STUDIES ON EXPERIMENTAL FORMATION OF OVARIAN TUMORS

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1 THE KURUME MEDICAL JOURNAL 1975 Vol.22, No.3, P STUDIES ON EXPERIMENTAL FORMATION OF OVARIAN TUMORS ESPECIALLY, THE DISCUSSION OF THE DEVELOPING PROCESS OF OVARIAN TUMORS FOLLOWING AN APPLICATION OF DMBA TOSHI KATO, MICHIAKI YAKUSHIJI, AKITSU TSUNAWAKI, KAIKITSU IDE, NOBUYUKI HIROSE, SUMIO ARAKI AND MASAKATSU ABE Department of Obstetrics Gynecology, Kurume University School of Medicine, Kurume, 830, Japan (Received for publication August 21, 1975) The histogenetic process of experimental ovarian tumors induced by a chemically carcinogenic substance, 9, 10-dimethyl-1, 2-benzanthracene (DMBA) in rats was studied. Morphologically, induced tumors can be classified into two groups : Adenocarcinoma sarcoma. A particular pattern of histogenetic process in se tumors was evidenced by killing following se animals at staged intervals initiation of experiment. When treated with DMBA, an inflammatory change occurred around region of a silk thread insertion ; subsequently, connective tissues proliferated. In following stages, a layer of epilial cells which constitutes glular cysts of various sizes, on one h interstitial connective tissue on or, proliferated around m, presenting findings of f ibroadenoma. This f ibroadenoma provided a basic type which two different histogenetic processes bifurcated. In one direction, cystic components dominated proceeded toward adenocarcinoma, in or connective tissue proliferation prevailed to form a sarcoma type. Between two of m, process toward adenocarcinoma is of much interest because of its incidence clinically ; it was found that inclusion cysts appeared to play an important role in developmental process, which should be of special interest when compared with various reports on histogenesis of human adenocarcinoma. The ovary is a unique organ in that it develops tumors of multiple characters. Because each ovarian tumor shows complex pathological features, re has been no unified view on ir histogenesis, etiology, or endocrine character. Analysis a new viewpoint has been refore awaited. The present authors had approached this problem through observation of experimental tumor development. In previous paper, results of experimental tumor induction by chemically carcinogenic substances like 20 MC DMBA were described. In experiment with DMBA, we had found a few points of interest with regard to developmental process of tumor, which was already reported orwise. The present paper reports results of interest obtained through additional experiments. 169

2 170 KATO, MATERIALS Experimental AND METHODS materials Female Wistar rats weighing about 180 grams were used. Before experimentation, y were kept in laboratory two weeks after procurement in order to enable m to adapt to laboratory environment. Experimental ET AL. 47 solid tumors. With solid tumors, incidence was 7% before 20th week tended to increase with number of experimental weeks : thus, 30% between 21st to 30th week, 60 % between 31st to 40th week 70% between 41st to 50th week. methods The clipping method was employed for DMBA treatment. In this experiment, in order to periodically follow up changes after silk thread insertion, rats were sacrificed at staged intervals with emphasis on 20 weeks after treatment. The number of rats examined totaled 121, which were classified in Table 1 in weeks at sacrifice. TABLE The number of rats 2 3 RESULTS period TABLE examined Table 2 reviews tumor development in a total of 121 rats. The induced tumors are as follows : 4 cystic tumors Development 1 1 EXPERIMENTAL Development 2 period

3 EXPERIMENTAL OVARIAN TUMOR 171 Histologic classification of induced tumors Table 3 shows histologic classifications of induced tumors. All of 4 tumors showed findings of serous cystadenoma (1). With solid tumors, histologic classifications, although y could be open to furr discussion, showed that re were 12 f ibroadenomas or adenoma-types, 12 sarcoma types, 23 adenocarcinoma types (Table 3, Figs. 2, 3). TABLE 3 Histologic classification of induced tumors induced between 21st to 30th week, four were f ibroadenomas, one was sarcoma, one or was of adenocarcinoma type. In 31st to 40th week period, twenty-four tumors were induced, of which 4 were f ibroadenomas, seven were sarcomas, thirteen were of adenocarcinoma type. Between 41st 50th week, one was f ibroadenoma, four were sarcomas, nine were of adenocarcinoma type. They suggest that f ibroadenoma is a basic type. Hence, when changes induced by DMBA were analized by stages were taken in a model, developmental process may be classified into following four stages ( 4) : A. The first stage Analysis of developmental process of tumors The histologic classification of induced solid tumors ir incidence in numbers of experimental weeks are illustrated in Table 4, which shows a particular pattern. Three tumors induced before 20th week are all of f ibroadenoma type of 6 tumors when silk thread was inserted, an inflammatory change took place around it. Then hyperplasia of connective tissue occurred around region of silk thread insertion. At this stage, few effects on ovarian stroma were noted. 5 shows a case 14 weeks after DMBA treatment. Connective tissue surrounds region of silk thread insertion ; but it was still circumscribed, change of ovarian stroma as growing follicles is almost neglibible. TABLE 4 The hystrogie classification of induced solid tumors ir incidence in numbers of experimental weeks

4 172 KATO, B. The second 4 stage Subsequently, in area surrounding silk thread insertion, a layer of epilial cells which constitutes cysts of varying size with glular structure on one h hyperplasia of connective tissue on or. They gradually displace normal region to periphery take character of a tumor, that is a fibroadenoma type by histology. C. The third ET AL. stage The fibroadenoma type, as a basic type, n takes two different developmental courses. One is a process toward a pure adenoma type with dominant 5 6 cystic components. The or course comprises hyperplasia of connective tissue while cystic components gradually disappear. 6 shows an adenoma type with dominant cystic components. D. The fourth stage Variously sized cysts of adenoma type proliferate furr, y produce a network which fuses to each or to make a focus of adenocarcinoma type. In or instance, tumor-like hyperplasia of connective tissue occurs develops to produce a type of sarcoma. 7 shows fusion of variously sized cysts ; in 8, continuous changes adenoma type to adenocarcinoma are shown.

5 EXPERIMENTAL 9 is very interesting showing on left upper corner region of silk thread insertion around which connective tissue proliferates to right below subsequent continued change patterns carcinoma. fibroadenoma 7 8 to adeno- OVARIAN TUMOR 173 DISCUSSION There are two ways to study which cells or tissues a tumor develops. One way is retrospective analysis as in clinical cases, this is usually employed. The or way is a prospective analysis, which is primarily employed in study of experimental tumor. The present authors have chosen latter way, prospective one, to analyze histogenetic process in experimental tumors found results of interest in developmental process induced by DMBA. It should be emphasized, of course, that histogenetic mechanism induced by chemically carcinogenic substances is not simply applicable to that of human tumors. Neverless, re have been a few both interesting suggestive results obtained by experimental study, which will be discussed with reference to reports on histologic study of human tumors. The histogenesis is usually discussed on basis of morphological similarity between histologic features of tumor those of organ or mor tissue which tumor developed. In regard to ovarian tumors, however, it is not uncommon that few morphological similarities exist between tumor corresponding tissue ; n similar histologic features must be sought in variously staged fetal tissues. Therefore, one may find different opinions in interpretation of one same histologic picture. This is quite case with histogenesis of adenocarcinoma in human also. In recent past, numberous substantiating findings have been re- 9 ported ; thus mechanism of histogenesis appears to be emerging scope of an hyposis. For example, according to Luisi 3', Hertig

6 174 KATO, ET AL. Gore, surface epilium which shows enfolding may constitute germinal inclusion cyst. Then, this epilium gains a multipotential character, resulting in histologic features where both serous mucinous cells are coexistent in a same small cyst. They furr presumed that this inclusion cyst produces a cystic adenoma in its developmental process. When epilium is of fallopian origin, it produces serous epilium, while epilium of cervical origin produces mucinous epilium, that interstitium of endometrium shows endometrium-like epilium. They stated that one or more epilia of different origins may occur in same cyst. With serous cystic adenocarcinoma, it is unanimously concluded that it has a Mullerian origin ; but in regard to its developmental process, opinions are diverging. Hertig Gore contended that it may occasionally originate infolding of epilium or directly surface epilium ; but it may mostly develop a germinal inclusion cyst. Woodruff, on or h, is of opinion that it develops invagination of germinal epilium, shows various stages of development to papillary hyperplasia. In regard to morphological process of development of this tumor, he also stated that fibroadenoma of ovary is intracortical invasion of tubular, branching duct lumina produced by germinal epilium. Thus, accumulation of numerous glular ducts develops into cystic forms finally to produce cystoadenof ibroma. The difficulty which is met in study of histogenesis of mucinous adenocarcinoma is that normal ovary lacks in mucin- or pseudomucin-producing cells. When origin of mucinproducing cells is sought outside ovary, it should be sought in epilium of cervix or intestine. From view point of morphological similarity, former is of Mullerian system origin latter of teratomatous origin. Hertig Gore believe similar histogenesic concepts ; y stated that when tumor originates germinal epilium, n it is because tumor epilium resembles mucosa of cervix, regardless of wher it has an origin of Mullerian remnant or metaplasia. Furrmore, cystic tumor of germinal epilial origin may show complete elements of Mullerian tube in one cyst or in a number of cysts or in same tumor. Canker Dockerty6 found in admixture of serous mucinous components 11.25% of mucinous tumors. The presence of such transitional types is very important, Glazunov attempted to designate it dimorphous serous-pseudomucinous tumor. Woodruff showed a similar histologic picture concluded that metaplasia of epilial cells of body cavity may possibly occur, but it may also be possible that tumor which presents numerous common features may have different origins. The study of histogenesis of ovarian tumors viewpoint of experimentally produced tumors has long been attempted. With granulosa cell tumor in particular, since report of Biskind on tumor development by transplantation of ovary in spleen, it has been analyzed various aspects. Except diverging opinions on character of induced tumor, its relationship to gonadotropinl of hypophysis is considered to be of significance in developmental process of tumor. Experimental study on histogenesis of clinically prevalent ovarian adenocarcinoma has been rare. In Japan

7 EXPERIMENTAL OVARIAN TUMOR 175 re has been only that of Hayashi et al. who described two experimental cases induced by transplantation of ovary in spleen ; y contended that continued secretion of intrinsic gonadotropin may play an important role in histogenesis. The present authors have been able to produceadenocarcinoma in considerable incidence also to examine its developmental process at staged intervals. It appears that it is first systematic study of this kind. It is interesting to note that in developmental process, f ibroadenoma presented itself as a basic form regardless of time lag in its development that subsequently two processes bifurcate : one is hyperplasia of cystic components to produce adenocarcinoma ; or way is hyperplasia of connective tissue components to form a sarcoma type. The interpretation of such a developmental process is, needless to say, not easy considering problems of dosage, time factors of DMBA treatment, reaction of organism. Still, present study allows one to conceive a pattern in developmental process. Subsequently, except tumors of sarcoma type, mor tissue of induced adenocarcinoma may present a problem. It may originate eir surface epilium of ovary or mesodermal tissue. However, when it be of mesodermal origin, n induced tumor may well show mixed tumor histologically. Furrmore, staged observation which allowed one to recognize germinal inclusion cyst suggests that induced adenocarcinoma in this experiment may be of surface epilial origin. Clinically, germimal inclusion cysts are frequently found in ovary of periclimacteric patients ; incidence of adenocarcinoma is high in this period. Furrmore, re are observations of Hertig, as described above, who found development of adenocarcinoma germinal inclusion cysts also Woodruff's clinical observation on developmental process of f ibroadenoma or cystoadenofibroma. All se observations are of significance with reference to our experimental findings. The results obtained by present authors should remain in framework of experimental conditions but y suggest that in development of adenocarcinoma inclusion cyst certainly plays a very important role. REFERENCES 1) KATO, T1 YAKUSHIJI, M., TSUNAWAKI, A. IDE, K.: A study of experimental ovarian tumors in rats by chemical carcinogen, 20-Methylchlanthrene. Kurume Med. J., 20, , ) KATO,T., YAKUSHIJI, M., TSUNAWAKI, A. IDE, K.: Studies on experimental ovarian tumors. Ovarian tumors developed in rats receiving chemical carcinogen 9, 10-dimethyl-1, 2, benzanthracene. Kurume Med. J., 21, 11-19, ) LUIsi, A.: Malignant ovarian tumors of mullerian origin. Ovarian cancer., P. 9, 1968, Springer-Verlag. 4) HERTIG, A. T. GORE, H.: Classification. Tumors of female sex organs ; tumors of ovary fallopian tube, P. 9, 1961, Armed Forces Institute of Pathology. 5) WOODRUFF, J. D.: Embryology its relation to tumorigenesis in ovary adjacent structures. The Ovary, P. 82, 1968, C. C. Thomas. 6) CARIKER, M. DOCKERTY, M. B.: Mucinous cystadenomas mucinous cystadenocarcinomas of ovary ; a clinical pathological study of 355 cases. Cancer, 7, , ) GLAZUNOV, M. F.: Ovarian tumors. Morphology, histogenesis problems of pathogenesis. second ed., 1961, Leningrad 8) BISKIND, M. S. BISKIND, G. R.: Development in Proc. Soc. Exp. Biol., N.Y. 55, , 1944.

8 176 KATO, ET AL. 9) BISKIND, Gr. R. BISKIND, M. S.: Atrophy of ovaries transplanted to spleen in unilaterally castrated rats ; proliferative changes following subsequent removal of intact ovary. Science, 108, 137, ) NISHIZUKA, Y., SAKAKURA, T., YAMASHITA, K., TANAKA, Y. KOJIMA, A.: Experimental ovarian tumors. Proceedings of Japanese Cancer Association. The 32nd Annual Meeting 157, 1973.