Canad. Med. Ass. J. 1102 Current Progress: Ovarian May 21, 1966. vol. 94

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The Nature and Classification of Ovarian Neoplasms M. R. ABELL, M.D., Ph.D., Ann Arbor, Mich., U.S.A.

ABSTRACT SOMMAIRE The classification of ovarian neoplasms on L'auteur etudie la classification des neo- a histogenetic basis according to present- plasmes ovariens d'apres des criteres histo- day concepts of development and structure genetiques bases sur nos connaissances of the is considered. There are four actuelles du developpement et de la struc¬ histogenetic categories of primary ovarian ture de l'ovaire. II admet quatre categories tumours: neoplasms of germ cell origin, neo¬ histogenetiques des tumeurs ovariennes plasms of celomic (germinal) epithelium and primaires: les neoplasmes des cellules ger- its derivatives, neoplasms of specialized minales, les neoplasmes de Tepithelium gonadal stroma (sex cords and mesen- ccelomique (crete ge*nitale) et de ses de- chyme), and neoplasms of non-specialized rives, les tumeurs du stroma gonadique dif- gonadal stromal and heterotopic elements. ferencie (cordons sexuels et mesenehyme) et In patients of all ages, 70% of ovarian neo¬ les neoplasmes des cellules du stroma gona¬ plasms were of celomic epithelial origin, dique nos differenciees (gonocytes) et des 16% of germ-cell origin, 5% of specialized elements heterotypiques. Chez l'ensemble gonadal stromal origin, and 9% arose from des patientes, considerees independamment the non-specialized stroma and heterotopic de Tage, 70% des neoplasmes ovariens elements. Before 20 years of age, 59% of avaient leur origine dans Tepitheiium ccelo¬ ovarian neoplasms were of germ cell origin mique, 16% dans les cellules germinales, and before puberty they accounted for 90% 5% dans les cellules differenciees du stroma of all ovarian tumours. The different struc¬ gonadique et 9% provenaient du stroma non tural types of neoplasms within the four differencie et d'el&nents heterotypiques. categories are described. Accurate classifica¬ Chez les femmes agees de moins de 20 ans, tion of ovarian neoplasms on a histogenetic les neoplasmes ovariens avaient comme basis is stressed if proper treatment is to origine les cellules germinales et, avant la be given and intelligent assessment of end puberte, ils expliquaient 90% de toutes les results is to be made. tumeurs ovariennes. L'auteur decrit les divers types structuraux des neoplasmes des quatre categories. II souligne la necessite de classifier les neoplasmes ovariens d'apres une base histogenetique. Si on veut donner A BEWILDERING variety of structurally differ- le traitement convenable, il importe ¦"¦ ent neoplasms, benign and malignant, occur in d'evaluer intelligemment les resultats the ovary. The majority of these (75% ) are benign ultimes. when discovered but many have the potential of becoming malignant if they are not removed or of behaving so if they escape the confines of the ovary. The latter lesions are malignant by virtue of posi¬ is about 15%. The overall survival rates for pa¬ tion rather than of cytological structure. In roughly tients with frankly malignant ovarian neoplasms are 20% of patients with ovarian neoplasms there are low, but there is considerable variation according bilateral autochthonous lesions, usually synchronous. to histological type. These aspects of ovarian neo¬ The percentage is somewhat higher for malignant plasms, together with the apparent two- to three- neoplasms, but it is often difficult to separate bi¬ fold increase in their occurrence since 1930,2 make lateral primary lesions from single unilateral this problem both interesting and vitally important. primaries with metastases. The ovary ranks third Most pathologists, and I am no exception, are as the primary site of gynecological cancers follow¬ collectors of things and thoughts. In this instance ing the uterine cervix and corpus uteri. In our ma¬ the things are ovarian neoplasms and the thoughts terial ovarian lesions account for 9% of female are observations on pathogenesis, structure and genital cancers1 but in other series the percentage natural course. It is inevitable that such a collec¬ tion be put in order and that a classification evolve. From the Department of Pathology, The University of Many of the classifications that have been offered Michigan, Ann Arbor, Michigan, U.S.A. are either and too cumbersome for Presented at the Clinical Conference on Cancer of the Ovary illogical practi¬ sponsored by the Ontario Cancer Treatment and Research cal use or are far too and fail to recognize Foundation. University of Windsor, Windsor, Ontario, simple November 5, 1965. neoplasms that have distinctive clinical and histo- Canad. Med. Ass. J. Progress: Ovarian Neoplasms 1103 May 21, 1966, vol. 94 Current

Pig. -j..Section of a normal ovary from a prepubertal child. The surface is covered by a single layer of flattened epithelial (celomic) cells. Groups of ova surrounded by single layers of follicular (granulosa) cells are scattered throughout the cortex. One developing follicle deep in the cortex consists of proliferating granulosa cells about an ovum with a surrounding in- distinct zone of pale fibroblastic cells representing a developing theca. (H & E X 125.) logical features. The ideal classification, if there be sex cord cells persist as supportive elements about such, should be basically simple, yet accurate, the ova. Remnants of the sex cords may be found systematic, and capable of quick expansion and in the medulla and are a constant finding in the modification as questionable lesions are more cor¬ hilum in the form of the rete ovarii.4 rectly defined and new entities delineated. These At birth the surface of the ovary is covered by requirements are best met by a classification that is a single layer of flattened cuboidal cells represent¬ based on histogenesis according to our present-day ing a modified peritoneum and referred to as understanding of the development and structure of celomic or germinal epithelium (Fig. 1). These the ovary. cells often become hyperplastic during the repro- ductive years and may take on the characteristics Aspects of Normal Development and of epithelial cells of the fallopian tube (endo- Structure of Ovary salpingiosis), endometrium (endometriosis) or endocervix. As a result of of Before discussing the components of a histo¬ repeated rupture genetic classification of ovarian neoplasms, it is follicles and following inflammatory changes in the essential to consider certain aspects of normal de¬ area, pieces of this surface epithelium become and structure. The first sequestered and form small cortical inclusion cysts. velopment gonads appear of as condensations of mesenchyme, the gonadal These are commonly encountered near the end ridges (folds), beneath the posterior celom into the reproductive period and thereafter. which migrate primordial germ cells from the endo- Numerous germ cells are present in the ovarian derm of the yolk sac.3 Shortly thereafter, differentia- cortex at birth and remain prominent but decrease tion begins and cords of cells grow down from the in numbers during childhood (Fig. 1). They are covering celomic (germinal) epithelium. These are absent at the end of the reproductive period. Most clearly visible by the sixth week of gestation. If of these cells can be recognized as ova but others the gonad is destined to become a testis, the sex are smaller and less mature in appearance. The cords persist and form seminiferous tubules, where¬ immature cells are more easily identified in dys- as if the call is for an ovary, the cords disintegrate genetic . During the reproductive period and largely disappear. Some workers believe that (Figs. 2 and 3), developing and atretic follicles Canad. Med. Ass. J. 1104 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 2..A developing follicle. The wall is formed by granulosa cells which, at one pole. encase the ovum and form the cumulus oophorus. Surrounding the granulosa cells is the thecal zone consisting of two ill-defined layers, the theca interna and the theca externa. (H & E X 66.)

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Fig. 3..This is a higher magnification of the follicle shown in Fig. 2. Scattered division figures can be seen among the proliferating granulosa and theca cells. (H & E X 320.) Canad. Med. Ass. J. Current Progress: Ovarian Neoplasms 1105 May 21, 1966, vol. 94

Fig. 4..Section from the hilum of a normal ovary. The irregular-shaped tubule is part of the rete ovarii Small polvgonal hilus (Leydig) cells form an ill-defined mass adjacent to this tubule. (H & E X 160.)

are found in the cortex, and corpora lutea, formed by pale or vacuolated cuboidal cells albicantia and fibrosa are located in the adjacent supported by a basement membrane and a muscular medulla. wall. Accessory adrenal tissue is present in the The stroma is a region of the ovary in 10 to 20% of patients (Fig. cortical specialized mesenchyme cortical that varies considerably in structure with age. It 5). These adrenals of Marchand consist of masses contained is scant in infants and very prominent in women cells only and are sharply defined near the and for there¬ within a definite fibrous capsule. This arrangement menopause varying periods col¬ after. It forms a thin outer zone of relatively hyaline contrasts with the scattered, non-encapsulated fibrous tissue, the tunica albuginea. Beneath this is lections of hilus cells with which they have been the cellular functioning cortex which gives rise to confused. theca and lutein cells, and possibly granulosa cells, although the latter may be derived from the sex A Histogenetic Classification cords. In the histogenetic classification of ovarian neo¬ Certain structures are present in the hila and/or plasms that we employ, there are four basic cate¬ adjacent mesovarii of ovaries and are important in gories (Table I). In the germ-cell category, all neo¬ the pathogenesis of some neoplasms. The retia plasms are included that are thought to arise from ovarii are always present, and if the work of Gill- primitive germ cells and those that may develop in man4 is accepted, they represent remnants of the these tumours as secondary cancers, such as a primitive sex cords from the celomic epithelium. that appears in an old Commonly there is some cortical stroma about these structures. It is in this area that the hilus cells are TABLE I..Histogenetic Categories of Primary Ovarian found which are histologically identical to the Neoplasms interstitial cells of Leydig in the testis and in which A. Neoplasms of germ cell origin. crystalloids of Reinke may be seen (Fig. 4). These B. Neoplasms of celomic (germinal) epithelium and its cells are present in every ovary but vary in num¬ derivatives. and the hormonal C. Neoplasms of specialized gonadal stroma (sex cords and ber with the age of the patient mesenchyme). status. Mesonephric tubules are also present in the D. Neoplasms of non-specialized stroma and heterotopic hilum and/or mesovarium of every ovary. They are elements. Canad. Med. Ass. J. 1106 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 5..A nodule of adrenal cortical cells in the hilum of an ovary. The individual cells resemble hilus cells but they are arranged in cords and are encompassed by a fibrous capsule. (H & E X 135.) cystic (dermoid cyst). The basic structural In the category of neoplasms of specialized types are exactly the same as germ cell neoplasms gonadal stroma we include all lesions that arise encountered in the testis or in the extragonadal from cortical or hilar mesenchyme and from locations such as retroperitoneum, thymus gland, specialized elements of the sex cords. These and pineal body. In the ovary the majority of germ tumours as a group tend to manifest hormonal cell neoplasms are benign whereas in the testis they activity. If they appear to arise from or reproduce are nearly always malignant. tissues considered structurally characteristic of The celomic (germinal) epithelium is repre¬ ovary proper, they are classed as granulosa-theca sented by the surface cells proper, the small cortical cell neoplasms, whereas if they arise from or re¬ inclusion cysts, and, if we adhere to Gillman's con¬ produce hilar structures that are usually associated cept, by the rete ovarii and tubular remnants of with testis, they are placed in the Sertoli-Leydig sex cords in the medulla. The neoplasms that arise cell group. The assignment of a to one of from these cells possess the same potential of differ- these two divisions does not dictate, however, that entiation toward elements of the paramesonephric it will be either feminizing or masculinizing physio- (Mullerian) system as do benign hyperplastic and logically, for lesions in both groups may cause prosoplastic processes of these cells. Thus neo¬ either or both of these effects. plasms are encountered in which the epithelium re- The neoplasms of non-specialized stroma include sembles that of the fallopian tube (serous neo¬ those that arise from tissues common to all organs plasms), endometrium (endometrial cell or endo- of the body and thus are not structurally or func¬ metrioid neoplasms) and endocervix (mucinous tionally distinctive. A small group of neoplasms neoplasms). Less frequently neoplasms in this arises in the mesonephric tubules in the hilum or category consist of a transitional or glandular epi¬ mesovarium. The adrenals of Marchand give rise thelium which resembles that of the urinary system: to the occasional adenoma or carcinoma which may these are the Brenner tumours. Neoplasms derived produce excessive amounts of steroids and cause from celomic epithelium may consist of two or masculinization and/or Cushing's syndrome. more distinct types of epithelial cells, such as tubal It is of interest to compare the relative frequency (serous) and cervical (mucinous), cervical and of the various histogenetic groups of ovarian neo¬ Brenner, or cervical and endometrioid. plasms and the age periods when they generally Canad. Med. Ass. J. 1107 May 21, 1966, vol. 94 Current Progress: Ovarian Neoplasms

TABLE II..Relative Frequency of Histogenetic Cate¬ Pierce10 implanted single gories of Ovarian Neoplasms cells and obtained similar results. The exact rela¬ Total number Per cent of the to the other germ cell Histogenetic category of total tionship of patients neoplasms is uncertain but there is an association Germ cell. 16298 that cannot be explained by chance alone. Celomic epithelium. 132670 Specialized gonadal stroma. 915 Non-specialized stroma and Pure Germinoma (Ovarian , heterotopic elements. 1729 , Gonocytoma) Totals. 1887 100 The germinoma is believed to arise from un- differentiated germ cells that do not have or have lost the to differentiate. These occur (Tables II and III). Neoplasms of celomic faculty neoplasms about time of and are epithelium account for 70% of all ovarian neo¬ first appear the puberty plasms: those of germ cell origin 16%, supportive encountered mainly during the early reproductive tissue and heterotopic elements 9%, and special¬ years. It is doubtful if they ever occur in infancy are rare after ized gonadal stroma 5%. However, before the age or early childhood and they extremely is an increased of 20 years, 59% of neoplasms are of germ cell the fourth decade. There tendency origin and before puberty they account for 90% for to occur in dysgenetic and dys- of all tumours.5 plastic ovaries in patients of somatosexual ambig- uity. They generally exert no hormonal activity, but in a few instances the patients have shown signs TABLE III..Histogenetic Neoplasms Related to Age of masculinization. Childhood and adolescence Adulthood Patients Germinomas are usually quite large when de¬ (up to 20 yr.) (20 yr. to 50 yr.) 50 yr. and over tected and often pregnancy is wrongly suspected, Per cent Per cent Per cent a in The outer Histogenetic No. of of No. of of No. of of resulting in delay the diagnosis. category patients category patients category patients category surface of the tumour is smooth, sometimes bos- Germ cell. 107 59 156 14 35 6 and the cut surface is a Celomic epithelium. 53 29 817 71 456 81 selated, homogeneous pink- Specialized gonadal with areas of necrosis and hemor¬ stroma. 14 8 57 5 20 4 grey, perhaps Non-specialized stroma The pathologist is obligated to search for and heterotopic rhage. elements. 8 4 111 10 53 9 areas of different colour and consistency and to Totals. 182 100 1141 100 564 100 examine these for other germ cell patterns of growth which may influence the treatment and prognosis. Neoplasms of Germ Cell Origin The neoplastic cells are fairly uniform in appear¬ The majority of neoplasms of germ cell origin ance, large with pale or vacuolated cytoplasm, are teratomatous and comprise a spectrum of reticulated nuclei and prominent nucleoli. Although lesions that varies from the aggressive undiffer- division figures are present, they are not usually entiated embryonal teratoma (carcinoma) to the numerous and the neoplasms are characterized by mature benign cystic teratoma (Table IV). Most of a certain uniformity in appearance. The cells are in the experimental work on germ cell neoplasms has clusters, sheets or cords separated by fibrous parti- been done with testicular tumours, but there is no tions in which lymphocytes are usually present reason to believe that the process is significantly (Fig. 6). In a few neoplasms the lymphocytic re¬ different in the ovary. The concept advocated by action is marked and may be accompanied by Askanazy6 that the various teratomatous neoplasms lymphoreticular follicles. A feature of many germin¬ arose from multipotential cells by somatic differ- omas is the presence of a granulomatous reaction entiation has been demonstrated by Pierce and in the stroma, with multinucleated giant cells of the Dixon7' 8 and by Stevens.9 The former workers took Langhans type. Areas of coagulation necrosis may groups of embryonal carcinoma cells (embryoid be extensive. bodies) and implanted these into animals, with the Germinomas are not overly aggressive lesions and resultant development of partially differentiated the prognosis for patients with pure neoplasms is and mature benign . Kleinsmith and good when they are adequately treated (Table V). There are many examples of such tumours that have been removed from women who TABLE IV..Neoplasms of Germ Cell Origix young subsequently had one or more normal pregnancies. 1. Germinoma (dysgerminoma, seminoma ovarii, gono- cytoma I). They are radiosensitive and thus even when metas¬ 2. Embryonal teratoma (embryonal carcinoma). tases are present, the prognosis is not hopeless. The 3. Partially differentiated teratoma (malignant teratoma, for with testicular solid teratoma). prognosis patients germinomas 4. Mature teratoma (benign cystic teratoma, benign solid in which there is abundant lymphoid stroma is teratoma, dermoid cysts). better than for those in which such a reaction is 5. Mixed germ cell neoplasms (teratocarcinoma). Teratomatous . minimal or absent, and there is some evidence that 6. Carcinoma or sarcoma arising in a mature teratoma. the same may be true for ovarian germinomas. Canad. Med. Ass. J. 1108 Current Progress: Ovarian Neoplasms May 21, 196G, vol. 94

iiti Fig. 6..Germinoma (dysgerminoma) of ovary. There are irregular anastomosing masses of undifferentiated but uniform neoplastic cells separated by a stroma containing numerous lymphocytes. Several small collections of pale epithelioid cells forming granulomas are present. (H & E X 160.)

Embryonal Teratoma (Embryonal Carcinoma) basically solid they are very soft, spongy and some¬ uniform This arises from undifferentiated multi- what gelatinous. They lack the appearance neoplasm of germinomas but do not have the variety of potential cells that possess the ability of somatic differentiated It is tissues or the firmness of partially and sometimes trophoblastic differentiation. teratomas. a teratomatous in which the (malignant) basically neoplasm these consist of a tissues are extremely undifferentiated and show Histologically neoplasms an abortive at differentiation. The medullary meshwork of large, actively proliferating, only attempt cells with division nature of this in ovary undifferentiated frequent neoplasm (embryonal often show some at¬ was not until and figures (Fig. 7). The cells teratoma) recognized recently, or ar¬ for a time it was called Schiller's tempt at a papillary, trabecular glandular long mistakenly Intra and extra-cellular mesonephroma on the assumption that it arose rangement (Fig. 8). from elements. Teilum11 referred to globules of bright hyaline may be a prominent mesonephric areas to it as an entodermal sinus tumour and feature. Certain of the neoplasm prove (yolk sac) A hallmark of Simard12 as a be rich in glycogen, others in lipids. polyembryonic embryoma. teratomas is the of teratoma occurs in and then embryonal presence caps, Embryonal infancy and even tubules of more uniform is not usually encountered until about the time of clusters, smaller, puberty. Its peak incidence is in the latter part of cells that suggest initial attempts at differentiation. the second decade and the early part of the third Some of these structures are multipotential em- decade; is it encountered in patients over bryoid bodies, also called Schiller-Duval bodies, rarely structures. In other cellular 25 years of age. It exerts no feminizing or mascu- and blastula-like groups or mucin- effect. The tumours are soft and isolated tubules are formed by ciliated linizing bulky, which the friable, and rupture readily. Commonly there is a producing columnar cells surrounding hemorrhagic fluid in the peritoneal cavity, and neoplastic cells may have features of primitive gross metastases are present in about one-half of muscle or neuroglia. the patients at the time of initial celiotomy. The Embryonal teratoma of the ovary is a very ag¬ cut surfaces are mixtures of greys, yellows, browns, gressive neoplasm which in our experience has been and reds due to necrosis and hemorrhage. Although uniformly fatal, with an average survival period Canad. Med. Ass. J. May 21, 1966, vol. 94 Current Progress: Ovarian Neoplasms 1109

Fig. 7..Embryonal teratoma (carcinoma). This is a medullary meshwork of undiffer¬ entiated vacuolated and almost clear cells with scattered small groups of somewhat darker stained cells. (H & E X 400.)

Fig. 8..Embryonal teratoma. In this area of the neoplasm there is an attempt at organization of undifferentiated cells but no recognizable tissues. (H & E X 320.) Canad. Med. Ass. J. 1110 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

TABLE V..Summary of Survival Information on Malignant Germ Cell Neoplasms* No. of Survival information No. of Age average patients- Type of neoplasm patients and range qualifying DeadAlive Embryonal carcinoma. 9 10.4 (7 months (0-1488 months)0 to 19 years) Partially differentiated teratoma. 13 14.5 (10 to 19 years) 12 9 (2, 3, 4, 4, 5, 3 (7, 10 and 15 months) 9, 18, 20, 23 years) Germinoma. 11 14.8 (8 to 19 years) 10 9 (2, 6, 8, 9, 13, 1 (28 months) 16, 26, 27, 32 years) Mixed germ cell (Teratocarcinoma). 8 13 (8 to 17 years) 8(18to 14 months)0 Totals. 41 13.4 3820 18 *This table is a modification of Table VIII in Amer. J. Obstet, Gynec, 92:1059, 1965.5 of slightly more than one year (Table V)."' Cer¬ ponent in the neoplasm may predominate by tainly this neoplasm is entirely different structurally overgrowth so that a good proportion of the mass and in its natural course from germinoma, with is rhabdomyosarcoma, liposarcoma, neuroblastoma which it unfortunately has been confused. If pa¬ or . Attempts to grade these neo¬ tients with this neoplasm are to be salvaged, treat¬ plasms on the basis of immaturity has met with ment must be aggressive and it may be that the some success: the patients with the more mature only hope for survival rests with the discovery of lesions have a better prognosis than do those with factors that induce differentiation in the neoplasms the more immature ones.13 so that they may be converted into less malignant or even histologically benign lesions. Mature Teratoma (Benign Cystic Teratoma; Dermoid Cyst) Teratomas Partially Differentiated (Malignant) Mature teratomas arise by neoplastic transforma- Partially differentiated teratomas may be viewed tion and differentiation of multipotent germ cells as embryonal teratomas that have reached ado¬ and consist of melanges of mature somatic tissues, lescence; the undifferentiated multipotential cells representing, in most instances, three germ layers. have matured to varying degrees and in so doing They are considerably more frequent and occur have become less malignant (Table V). They oc¬ later in life than the malignant neoplasms of cur primarily in patients about the time of puberty germ cells. Although they may be discovered at any and in the early reproductive years. age, most examples are detected in the third and These neoplasms are large, lobulated, and par¬ the early part of the fourth decades; on rare oc¬ tially cystic masses in which a variety of tissues casions they are responsible for an autoimmune are easily recognized (Fig. 9). The tissues are only hemolytic anemia.14 partially differentiated and thus possess the histo¬ Nearly all mature teratomas are cystic, with one logical features of cancer, but considerable variation or more large cysts lined predominantly by skin and in the degree of differentiation and hence of malig¬ containing hair, sebaceous material and debris; a nancy exists (Fig. 10). Residual small foci of em¬ very few mature teratomas are relatively solid. One bryonal teratoma are sometimes present. One com- or more dermal papillae are visible in the cysts and it is from these that the hair grows and in them that bone and teeth are found (Fig. 11). Ecto- dermal and neural tissues usually are present. Other tissues commonly encountered are respira¬ tory and intestinal epithelia, and various types of supportive tissues. Lung, cardiac muscle, pancreas, kidney, adrenal gland and gonadal tissues are en¬ countered rarely. The occasional neoplasm may consist almost entirely of thyroid tissue, "the struma ovarir, or of neuroglia, "the glioma ovarii". Neural tissue forms a more prominent component of tera¬ tomas in children than adults, and the cysts may be lined entirely by neuroepithelium. Secondary neoplastic changes, represented by either carcinoma or sarcoma, may occur in mature teratomas that have been present for a consider¬ Fig. 9..A partially differentiated (malignant) teratoma able time and thus are seen in older patients. This which was partly cystic and has been opened. A variety of tissues of different colours and consistency are visible. change occurs in less than 1% of tumours. The Canad. Med. Ass. J. Current Progress: Ovarian Neoplasms 1111 May 21, 1966, vol. 94

^li^KlPI1 Fjg< 10..A partially differentiated teratoma revealing- a variety of different tissues of fetal appearance. In the upper right field there is cartilage and bone. Beneath this, and in the upper left field, there is immature neuroepithelium and neuroglial cells. To the left of centre there is a mass of squamous cells and an immature tooth bud. Between these tissues there is an immature mesenchyme of varying- density. (H & E X 60.) cancer may take the form of a squamous cell car¬ Neoplasms of Celomic Epithelium and cinoma, thyroid carcinoma or leiomyoscarcoma, or its Derivatives arise from and simulate neoplasms of any of the These lesions comprise the bulk of ovarian neo¬ mature somatic tissues. plasms (Table VI). They do not occur before puberty and the frequency drops off sharply after Mixed Germ Cell Neoplasms the sixth decade. Those that appear later in life are much more likely to be malignant than are those (Teratocarcinomas) encountered during the early reproductive years. These germ cell neoplasms consist of a combina¬ Their development depends in some manner on tion of two or more of the neoplastic patterns al¬ hormonal stimulation and seem to be ready described. For this group Friedman and particularly important. Clinical observations indi- Moore15 coined the term "teratocarcinoma". Em¬ one the com¬ bryonal teratoma commonly forms of TABLE VI..Neoplasms of Celomic (Germinal) ponents in this neoplasm, and areas which are Epithelium and Its Derivatives identical in growth pattern to germinoma are also 1. Serous (tubal cell) type: Cystadenoma (cystoma) often present. It is in this group that, on rare Papilloma Papillary occasions, extensive areas of choriocarcinoma are Cystadenofibroma cystadenocarcinuma is then called a teratomatous Adenofibroma found and the lesion 2. Mucinous (cervical cell) type: choriocarcinoma. Other components are, however, Cystadenoma Cystadenofibroma invariably present and it is doubtful if a pure Adenofibroma teratomatous choriocarcinoma exists. When em¬ 3. Endometrioid (endometrial cell) type: Cystadenoma (cystoma) Cystadenocarcinoma bryonal teratoma is a component of these mixed Acanthoadenocarcinoma the prognosis is essentially the same as 4. Brenner tumours: neoplasms, Benign Malignant if the tumour were a pure embryonal teratoma 5. Mixed and unclassified cell types: (Table V).5 Cystadenoma (cystomas) Cystadenocarcinoma Canad. Med. Ass. J. 1112 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 11..The dermal papilla of a mature cystic teratoma. It is covered by mature squamous epithelium and contains hair follicles, sebaceous glands, apocrine glands and adipose tissue. The lighter-stained areas to the base of the papilla consist of neuroglial tissue. (H & E X 15.)

Fig. 12..A sessile papillary area from the wall of a unilocular serous cystadenoma (cystoma). Nubbins of mature connective tissue project into the lumen and are covered by a single layer of cuboidal cells. (H & EJ X 60.) Canad. Med. Ass. J. Progress: Ovarian Neoplasms 1113 May 21, 1966, vol. 94 Current

Fig. 13..A higher magnification of a serous cystadenoma. The epithelial cells are cuboidal with little cytoplasm and resemble the epithelial cells of endosalpinx. (H & E X 200.) cate that these neoplasms grow more rapidly and is hormonally inert, but in some neoplasms it is may appear suddenly in patients subject to exces¬ identical with the more cellular hormonally active sive stimulation. cortical stroma in which areas of thecosis and In all neoplasms in this category the ovarian luteinization may exist. A few of these neoplasms cortical stroma participates to some extent and in a are associated with signs of excessive estrogenic few tumours, such as the adenofibromas, it may stimulation or of masculinization. The stroma in comprise the bulk of the lesions. Commonly the these neoplasms may also respond to stimulation by stroma resembles the hyaline tunica albuginea and progestins, with the formation of decidua. Serous (Tubal Cell) Neoplasms The epithelium in these neoplasms resembles that of the uterine tube and is a mixture of peg, secretory and ciliated cells (Figs. 12 and 13). The neoplasms that arise from the surface epithelium proper and form exophytic growths are either papil- lomas or papillary carcinomas (Fig. 14). Most are, however, basically cystic and intraovarian with in- traluminal papillary growths and arise from cortical inclusions (Figs. 12 and 13). They are termed papillary cystadenomas and (Figs. 15, 16 and 17) or if there is considerable proliferation of cortical stroma they are cystadeno- or adenofibromas, and the carcinomas that arise in them are serous carcinomas which attempt to form papillary structures. The serous (tubal cell) neoplasms are by far Fig. 14..A well-differentiated papillary carcinoma of the most common that is en¬ serous (tubal) cell type that has arisen from the surface histological type of the ovary. countered and comprise about 40% of all primary Canad. Med. Ass. J. 1114 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 15..This is the external surface of a serous cystadeno¬ Fig. 16..The cut surface of the tumour depicted in Fig. carcinoma showing nodular granular masses of carcinoma. 15. There are multiple cystic spaces with intraluminal papillary masses and solid nodules of carcinoma. neoplasms of ovary. Among these cancers there is abnormalities. considerable variation in of differentiation. tion rather than of cytological degree Patients with these neoplasms may survive for long Patients with the more aggressive sero-anaplastic with extensive carcinomas have a much poorer prognosis than do periods intraperitoneal implants. those with the better differentiated seropapillary Mucinous tumours. There is a small group of hyperplastic (Endocervical Cell) Neoplasms but histologically benign neoplasms that are The basic epithelial cells in these neoplasms are capable, if ruptured, of implantation and progres¬ columnar, mucin-secreting with basally placed sive growth within the peritoneal cavity; these are nuclei and are identical to those of endocervix the tumours that are carcinomas by virtue of posi- (Figs. 18 and 19). These tumours arise from cortical

Fig. 17..Papillary serous cystadenocarcinoma. Fibrous stalks are covered by several layers of carcinomatous cells which in turn send fingers of cells into the lumen. (H & E X 150.) Canad. Mecl. A =;s. J. May 21, 1966, vcl. 94 Current Progress: Ovarian Neoplasms 1115

tents of the cystic spaces are thick and mucinous. Mucinous adenofibromas are much less frequent than are the serous (tubal cell) type. The majority of these neoplasms are histologically and clinically benign. Those that are malignant (Fig. 20) are less aggressive generally than are the serous cystadeno- carcinomas in that they remain confined to the peritoneal cavity for longer periods and have less of a tendency to infiltrate and metastasize. Rupture of well-differentiated carcinomas or of hyper- plastic but cytologically benign neoplasms may lead to pseudomyxoma peritoneii. The mucinous neoplasms are considered to be of celomic epithelial origin, but there is a very small group that arises within cystic teratomas from respiratory or intestinal epithelium. Thorough ex¬ amination of the entire specimen, in these instances, usually reveals the basic teratomatous nature. Endometrioid Fig. 18..The cut surface of a . (Endometrial Cell) Neoplasms There are multiple cysts of varying size that contain mucin. These cystadenomas and carcinomas are com- posed of epithelial cells that are cytologically the inclusion cysts, rete ovarii, and less frequently from same as those of the endometrium. The problem is the surface epithelium proper. Exophytic growths to separate the benign neoplasms from cystic endo- are rare and most lesions are multicystic with no metriosis, and the differences have not as yet been gross papillary formations (Fig. 18). They grow clearly delineated. The epithelial cells of benign by the development of daughter glands and cysts lesions are columnar, with pale flocculent cyto¬ that progressively increase in size, and the intact plasm and small oval nuclei, somewhat variable in neoplasm may reach huge proportions. The con¬ position but usually placed near the centres of the

Fig. 19..Mucinous cystadenoma. The neoplastic cells are columnar with basally placed nuclei and abundant pale cytoplasm. (H & E X 200.) Canad. Med. Ass. J. 1116 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 20..Mucinous cystadenocarcinoma. Irregular glandular spaces with daughter glands are formed by columnar epithelial cells. The nuclei are variable in position although still tend- ing to have a basal position. Division figures are frequent. (H & E X 200.)

Fig. 21..Well-differentiated endometrioid (endometrial cell) carcinoma. There are closely packed glandular structures formed by thin columnar cells in which the nuclei are generally central in position. A few division figures are visible. (H & E X 220.) Canad. Med. Ass. J. 1117 May 21, 1966, vol. 94 Current Progress: Ovarian Neoplasms

Fig. 22... There are nodular masses of tumour cells separated by fibrous septae. Within these the granulosa cells form small follicle-like structures. A folliculoid pattern of this type is fairly characteristic of this neoplasm. (H & E X 215.) cells. There may be vacuolation of the cytoplasm, system and the cell nests of von Brunn that arise reminiscent of the secretory change that occurs in from them. Often there is a small central lumen or the endometrium, and the adjacent stroma some¬ cystic space about which the cells assume a low times has a cytogenic appearance. columnar configuration. Malignant Brenner tumours The carcinomas are well-differentiated neoplasms may retain the basie structural features of cell nests (Fig. 21), sometimes acanthoid, but so may be the in a fibrous stroma but may also assume an adeno- carcinomas that arise in implantation endometriosis. matous or squamoid appearance. The justification for separating the endometrioid carcinomas from other celomic epithelial neoplasms Mixed Celomic Neoplasms is that the evidence to date suggests that the prog¬ nosis for with them is better. Approximately 10% of the neoplasms derived patients considerably from the celomic epithelium consist of combina¬ Brenner tions of two or more of the structural patterns that Neoplasms (Fibroepithelioma, have been described or are so nondescript that they Urothelioma) cannot be classified. A mixture of serous and These fibroepithelial neoplasms are considerably mucinous types is probably seen most commonly, less common than the other types of celomic cell but Brenner tumours are encountered with either tumours. They are usually solid neoplasms related a mucinous or serous component, and mucinous and to adenofibromas but there may be a cystic com¬ endometrioid patterns occur together. ponent. Generally they are benign and hormonally are to of these inactive, but there exceptions both Neoplasms of Specialized Gonadal Stroma generalizations. A variety of theories concerning the pathogenesis of these neoplasms have been suggest¬ This is a challenging group of tumours (Table ed over the years, but the evidence supports origins VII) in that they exert a variety of systemic mani¬ from surface germinal epithelium and rete ovarii. festations due to the production of different The usual neoplasm consists of branching cords steroids. Most neoplasms can be accurately clkssi- and tunnels forming a root-like network of epithelial fied as to cell type and associated hormonal effects cells with knobby and cystic projections sur- predicted, but the level of differentiation in some rounded by dense fibrous tissue. The epithelial cells may be such that a specific categorization other are stratified and resemble those of the urinary than gonadal stromal tumour is not possible. A dis- Canad. Med. Ass. J. 1118 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 23..Granulosa cell tumour. This shows a diffuse pattern of growth but the cells are still uniform in appearance and attempt to line up in cords. (H & E X 480.)

Fig. 24... There are interlacing streams of plump spindled cells with abundant pale cytoplasm. (H & E X 360.) Canad. Med. Ass. J. 1119 May 21, 1966, vol. 94 Current Progress: Ovarian Neoplasms

TABLE VII..Neoplasms of Specialized Gonadal Stroma of decidua in the endometrium. Most are 1. Granulosa-thecal cell group preceded by nodular cortical hyperplasia in the Granulosa cell tumour (folliculoma) ovary or of the Stein-Leventhal syn¬ Theca cell tumour (thecoma) hyperplasia Granulosa-theca cell tumour (thecogranulosa drome. tumour) these are solid fibrous tumours 2. Grossly neoplasms Sertoli- group with a micro¬ tumour (folliculoma lipidique) distinctly yellow appearance, and (hilus cell tumour) scopically they consist of large, plump, pale, Arrhenoblastoma (Sertoli-Leydig cell tumour) and cells that contain stainable 3. Luteomas spindled polygonal 4. Gynandroblastoma cytoplasmic lipids (Fig. 24). Areas of hyalinization may be prominent, and it is possible that some so- called fibromas may represent thecomas that for tinction, histologically, between benign and malig¬ some reason and became nant stromal tumours is also not regressed hyalinized. Very gonadal always few thecomas are malignant. possible. In general, however, the neoplasms that 20% of are are not as as are most of Thecogranulosa tumour..Approximately malignant aggressive the in the cell are the carcinomas that arise from celomic neoplasms granulosa-theca group epithelium. a mixture of the two elements, both being neo¬ It is that arise frcm Granulosa-Theca Cell plastic. suggested they gonadal Group of Neoplasms mesenchyme which possesses the potentiality to This is the largest group of gonadal stromal differentiate into both granulosa and theca cells. tumours and many exert a feminizing effect owing These tumours consistently exert a feminizing to the production of estrogens; however, a few may action, but whether they have any greater malig¬ cause a masculinization of the host. There is an nant potential than the other members of the group association between these neoplasms and endo¬ has not been established. metrial carcinoma that cannot be explained by chance, but whether there is truly a cause-and- Sertoli-Leydig Cell Group of Neoplasms efFect has not been established. relationship clearly These neoplasms, although rare, have attracted Neoplasms of this group have been produced ex- considerable attention because of the in small animals dramatic perimentally by x-irradiation, by that are the administration of chemical and systemic changes they often produce. They carcinogens, by to cause defeminization and ovarian into in generally thought transplants spleens gonadectomized masculinization but a few actually cause feminiza- animals. Three basic types of neoplasms are tion with of excessive in this theca signs estrogenic activity. recognized group: granulosa cell, cell, arise from the sex cord elements and mesen¬ and tumours. They thecogranulosa chyme in the hilar region. Structurally they re¬ Granulosa cell tumour This neo¬ (folliculoma).. semble and are often identical to the similarly plasm has a distinctive epithelial appearance and named tumours that occur in the testis. Three arises either from granulosa cells of follicles or histologically different neoplasms comprise the from precursor cells in the ovarian mesenchyme. group: pure Leydig cell tumour, pure Sertoli cell It is the most common tumour in the granulosa- tumour, and Sertoli-Leydig cell tumour or arrheno¬ cell Before this tumour causes theca group. puberty blastoma, in which both types of cells are present precocious development and after the menopause often with a nondescript of the uterus and breasts with endo¬ mesenchyme. enlargement Leydig cell tumour (hilus, interstitial cell or metrial hyperplasia and bleeding. During the re¬ small arise in to its Bergers tumour)..These neoplasms productive period symptoms and signs due the ovarian hilum and cause masculinization16 due not be hormonal activity may apparent. in part to the production of . They The tumours are either solid or cystic and usually occur in women near menopausal age and for a have a distinct yellow hue. Microscopically the epi¬ time thereafter. Histologically they consist of thelial cells are uniform in appearance, cuboidal or clusters, sheets and/or cords of eosinophilic poly¬ polygonal, and form a variety of patterns even in gonal cells that contain some lipid and lipochrome the same neoplasm (Figs. 22 and 23). The more pigment. The cells sometimes become spindled and common patterns of growth are folliculoid, trabecu¬ in the larger neoplasms there is often considerable lar, cylindroid and pseudoadenomatous. There may central hyaline change. The hallmark of these be stromal hyperplasia in these tumours but not to lesions is the presence of intracytoplasmic eosino¬ the extent that confusion with thecogranulosa philic crystalloids of Reinke, but these cannot to occur. of these tumours is likely Roughly 25% always be identified. With one exception, the ex¬ neoplasms behave as carcinomas. amples reported thus far have been benign. A few Theca cell tumour (thecoma)..In most series of these tumours have occurred in dysgenetic these tumours occur less frequently than granulosa ovaries. cell tumours and later in life. They are generally (folliculoma lipidique, andro- feminizing but if there is associated luteinization blastoma)..These are feminizing neoplasms that () they may cause masculinization and arise from the sex cord remnants in the ovarian produce a progesterone effect with the formation hilum. In children they cause precocious develop- Canad. Med. Ass. J. 1120 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

Fig. 25..Sertoli cell adenoma of ovary. The neoplastic cells form tubular structures which bear a close resemblance to the Sertoli-cell-lined tubules of testis. (H & E X 30.)

Fig. 26..This is a less well-differentiated Sertoli cell tumour which, however, still shows a grroupmg of cells and an attempt to form tubules. (H & E X 300.) Canad. Med. Ass. J. Progress: Ovarian Neoplasms 1121 May 21, 1966, vol. 94 Current

Fig. 27..An arrhenoblastoma. Most of the cells in this field are interstitial (Leydig) cells. There is, however, one distinct tubule formed by Sertoli cells. (H & E X 300.) ment of secondary sex characteristics.17,18 They tumours. Thus, uncertainty has existed as to consist of tubules and cords of eosinophilic cub- whether such neoplasms actually exist. It now oidal cells that in some instances contain a good seems clear that there is a small group of uncom¬ deal of lipid (Figs. 25 and 26). Most of these mon ovarian tumours, usually benign and related tumours are histologically benign and behave so, to the granulosa-theca cell group, that can be called but we have recently seen a poorly differentiated luteomas. They may cause and mascu¬ some a effect on Sertoli cell tumour in a young girl which was linization and exert progesterone histologically malignant and which metastasized.19 endometrium and related tissues. There is a tendency for Sertoli cell tumours to de¬ The luteinized theca cell tumour is termed a velop in dysgenetic ovaries. luteoma when the change is extensive and results in cell tumour (arrhenoblastoma).. a nearly pure culture of clear or eosinophilic poly¬ Sertoli-Leydig cells. The luteoma of is a solid These neoplasms are mixtures of Sertoli cells, gonal pregnancy and undifferentiated in yellow neoplasm that appears during pregnancy Leydig cells, mesenchyme from cells.20 It con¬ various The of and probably arises the theca proportions (Fig. 27). majority sists of sheets of large eosinophilic and somewhat them cause masculinization but a few may actually vacuolated cells (Fig. 28). Although cellular with be feminizing and occasionally both effects are identified division the is noted. occur in the easily figures, neoplasm They mainly early reproductive and there is some evidence that it may re- Testosterone is some of these benign years. produced by gress spontaneously after pregnancy, much like neoplasms and is presumed to come from the luteinalis. the are to be hyperreactio Scully21 recently reported Leydig cells; estrogens thought pro¬ on stromal luteoma, a small benign neoplasm that duced by the Sertoli cells. Approximately 20% of arises from lutein cells in the cortical stroma of the these are neoplasms malignant. ovaries of postmenopausal women. This neoplasm causes uterine bleeding and masculinization, and Luteomas the curettings may reveal a decidual change in the The term luteoma has been much abused during endometrial stroma. the past, and many neoplasms in which the cells Gynandroblastoma is an exceedingly rare neo¬ had an eosinophilic or clear cytoplasm have been plasm not accepted by all as an entity.22 In it there so named, including adrenal cortical and hilus cell are granulosa-theca cell elements and Sertoli-Ley- Canad. Med. Ass. J. 1122 Current Progress: Ovarian Neoplasms May 21, 1966, vol. 94

9 %j|.- Ik, ®

Fig. 28..Section from the periphery of a luteoma of pregnancy. The neoplastic cells are large compared to the lymphocytes and have pale vacuolated cytoplasm and large open nuclei with prominent nucleoli. (H & E X 150.)

Fig. 29..Malignant lymphoma of ovary consisting of sheets of neoplastic reticulum cells and scattered pale histiocytic cells that account for the "starry-sky" pattern. (H & E X 190.) Canad. Med. Ass. J. May 21, 1966, vol. 94 Current Progress: Ovarian Neoplasms 1123

Fig. 30..Tubule formation in a mesonephric carcinoma (mesonephroma) of ovary. The neoplastic cells are cuboidal with vacuolated or clear cytoplasm, relatively large dark nuclei and prominent nucleoli. (H & E X 320.) dig cell elements, representing a mixture of the after the menopause and forms a large, hard, white various gonadal stromal components. This neo¬ tumour that sometimes calcifies. The Demons-Meigs plasm usually causes virilization and masculiniza¬ syndrome develops with some of the fibrous tion without loss of feminine characteristics, and tumours of ovary and consists of massive ascites and sometimes signs of estrogenic stimulation. hydrothorax which are relieved when the tumour is removed. Other non-specialized neoplasms that Neoplasms of Non-Specialized Stroma are occasionally found in the ovary are angiomas, tumours. and Heterotopic Elements lipomas and various neurogenous The be the initial site of A collection of neoplasms, non- ovary may malignant heterogenous so that the clinical features specific for ovary, comprise this group and arise lymphoma presenting from the and vascular stroma that the are those of a primary ovarian neoplasm. Rarely, supportive if is the disease restricted to an or has in common with other or from ever, ovary ovary organs and in most instances other lesions the heterotopic elements that occur in the hilum ovaries, systemic and mesovarium is the soon appear. Attention has been focused on malig¬ (Table VIII). nant of the most common one in the it occurs lymphoma ("African lymphoma") ovary group; usually in children and adolescents in certain parts of Africa, where it forms the commonest ovarian neo¬ TABLE VIII..Ovarian Tumours of Non-Specialized encountered in 24 The Stroma and Heterotopic Elements plasm young girls.28' disease, however, is not restricted to Africa and similar lesions, either unilateral or bilateral, are en¬ countered on this continent (Fig. 29). Most lymph- omas of the ovary are probably reticulum cell sarcomas rather than lymphosarcomas, but some confusion exists in the literature because the latter term is sometimes used in a generic sense for all sarcomas of lymphoreticular tissues. 1124 CUBRENT PROGRESS: OVARIAN NEOPLASMS Canad. Med. Ass. J.

Mesonephric Adenoma and Carcinoma genesis according to present-day concepts of de- These neoplasms arise from the mesonephric velopment and structure. This approach has served remnants in the ovarian hilum, broad ligament, to define more clearly some of the less well-under- parametrium, uterine cervix and vagina. In all stood lesions and has shown the interrelationships locations their histological features are basically of certain structurally different patterns of growth the same. They consist of tubules, cysts and papil- in other lesions. It points up the naivet6 of sugges- lary formations of pale or clear cuboidal and poly- tions that all malignant neoplasms of the ovary gonal cells (Fig. 30). The term mesonephroma has, have a single genesis, a uniform natural course, and unfortunately, been applied to several neoplasms a like response to treatment. Some neoplasms, such that we now recognize to be of different origin and as those in the germ cell group, are intimately con- thus there has been considerable confusion as to nected with differentiation and maturation of the course of these neoplasms and their response tissues, some with an abnormal hormonal milieu, to treatment. True mesonephric carcinomas of the and still others are possibly due to chemical car- ovarian region are not as malignant as the older cinogens, physical factors and viruses. Some neo- literature suggests, and the five-year survival rates plasms, such as germinomas, are very radiosensitive for patients with these are better than for those and if the patients are properly treated the results with serous cystadenocarcinomas. are good, whereas other germ cell tumours are completely resistant to radiation and pursue a Adrenal Cortical Tumours progressively fatal course. The wide divergence in biological nature and response to different forms (Masculinovoblastoma) of therapy of ovarian neoplasms makes it manda- Rare lipidic cell neoplasms arise from the tory that all lesions be accurately classified on a adrenals of Marchand; they occur in young, previ- histogenetic basis if proper treatment is to be given ously normal women and cause masculinization and intelligent assessment of end results is to be with or without Gushing's syndrome. The 17- made. ketosteroids are considerably elevated, in contrast to normal or only slightly elevated levels in pa- REFERENCES tients with arrhenoblastomas and hilus cell neo- 1. PEARSE, W. H. AND BEHRMAN, S. J.: Obstet. Gynec., 3: 32, 1954. plasms. 2. GORDON, T., CRITTENDEN, M. AND HAENSZEL, W.: cancer mortality trends in the United States, 1930-1955, In: United States National cancer Institute: End results and mortality trends in cancer, monograph No. 6, CONCLUSION Washington, 1961, p. 131. 3. WITsCHI, E.: Contr. Embryol. Carneg. Instn., 32: 67, In this discussion of the classification of ovarian 1948. neoplasms some lesions have been purposely 4. GILLMAN, J.: Ibid., 32: 81, 1948. 5. ABELL, M. R., JOHNSON, V. J. AND HOLTE, F.: Amer. J. neglected either because of their extreme rarity or Obstet. Gynec., 92: 1059, 1965. because of uncertainty as to whether they are truly 6. ASKANAZY, M.: Verh. Deutsch. Ges. Path., 11: 39, 1907. 7. PIERCE, G. B. AND DIXON, F. 3., JR.: Cancer, 12: 573, neoplastic entities. Carcinosarcoma, mixed mesen- 1959. chymal sarcoma, Krukenberg tumour, melanotic 8. PIERCE, 0. B., JR., DIXON, F. J., JR. AND VERNEY, E. L.: Lab. Invest., 9: 583, 1960. sarcoma, osteogenic sarcoma and rhabdomyo- 9. STEVENS, L. C.: ,T. Nat. Cancer Inst., 23: 1249, 1959. sarcoma were not considered although examples 10. KLEINSMITH, L. J. AND PIERCE, 0. B., JR.: Cancer Res., 24: 1544, 1964. of such as well as several other unusual neoplasms 11. TEILUM, G.: Cancer, 12: 1092, 1959. have been reported as primary lesions in the ovary. 12. SIMARD, L. C.: Ibid., 10: 215, 1957. 13. THURLBECK, W. M. AND SCULLY, R. B.: Ibid., 13: 804, In all probability some lesions will become more 1960. and their inclusion in the schema 14. ALLIBONE, B. C. AND COLLINS, D. H.: ,T. Clin. Path., 4: clearly defined 412, 1951. will then be required. It is also possible that a new 15. FRIEDMAN, N. B. AND MOORE, R. A.: Milit. ,Surg., 99: category may be required in the future for ovarian 573, 1946. 16. BERGER, M. L.: Rev. Canad. Biol., 1: 539, 1942. tumours that consist of a mixture of germ cell and 17. ABELL, M. R. AND HOLTE, F.: Amer. J. Obstet. Gynec., gonadal stromal elements for which such terms as 93: 850, 1965. 18. TEILUM, G.: J. Clin. Endocrinol., 9: 301, 1949. gonadoblastoma, gonadoma, and gonocytomas have 19. SMOTJT, M.: To be published. been used. However, at the present time much 20. STERNBERG, W. H.: Nonfunctioning ovarian neoplasms, In: The ovary, edited by H. G. Grady and D. E. needs to be done to delineate these lesions more Smith, International Academy of Pathology mono- graph No. 3, The Williams and Wilkins Company, clearly and to determine whether all are neoplasms Baltimore, 1963, p. 209. or whether some are hyperplasias and dysplasias in 21. SCULLY, R. B.: Cancer, 17: 769, 1964. 22. NEUBECKER, R. D. AND BREEN, 3. L.: Amer. J. Clin. Path., malformed gonads. 38: 60, 1962. 23. BREW, D. S. AND JACKSON, J. G.: Brit. ,J. Cancer, 14: 621, The logical approach to the problem of classifi- 1960. cation of ovarian tumours is that based on histo- 24. BURKITT, D. AND O'CONOR, 0. T.: Cancer, 14: 258, 1961.