the finding of germ cells in biopsies following therapy may be a risk factor. Efficient therapy of contralateral CIS has to preserve a patient from developing a second solid germ cell tumor. This aim seems not to be attained by the application of chemotherapy. For evident reasons, an orchiectomy of the second testis should be avoided. Radiation of the CISbearing testes (20 Gy) is an efficient therapy for eradicat ing tumor and germ cells without impairment of the Leydig cell population [7, 8], In the case of 1 patient who pre sented with unilateral CIS and a retroperitoneal teratocarcinoma, orchiectomy of the affected testis was performed, being certainly the most secure treatment. The finding of CIS (by bilateral screening biopsies) supports the pre sumption that primary extragonadal germ cell tumors possibly do not exist [15], Patients exhibiting apparently extragonadal germ cell tumors should be biopsied bilater ally. All patients with germ cell tumors have a higher risk to develop a second tumor in the remaining testis [ 16], Addi tional individual risk factors for developing contralateral CIS (diminished testicular volume, azoospermia and cryptorchidism), reported by Kleinschmidt et al. [7], were not found in patients included in this study (table 2). Without further restriction, contralateral biopsies should be taken from patients with gonadal germ cell tumors. However, up to now, it is a subject of controversial dis cussions whether contralateral biopsies should be rou
5 Dieckmann KP: Multicenter-Studie Carci noma in situ des Hodens. Berlin. 1989. 6 Holstein AF. Wulfhekel U: Die Scmidiinnschnittechnik als Grundlage für eine zytologische Beurteilung der Spermatogenese des Menschen. Andrologie 1971:3:65-69. 7 Kleinschmidt K. Weissbach L. Holstein AF: Früherkennung des kontralateralen Zweitkar zinoms bei Hodentumorpatienten durch das Carcinoma in situ testis. Urologe [A] 1989:28: 281-284.
8 Von der Maase H. Giwercman A. Müller J. Shakkebaek NE: Managment of carcinoma in situ of the testis. Int J Androl 1987;10:209— 210. 9 Nagler HM. Kaufman DG. O’Toole KM. Sawczuk I: Carcinoma in situ of the testis: Diagnosis by aspiration flow cytometry. J Urol 1990:143:359-361. 10 Giwercman A, Hopman AHN, Ramaekers FCG. Shakkebaek NE: Carcinoma in situ of the testis - Detection of malignant germ cells in seminal fluid by means of in situ hybridization. Am J Pathol 1990:136:497-502. 11 Fowler JE, Vugrin D, Cvitkovic E. Whitmore WF: Sequential bilateral germ cell tumors of the testis despite interval chemotherapy. J Urol 1979;122:421-425. 12 Von der Maase H. Meinecke B, Shakkebaek NE: Residual carcinoma in situ of contralateral testis after chemotherapy. Lancet 1988;i:477478. 13 Bottomley D, Fisher C. Hendry WF. Horwich A: Persistent carcinoma in situ of the testis after chemotherapy for advanced testicular germ cell tumours. Br J Urol 1990:66:420424.
14 Shakkebaek NE. Berthclsen JG. Müller J. Gi wercman A, Van der Maase H. Rörth M: Carci noma in situ testis; in Schmoll HJ, Weissbach L (eds): Diagnostik und Therapie von Hodentu moren. Berlin, Springer. 1988. pp 471-482. 15 Daugaard G. Von der Maase H. Olsen J. Rörth M, Shakkebaek NE: Carcinoma in situ testis in patients with assumed extragonadal germ-cell tumours. Lancet 1987:ii:528—530. 16 Höppner W. Hartmann M: Besonderheiten in der Nachsorge maligner Hodentumoren. Uro loge [B] 1987;27:33-37. 17 Walz PH. Eitner S. Tan HK. Böhm E: Auf treten und Ausbreitung von Carcinoma in situ und intratubulärer Keimzellneoplasic bei tumorbcfallenem Hoden. Urologe [A] 1990; 29(suppl):A37.
166
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CIS of the Testis
1 Shakkebaek NE: Possible carcinoma-in-situ of the testis. Lancet 1972;ii:516—517. 2 Dieckmann KP. Loy V. Huland H: Das Carci noma in situ des Hodens: Klinische Bedeutung. Diagnostik und Therapie. Urologe [A] 1989: 28:271-280. 3 Berthclsen JG. Shakkebaek NE: Distribution of carcinoma in situ in testes in infertile men. Int J Androl 1981:4(suppl): 17 2 -183. 4 Loy V. Wigand I. Dieckmann KP: Incidence and distribution of carcinoma in situ in testes removed for germ cell tumour: Possible inade quacy of random testicular biopsy in detecting the condition. Hislopathology 1990; 16:198—
200.
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References
a Department of Urology, Armed Forces Hospital Hamburg, b Department of Microscopical Anatomy, University of Hamburg, FRG
Key Words Testicular tumor Carcinoma in situ Prevalence Therapy Biopsies
Further Practical Experiences in the Recognition and Management of Carcinoma in situ of the Testis
Abstract 99 biopsies from the contralateral testis in patients with unilateral germ cell tumor were investigated using the semithin section technique. Four cases (4%) revealed a carcinoma in situ (CIS) pattern. Two patients underwent a local radiation (20 Gy), 2 patients received combination chemotherapy (cisplatin, etoposide and bleomycin; PEB). No tumor cells were found in control biopsies 4-8 months after therapy. Both biopsy specimens taken from radiated patients lacked also germ cells. In contrast, 1 patient who was treated with PEB and also another 1 presenting with a teratocarcinoma of apparently retro peritoneal origin and unilateral CIS revealed germ cells after chemotherapy. The present data suggest radiation therapy to be the first line treatment for CIS-bearing testes. In order to get informations about the distribution of CIS cells in the affected testes, one or two biopsies were additionally taken from macroscopically unsuspicious tissue surrounding various solid germ cell tumors (74 patients). 56 cases (76%) revealed CIS. Even considering the possi bility of missing CIS, a screening biopsy is actually the only method for detect ing early manifestations of germ cell tumors and should be performed rou tinely in contralateral testes of patients with germ cell tumors.
Introduction The diagnosis of carcinoma in situ (CIS) is based on the histological evaluation of testicular biopsies [1, 2]. This first stage of germ cell tumor development in the male is characterized by the proliferation of intratubular cells. CIS may occur (1) in one testis representing a pri mary tumor; (2) in testicular tissue adjacent to solid germ
A brief report has been published previously in poster form (42. Kongress der Deutschen Gesellschaft für Urologie, Hamburg 1990).
Received: May 22, 1991 Accepted: Junc5, 1991
cell tumors, and (3) in the contralateral testis of patients with solid germ cell tumors representing a second tumor. The clinical significance of diagnosing CIS is evident: an adequate treatment prevents the development of a solid germ cell tumor. Ablatio testis, radiation and che motherapy are at disposal for treatment. There are controversal discussions about the most effective therapy and in particular concerning the value of
Dr. F.bcrhard Mumperow Städtisches Krankenhaus Köln-Holwcidc. Urologie Neufclder Strasse 32 D-W-5000 Köln 80 (FRG)
© 1992 S. Karger AG. Basel 0042-1138/92/0482-0162 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/25/2018 11:23:20 PM
E. Mumperowa H. Lauke'0 A.F. HoIsteinb M. Hartmanna
Fig. 1. Semithin section. Seminiferous tubule exhibiting sper matogenesis adjacent to a tubule with tumor cells (T). Note the thick ened lamina propria. X 320.
Patients and Methods From 99 patients with malignant germ cell tumors, contralateral biopsies were taken (March 1989 to December 1990). Small pieces of tissue (about 3 X 2 mm) were transscrotally removed opposite the epididymis, fixed immediately in 5.5% glutaraldehyde and investi gated by the semithin sectioning technique [6]. In 4 cases (4%) the histological examination revealed CIS: large cells with large nuclei and dark cytoplasm due to considerable amounts of glycogen staining intensively blue with toluidine/pyronin. These tumor cells were predominantly found in a row along the basal membrane but also in the inner compartment of the tubule. Occasionally, single CIS cells lay within the spermatogenetic epithe lium. Most of the affected tubules exhibited Sertoli and tumor cells and a thickened lamina propria. Other tubules showed normal sper matogenesis (fig. I).
The treatment of contralateral CIS depended on therapeutical requirements of the primary tumor (table l ). In clinical stage I (according to the European Organization for Research and Treatment of Cancer; EORTC), 2 patients received a total course of 20 Gy to the tumor bearing testis. In advanced stages (EORTC Ila and III), 2 patients received 2 and 4 courses of chemo therapy, respectively (cisplatin, etoposide and bleomycin; PEB). No tumor cells were found in control biopsies performed several months after therapy (table l). The biopsies revealed a 'Sertoli cell only’ syndrome, except 1 case where also germ cells were found. This biopsy was obtained from 1 patient who was treated with PEB. A special therapeutical proceeding required a case of ‘primary’ retro peritoneal teratocarcinoma (EORTC lie). Bilateral biopsies were taken, and histological evaluation revealed CIS of the left testis. The solid tumor was treated with 4 courses of PEB, and orchiectomy of the CIS-bearing testis was subsequently performed. The histological investigation after therapy showed an impaired spermatogenesis, tumor cells were not found. There was no anamnestical evidence of diminished testicular volume (less than 12 ml), maldescensus testes or azoospermia in the group of patients revealing a contralateral CIS. However, 2 patients refused a spermiogram (table 2). Three patients presenting a mature teratoma were not included in the study. Ipsilateral and contralateral biopsies were devoid of CIS. From 74 orchiectomized testes, one or two biopsies were taken from macroscopically normal tissue surrounding various solid germ cell tumors (table 3). These simulated biopsies were classified as ‘near’ (< I cm) or ‘distant’ (> 1 cm) from the visible tumor margin.
163
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screening biopsies of contralateral testes [3,4], In order to collect more informations about the incidence of CIS. a multicenter study was recently started by Dieckmann [5], In the present study, own clinical experiences in diag nosis and therapy of CIS are described. Prospective inves tigations of testicular tissue adjacent to solid germ cell tumors yielded data of the incidence and distribution of CIS.
Table 1. Histological and clinical data of 5 patients with germ cell tumors exhibiting CIS in the contralateral (in one) testis
Patient No.
Histology
Stage EORTC
Therapy
Biopsy (time) after therapy
1 2
III I
4 X PEB 20 Gy
Negative (7 months) Negative (5 months)
3
Teratocarcinoma Seminoma/embryonal carcinoma Teratocarcinoma
I la
2 X PEB
4
Seminoma
I
20 Gy
Negative (7 months) spermiogcncsis + Negative (8 months)
5
Teratocarcinoma (retroperitoneal)
lie
4 X PEB
Table 2. Findings in patients exhibiting contralateral CIS testis Patient No.
Testicular volume > 12 ml
Maldescensus testis
Spermiogram
1 2 3 4 5a
Yes Yes Yes Yes Yes
No No No No No
13.6 106/ml 22.8 106/ml Refused 34.7 106/ml Refused
Biopsy Single biopsy II
co CO
CIS in one testis.
Two different biopsies (n = 41 )
CIS
%
near(n= 14) distant (n = 19)
7 15
50 79
near distant
30 26
73 63
Biopsies were taken near or distant from the tumor.
Table 3. Histological features of the germ cell tumors in whom biopsies were taken from adjacent testicular tissue (n = 74)
Seminoma Nonscminoma/mixed tumor
Table 4. Incidence and localization of CIS testis in ipsilateral biopsies
c
a
Negative (4 months) spermiogcncsis +
Table 5. Incidence and localization of CIS testis in the total num ber of ipsilateral biopsies
n
%
Biopsy (n= 115)
CIS
%
20 54
27 73
Near (n = 55) Distant (n = 60)
38 41
69 68
Biopsies were taken near or distant from the tumor.
164
Discussion The incidence of contralateral CIS found in this study (4%) is consistent with findings of others [7, 8; Dieck mann, pers. commun.]. The diagnoses were based on the evaluation of semithin sections. Even single tumor cells within the spermatogenetic epithelium could be identi fied histologically by using epon-embedded material [6]. Various other methods are available to find CIS [2, 6, 9, 10], Frequently, paraffin sections of formalin or Bouin solution-fixed specimens are used for the histological
Mumperow/Lauke/Holstein/Hartmann
CIS of the Testis
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/25/2018 11:23:20 PM
56 (76%) of the testes revealed CIS additionally to the solid germ cell tumor. These data have to be pointed out in detail: at the begin ning of the study, only a single biopsy was arbitrarily taken (n = 24) and classified; later on, two local different biopsies were taken (n = 4 1), except for cases with large tumors where a small rim of testicular tissue only allowed a biopsy classified as ‘near’ (n = 9). These cases often showed hyalinized tubules without CIS. In 33 cases where 1 biopsy was taken (table 4) the histological investigation revealed CIS to be more frequent in specimens ‘distant’ the solid tumor. In 41 cases where two biopsies were taken (table 4), the data showed a different proportion (63 % ‘distant’ and 73 % ‘near’ the solid tumor). The total number of 115 biopsies (table 5) yielded a nearly bal anced proportion of CIS in biopsy specimens taken ‘near’ (69%) or ‘distant’ (68 %) the solid tumor.
tinely performed [3, 4], For obvious reasons, little is known about the distribution of tumor cells inside a testis in the earliest detectable stage of tumor development (ex clusively CIS) [3], Data about the incidence and distribu tion of CIS are predominantly received by investigating testicular tissue adjacent to solid germ cell tumors [4], In these ‘model systems’, the incidence of CIS was reported to be 63-98% [2], In the present study, testicular tissue adjacent to solid germ cell tumors was prospectively investigated by simu lated biopsies taken near or distant the tumor. Small locally precise biopsies were performed in order to adapt the procedure to a situation similar to screening biopsies. CIS was found in 76% of the biopsies. Presumably, inves tigation of the whole testis yielded a higher number of positive results. These results indicate that CIS was apparently present in the testis in a disseminated pattern. The total number of 115 biopsies (table 5) performed in testicular tissue adjacent to solid germ cell tumors yielded a nearly bal anced proportion of CIS in biopsy specimens taken ‘near’ (69%) o r‘distant’ (68%) the solid tumor. These results are consistent with histological findings showing that CIS is related to anatomical structures: the testicular lobules. Frequently, testicular lobules with normal spermatogene sis were found next to lobules exhibiting CIS-bcaring sem iniferous tubules. No decreasing incidence of CIS was found from close to the solid tumor to more distant areas as reported recently [ 17], Random biopsies yield possible false-negative results (24% in the present study), especially in cases where CIS is present in only a few testicular lobules [4]. Follow-up studies of negative cases have to be done. However, there is a high chance to find CIS in a testicu lar biopsy (76% in this study) presenting actually the only reliable method for detecting a tumor in the beginning of malignant development. For early germ cell tumors (CIS), radiation seems to be an effective therapy. Contralateral biopsies should be performed routinely in patients with germ cell tumors.
165
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/25/2018 11:23:20 PM
evaluation of CIS cells and the immunohistochemical demonstration of placental-like alkaline phosphatase in CIS cells [2], The choice of therapy had to consider firstly the differ ent requirements of the solid primary tumor. However, none of the biopsies revealed tumor cells after therapy (ra diation or chemotherapy, respectively). Contralateral germ cell tumors have been reported despite interval che motherapy [1 1], obviously without relevance to the thera peutic scheme. There are also reports on residual or per sistent CIS in a biopsy taken more than 1 year after che motherapy [12, 13], In this study, germ cells were found in biopsies of patients who were treated with chemotherapy. These germ cells (spermatogonia) possibly escaped from the influence of the chemotherapeutic drugs because their cell cycle between two periods of active proliferation was lon ger than the period of chemotherapy administration. Intratubular tumor cells appear to have also relatively low levels of mitotic divisions considering the clinical obser vation of long intervals between CIS and the development of a solid tumor [14], Comprehensive follow-up studies are needed to clarify whether the finding of germ cells in biopsies following therapy may be a risk factor. Efficient therapy of contralateral CIS has to preserve a patient from developing a second solid germ cell tumor. This aim seems not to be attained by the application of chemotherapy. For evident reasons, an orchiectomy of the second testis should be avoided. Radiation of the CISbearing testes (20 Gy) is an efficient therapy for eradicat ing tumor and germ cells without impairment of the Leydig cell population [7, 8], In the case of 1 patient who pre sented with unilateral CIS and a retroperitoneal teratocarcinoma, orchiectomy of the affected testis was performed, being certainly the most secure treatment. The finding of CIS (by bilateral screening biopsies) supports the pre sumption that primary extragonadal germ cell tumors possibly do not exist [15], Patients exhibiting apparently extragonadal germ cell tumors should be biopsied bilater ally. All patients with germ cell tumors have a higher risk to develop a second tumor in the remaining testis [ 16], Addi tional individual risk factors for developing contralateral CIS (diminished testicular volume, azoospermia and cryptorchidism), reported by Kleinschmidt et al. [7], were not found in patients included in this study (table 2). Without further restriction, contralateral biopsies should be taken from patients with gonadal germ cell tumors. However, up to now, it is a subject of controversial dis cussions whether contralateral biopsies should be rou
5 Dieckmann KP: Multicenter-Studie Carci noma in situ des Hodens. Berlin. 1989. 6 Holstein AF. Wulfhekel U: Die Scmidiinnschnittechnik als Grundlage für eine zytologische Beurteilung der Spermatogenese des Menschen. Andrologie 1971:3:65-69. 7 Kleinschmidt K. Weissbach L. Holstein AF: Früherkennung des kontralateralen Zweitkar zinoms bei Hodentumorpatienten durch das Carcinoma in situ testis. Urologe [A] 1989:28: 281-284.
8 Von der Maase H. Giwercman A. Müller J. Shakkebaek NE: Managment of carcinoma in situ of the testis. Int J Androl 1987;10:209— 210. 9 Nagler HM. Kaufman DG. O’Toole KM. Sawczuk I: Carcinoma in situ of the testis: Diagnosis by aspiration flow cytometry. J Urol 1990:143:359-361. 10 Giwercman A, Hopman AHN, Ramaekers FCG. Shakkebaek NE: Carcinoma in situ of the testis - Detection of malignant germ cells in seminal fluid by means of in situ hybridization. Am J Pathol 1990:136:497-502. 11 Fowler JE, Vugrin D, Cvitkovic E. Whitmore WF: Sequential bilateral germ cell tumors of the testis despite interval chemotherapy. J Urol 1979;122:421-425. 12 Von der Maase H. Meinecke B, Shakkebaek NE: Residual carcinoma in situ of contralateral testis after chemotherapy. Lancet 1988;i:477478. 13 Bottomley D, Fisher C. Hendry WF. Horwich A: Persistent carcinoma in situ of the testis after chemotherapy for advanced testicular germ cell tumours. Br J Urol 1990:66:420424.
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