Classification of Tumors of the Ovary: Developmental and Ultrastructural Considerations

BERNARD GONDOS, M.D.

Department o f Pathology, University of Connecticut, Farmington, CT 06032

ABSTRACT

The classification of ovarian tumors presents a difficult problem because of the great variety of tumor types that can occur. The complex structure of the normal ovary and the diversity of cell types present at different stages of development contribute to this difficulty. Developmental and ultrastructu ral studies have helped to clarify the problem by indicating specific cell types that correspond directly with the major tumor categories. Tumors may thus be grouped as being of epithelial, germ cell or sex cord stromal origin. The ultrastructural features of tumors in the different categories indicate common characteristics shared with corresponding cell types in the developing ovary. The findings clearly support a histogenetic approach in the classification of ovarian tumors.

Introduction they also behave in entirely different ways in their clinical presentation, laboratory The diversity in histologic appearance findings, response to various forms of and clinical behavior of tumors of the treatment and eventual outcome. It is ovary presents a particularly difficult therefore critical that the pathologist be problem to pathologist and clinician able to convey to the clinician an appro alike. For the pathologist, the number of priate and accurate diagnosis in cases of different categories of ovarian tumors is ovarian neoplasia. in itself an imposing challenge. In addi The complexity of the problem is un tion, there are so many sub-types in the derscored by the multiplicity of ap various categories that only a thorough proaches to the analysis of ovarian tumors understanding of the classification of that have existed over the years. The tumors of the ovary will enable a correct most successful of these have been based interpretation and proper designation in on histogenetic considerations. Utilizing evaluating such cases. For the clinician such an analysis, the World Health Or involved in the management of patients ganization has proposed a standardized with ovarian tumors, the problem is classification and nomenclature of ova further complicated. Not only do the rian tumors.26 This classification is re tumors have different appearances, but viewed in a recent paper51 to which the 179 0091-7370/79/0500-0179 $01.50 © Institute for Clinical Science, Inc. 180 GONDOS reader is referred. Since the present au germ cells, oogonia, oocytes), granulosa thor is in essential agreement with the cells and stromal cells. WHO classification, the purpose of this The surface epithelium of the fetal report is not to present a new classifica ovary represents an extension of the tion, but rather to add support to the his- coelomic epithelium (mesothelium) over togenetic approach, using data derived the developing gonad. The gonads ini from developmental and ultrastructural tially develop as outpouchings into the studies. coelomic cavity in the region of the geni tal ridge. Immediately adjacent to the forming gonads, the coelomic epithelium Development of the Ovary invaginates and extends caudally to give Implicit in a histogenetic approach to rise to the Mullerian ducts, the source of tumor classification is an understanding the major part of the female genital tract. of the different normal cell types in A special feature of the epithelium over- volved. The ovary is a complex structure lying the fetal ovary is that it undergoes participating in two major functions extensive proliferation during the second which are interrelated but distinct: re trimester,20 then reverts to a single layer production and hormone secretion. as is present in the adult.43 The prolifera These functions require several cell tion occurs during the formation of corti types, i.e., germ cells, supporting cells, cal sex cords which contain germ cells hormone secreting cells.19 and granulosa cells. The surface The development of these different epithelium contributes to the formation cell types within a single organ requires of the granulosa cells,16 some of which are intricate coordination and interaction. also derived from the rete ovarii.8 Much of this complex developmental The germ cells originate extragonad- process takes place in the fetal ovary.56 ally in the yolk sac endoderm, then mi Consequently, understanding of ovarian grate to the developing gonad during the histogenesis entails special consideration second month of gestation.58 Initially re of fetal stages of development. Table I ferred to as primitive germ cells, these indicates the principal cell types present cells become closely associated with ad in the fetal ovary. These are the surface jacent granulosa cells on arrival in the epithelial cells, germ cells (primitive gonad and undergo active proliferation,

TABLE I

Cell Types in Developing Ovary

Cell Type Specific Name Origin Characteristics

Epithelial cells Surface epithelium Coelomic epithelium Columnar cells on surface; multiple layers early, then single layer after second trimester. Germ cells Primitive germ cells Yolk sac Large round to oval ameboid cells. Oogonia Round cells in active mitosis, in clusters. Oocytes Round cells in meiosis, become incorporated in follicles. Supporting cells Granulosa cells Surface epithelium/ Oval to elongated cells associated Rete ovarii/ with germ cells in cortical sex Mesenchyme (?) cords. Stromal cells Theca interna Mesenchyme Elongated cells at edge of follicle. Theca externa Undifferentiated stromal cells. Interstitial cells Large oval cells with abundant cytoplasm. CLASSIFICATION OF TUMORS OF THE OVARY 181 at which time they are called oogonia. Another cell type of apparent mesen This mitotic phase is followed by a mei- chymal origin is that associated with an otic phase which begins at the end of the drogen production. Interstitial cells, hilar third month.22 The cells in meiosis are cells, Leydig cells are names given to the then referred to as oocytes. ovarian stromal cells which are homolo Until mid-gestation, the germ cells and gous to the Leydig cells of the testis. The granulosa cells are arranged in cortical latter are clearly derived from mesen aggregates without evident organization. chyme.21,25 Interstitial cells appear in the Toward the end of the fifth month the fetal ovary as early as the end of the third first follicles begin to appear, starting in month of gestation.23 Their capacity for the innermost region of the cortex. The and involvement in endocrine activity at process of folliculogenesis, involving the this time are unclear. In the mature ov surrounding of individual oocytes by a ary, it appears that such cells are involved unilaminar envelope of flattened, elon in androgen production. gated granulosa cells, continues over the next several months. By the early Tumors of the Ovary neonatal period, all of the oocytes present The developmental analysis described have become incorporated in follicles. previously indicates the following prin Many of the original population of oocytes cipal cell types: epithelial cells, germ in the fetal ovary degenerate prior to cells, granulosa cells and mesenchymal becoming incorporated in follicles, with (stromal) cells. As indicated in table II, only a limited number surviving the ear ovarian tumors can be grouped in a corre lier prefollicular stages. sponding manner, i.e., epithelial tumors, The final major tissue component of germ cell tumors and sex cord stromal the developing ovary, the mesenchyme, tumors. The last category represents a remains largely undifferentiated during combination of tumors derived from the fetal period. With the beginning of granulosa cells and stromal cells. The follicle growth in the latter part of gesta tion, mesenchymal or stromal cells be TABLE II come associated with the follicles. These Major Categories of Ovarian Tumors cells, located outside the basement membrane enlosing the granulosa cells C e l l T y p e Tumor Type Sub-Types and oocyte, constitute the theca interna. The stromal elements adjacent to but not Epithelium Epithelial Serous Mucinous associated with the follicle are referred to Endometrioid as the theca externa. The theca interna Clear cell Brenner tumor and granulosa cells are the cellular ele Mixed ments principally responsible for produc Undifferentiated tion of sex hormones. This activity be Germ cell Germ cell Dysgerminoma comes most evident in the reproductive Endodermal sinus tumor years when, following ovulation, the two Embryonal carcinoma cell types undergo luteinization, a proc Polyembryoma Choriocarcinoma ess whereby accumulation of organelles Teratoma associated with steroid hormone produc Mixed tion results in great cellular enlargement. Granulosa cell Sex cord Granulosa cell tumor Stromal cell stromal The coma-fibroma The hormones produced are of estrogenic Sertoli-Leydig cell and progestational type. Hormone secre tumor Gyn androb1astoma tion also takes place prior to luteinization Lipid cell tumors and in the immature ovary. 182 GONDOS frequent combination of these cell types common occurrence in the young age within a single tumor and their common group and as a rule are not associated involvement in hormone production with endocrine abnormalities. Almost support such a grouping. identical tumor types are found in the Epithelial tumors are the most frequent testis, where the special patterns of dif among both benign and malignant ova ferentiation from germ cells have been rian neoplasms. With some exceptions, classified in a similar manner.11,55 Inter most of the sub-types are cystic, have be estingly, clinical behavior and frequency nign, intermediate and malignant forms, of occurrence may be quite different and are not associated with endocrine when ovarian and testicular tumors of changes. They differ greatly in their corresponding cell type are compared.12 malignant potential and manner of Tumors of sex cord stromal type are therapy. However, all share origin from generally solid and characteristically surface epithelium. Several previous re produce endocrine symptoms as a result ports35,52 have pointed out the similarity of abnormal, excessive steroid hormone of the cellular components of various production. The symptoms may be re sub-types to cells lining structures de lated to estrogen secretion, as frequently rived from the Mullerian ducts, e.g., occurs in the granulosa cell and theca cell serous-tubal, mucinous-endocervical and tumors, or androgen secretion, as is gen endometrioid-endometrial. Evidently, erally associated with the lipid cell and formation of the Mullerian duct lining Sertoli-Leydig cell tumors. Included from epithelium adjacent to the ovarian among the lipid cell tumors are those de surface epithelium provides the latter rived from interstitial or hilar cells and with the same multipotential capacity for others whose origin is not clear but may differentiation conferred on the Mulle be from ectopic adrenocortical tissue. rian ducts. Similarly, the proliferative The occurrence of tumors in the ovary capacity of the ovarian epithelium as composed of Sertoli and Leydig cells is sociated with tumor formation may relate not surprising, since the ovary and testis to its earlier developmental ability to pro both begin from a similar undiffer liferate. entiated gonadal anlage.19 The cells of the ovary apparently retain the capacity Germ cell tumors include those de of the primitive gonad to undergo Sertoli rived directly from germ cells, dysger- cell and Leydig cell differentiation. Also minomas and those that are indirectly of noteworthy in this regard is that the vari germ cell origin. In the latter group are ous tumors in the sex cord stromal group tumors with differentiation in an extra- are potentially capable of producing a va embryonic direction—endodermal sinus riety of sex steroids, a reflection of the tumor, choriocarcinoma; those with interaction and differentiative capacity of primitive embryonic differentiation— the gonadal cell types involved in endo embryonal carcinoma, polyembryoma; crine function. Thus, for example, and those with more advanced em granulosa cell tumors may be virilizing bryonic differentiation—teratomas. In and Sertoli cell tumors may secrete estro cluded in the last group are some highly gens. Furthermore, combinations of ova specialized forms showing specific pat rian and testicular cell types may occur, terns of differentiation—carcinoid as in the gynandroblastoma. tumors, struma ovarii. Tumors in the germ cell category exhibit great variation Ultrastructure of Ovarian Tumors in clinical presentation, gross appear ance, microscopic findings, prognosis The clarification of ovarian his and response to therapy. They share a togenesis based on analysis of differentia- CLASSIFICATION OF TUMORS OF THE OVARY 183

TABLE I I I

Ultrastructure of Ovarian Tumors

Tumor Type Nucleus Cytoplasm Cell Membranes

Epithelial Large, irregular with Abundant ribosomes, rough Prominent junctional infoldings, marginated e.r., branched elongated complexes, long irregular and coarse chromatin. mitochondria with trans microvilli. verse cristae, prominent Golgi. Large, round to oval, even Scant organelles, rounded Smooth, rare loose attach chromatin pattern, large mitochondria with ment zones. nucleoli, often multiple. eccentric cristae. Sex cord Eccentric, round, si. Abundant smooth e.r., large Scattered microvilli, stromal chromatin margination, mitochondria with villiform numerous attachment zones large single nucleolus. tubular cristae, prominent occasional desmosomes, Golgi, lipid droplets gap junctions (?). tion of specific cell types is in large part these two sources, electron microscopic the result of electron microscopic studies. studies of normal ovarian development Similarly, classification of ovarian tumors and of ovarian tumors, provides the basis utilizing the histogenetic approach owes for the material summarized in table III. a great deal to ultrastructural studies. Ultrastructural characteristics of epi Correlation of information derived from thelial tumors vary somewhat depending

F i g u r e 1. Electron micrograph, mucinous cystadenocarcinoma of ovary. Note irregular nu clear configuration and numerous flocculent de posits in cytoplasm. The deposits represent mucin (x 6,200). 184 GONDOS on the type. For instance, serous tumors The description of germ cell tumor may contain apical secretory gran ultrastructure refers only to those derived ules,14,18,47 mucinous tumors (figure 1) directly from germ cells, the dysger- aggregates of mucinous material,13,33 and minomas.5,30,36,42 These tumors faithfully clear cell tumors abundant glyco reproduce the ultrastructural features of gen,40,41,50 while endometrioid car early germ cells (primitive germ cells, cinomas show large coiled nucleoli re oogonia). Particularly noteworthy are the sembling normal endometrial cells.10 homogeneous distribution of chromatin, However, the basic characteristics of epi the large, often multiple nucleoli and the thelial cells are evident in all of the differ paucity of organelles in the cytoplasm giv ent tumors (figure 2) and they can thereby ing the latter a rather watery appearance be distinguished from the other major (figure 3).22 The ultrastructural character categories. Ultrastructural studies of istics of other germ cell tumors will de Brenner tumors have supported the epi pend on the type. A particular place for the thelial origin of these neoplasms.7,9,48,54 It use of electron microscopy is in the diag has also been noted that the electron nosis of carcinoid tumors, which can be microscopic appearance of certain of the identified by the presence of neurosec surface epithelial tumors bears a striking retory granules.3,24,34,45,48,53 resemblance to surface epithelial cells in Sex cord stromal tumors frequently the fetal ovary.20 show cytologic features associated with

Figure 2. Papillary serous cystadenocarcinoma, with abundant microvilli and junctional complexes characteristic of epithelial cells (x 13,500). CLASSIFICATION OF TUMORS OF THE OVARY 185

production of steroid hormones (figure 4). some of the rare primary tumors not in Such findings as proliferation of smooth cluded in the major categories, such as endoplasmic reticulum, presence of large gonadoblastoma, 5,15 may show special mitochondria and accumulation of lipid ultrastructural features. droplets have been noted in granulosa cell Summary tum ors,6,17,37,44,57 thecom as,2 Sertoli- Leydigcell tumors4 28'29 '''9'49 and lipid cell The histogenetic approach to the clas tumors.27'31,38 These features are charac sification of ovarian tumors is supported teristic of steroid secreting cells in the and clarified by data derived from de adult and developing ovary.19 In addition, velopmental and ultrastructural studies. steroid secreting cells have varying kinds Ovarian tumors can generally be of attachment zones on their surfaces and categorized as arising from epithelial it is likely that gap junctions, which are cells, germ cells or cells of sex cord- prominent between normal steroid pro stromal origin. These tumor groups cor ducing cells,1 would also be present on respond directly with the principal cell the cell surface of corresponding types in the developing ovary: surface neoplasms. epithelial cells, germ cells, granulosa Although this discussion has dealt only cells and mesenchymal cells. Electron with primary ovarian neoplasms, it should microscopic evaluation of ovarian tumors be noted that electron microscopy might has demonstrated that special ultrastruc also be useful in identifying metastatic tural features characterize the tumors in tumors to the ovary on the basis of specific the different categories. The ultrastructu cellular characteristics.53 In addition, ral observations correlate closely with

F ig u r e 3. Germ cell tumor of seminoma- dysgerminoma type. Characteristic features are large, irregular nuc leolus, evenly distributed chromatin and paucity of cytoplasmic organelles (x 12,500). 186 GONDOS

F ig u r e 4. Granulosa cell tumor, with promi nent lipid droplets and numerous mitochondria (x 8,000).

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