Tumours of the ovary

XV. Tumours of the ovary SVEND W. NIELSEN,1 W. MISDORP,2 & KENNETH McENTEE3 Ovarian tumours are common in animals, the majority occurring in bitches and cows. The two most important germ cell tumours were dysgerminoma and teratoma; these morphologically resemble their counterparts in women, with the exception that teratomas in animals tend less to malignancy. The granulosa cell tumour is the most frequent sex cord-stromal tumour in all six species and it may contain luteinized areas or show differentiation towards a Sertoli cell pattern. The canine papillary adenoma and papillary adenocarcinoma, which are as common as granulosa tumours, have several features in common with their counterparts in women: they are of similar histological appearance, are frequently bilateral, and the adenocarcinomas have a great propensity for peritoneal implantation metastasis. Ovarian cysts are frequent in the bitch, sow, and cow and may originate from five different anatomical structures in the ovary. The classification and observations made in this study are based on approximately 200 ovarian tumours and tumour-like lesions made available by several veterinary schools in Europe, Canada, and the USA, and on 321 ovarian tumours from the New York State College of Veterinary Medicine. The histological typing is based primarily on morpho- logical features but with some consideration of histogenesis. A comparative study of embryology and tumorigenesis of both male and female gonads in several species of animal was helpful in arriving at a unified and simple scheme for the histological typ- ing. The majority of tumours fall within the follow- ing three categories: "epithelial" tumours; germ cell tumours; and sex cord-stromal tumours. In the last two groups, a histological similarity exists be- tween three types of ovarian tumour and their testicular counterparts. Among germ cell tumours, the ovarian dysgerminoma has the same histological appearance as the testicular seminoma and, among the sex cord-stromal tumours, granulosa cell tu- mours and luteomas may resemble Sertoli and Leydig tumours of the testes. The six major species of domestic animal included IProfessor of Pathology and Director of the North- eastern Research Center for Wildlife Diseases, University of Connecticut, Storrs, CT 06268, USA. ' Veterinary Pathologist, Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands. ' Professor, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. in this review have marked differences both in the overall frequency of ovarian neoplasms and in the types of tumour that occur. Some of these differ- ences may be real, whereas others are caused by an age bias owing to the fact that in only three of the species are female animals allowed to live out their normal life span (cat, dog, and horse). In some developing countries, cattle are often kept far be- yond their productive life, so that material from many aged animals should be available for future study. On the other hand, in industrialized countries cows, sows, and ewes are slaughtered as soon as their reproductive capacity begins to decline. A second bias is possibly present owing to the fact that, on a world-wide basis, more pathological examina- tions are carried out on dogs, cats, and cattle than on the other three species. The majority of tumours were found in bitches and cows. " Epithelial " and granulosa cell tumours occurred with equal frequency in the bitch, whereas granulosa cell tumours were more common in cows, cats, mares, and sows. There were considerably fewer cases available for study from the ewe than from any of the other species; those that did occur involved teratomas and granulosa cell tumours. Canine papillary adenomas and papillary adeno- carcinomas have several features in common with their counterparts in women. They have the same histological appearance, are frequently bilateral, and the adenocarcinomas of both species show great propensity for peritoneal implantation metastasis. 3431 - 203 - BULL. WORLD HEALTH ORGAN., Vol. 53, 1976 S. W. NIELSEN ET AL. HISTOLOGICAL CLASSIFICATION AND NOMENCLATURE OF TUMOURS OF THE OVARY I. " EPITHELIAL " TUMOURS A. PAPILLARY ADENOMA B. PAPILLARY ADENOCARCINOMA C. CYSTADENOMA D. UNDIFFERENTIATED CARCINOMA II. GERM CELL TUMOURS A. DYSGERMINOMA B. TERATOMA III. SEX CORD-STROMAL TUMOURS A. GRANULOSA CELL TUMOUR B. THECOMA C. LUTEOMA IV. SOFT TISSUE TUMOURS V. SECONDARY (METASTATIC) TUMOURS VI. UNCLASSIFIED TUMOURS VII. TUMOUR-LIKE LESIONS A. ADENOMATOUS HYPERPLASIA OF RETE OVARII B. PAPILLARY HYPERPLASIA OF OVARIAN SEROSA C. VASCULAR HAMARTOMA D. OVARIAN CYSTS DESCRIPTION OF TUMOURS 1. "EPITHELIAL" TUMOURS "Epithelial " tumours are believed to be derived from the ovarian surface " epithelium ", which is a coelomic mesothelium. In domestic animals they are predominantly serous and represent a rather uni- form group of tumours which, based on size, loca- tion, invasiveness, mitotic index, and morphology, have been divided into benign and malignant tu- mours, a division that is arbitrary in many cases. Tumours of this group occur frequently in the canine ovary but are comparatively rare in other species of ,domestic animal in which ovarian tumours have been studied. They correspond to the serous tumours of the human ovary. Mucin-producing tumours are -extremely rare; Brenner and clear-cell tumours and the endometrioid type of ovarian tumour that occurs in women have not been seen in domestic animals. A. Papillary adenoma (Fig. 1) These tumours frequently occur bilaterally and are usually seen on or near the ovarian surface as ,cauliflower-like lesions. Microscopically, long papil- lary fronds or shorter digitating projections are formed by small polygonal, cuboidal, or cylindrical cells, which may have cilia. The stroma is sparse and consists of a vascular framework on which the cells are positioned in a single layer. In some tumours the cells are arranged in a pseudoglandular fashion to form small, irregular cavities containing a protein- aceous fluid. B. Papillary adenocarcinoma (Fig. 2, 3) This is a very common canine ovarian tumour. It is often bilateral and has histological features similar to those of its benign counterpart, the papillary adenoma. The criteria for distinguishing between these two neoplasms are often difficult, but the following was used in this classification: (a) size of the tumour; (b) mitotic activity; (c) invasion into the ovarian stroma; and (d) extension into the ovarian bursa and the adjacent peritoneum, which frequently results in implantation metastases. The cells are cuboidal and located on delicate stromal septa, with frequent finger-like projections of cells into cyst-like microcavities containing either clear or pink protein- 204 Fig. 1. Papillary adenoma of the ovarian surface (bitch). Fig. 2 and 3. Papillary adenocarcinoma (bitch). 14 Fig. 4 and 5. Dysgerminoma showing lymphocytic infiltrate (cow). *MirsB ifitY k s 9 W '*R wg: g G Y . >S: :.: .. < . kR. Fig. 6 and 7. Dysgerminoma (bitch). Large vesicular nuclei, many mitoses, and some vacuolated histiocytes (arrows) are shown. Fig. 8-10. Teratoma with well developed sebaceous glands and cartilage, showing cysts lined by squamous cells (Fig. 9) and tall cylindrical and ciliated epithelium (Fig. 1 0). Fig. 11. Granulosa cell tumour with lobules of cells forming protein-filled microcystic spaces. Fig. 12. Granulosa cell tumour showing solid lobulated tumour with cells having an abundant eosinophilic cytoplasm. Fig. 13 and 14. Granulosa cell tumours with Call-Exner bodies, which in the small benign tumours in Fig. 13 are well differentiated and which in the malignant tumour in Fig. 14 are poorly developed. Fig. 15 and 16. Granulosa tumour with Sertoli cell pattern (bitch). Fig. 17-19. Thecoma showing mostly spindle cell pattern, with areas of luteinization in Fig. 19. Fig. 20-22. Luteomas with Leydig cell pattern. Fig. 24. Subsurface epithelial cysts (bitch). s1t e }f :s .:: * @ 1 t~ ~ ~~~i2 ,:.f 25 r Fig. 25. Cystic rete tubules (bitch). Fig. 26. Parovarian cyst (epoophoron) (cat). Fig. 23. CYstic corpus luteum (cow). OVARY aceous fluid. Rarely, the tumour contains intracell- ular mucin or shows evidence of squamous transi- tion (adenoacanthoma). C. Cystadenoma Cystadenomas, apparently originating in the rete ovarii, have been found in the dog and cat. The tumours consist of multiple, thin-walled cysts up to several centimetres across. The cysts contain a clear watery fluid and are lined by cuboidal-to-flattened epithelium. D. Undifferentiated carcinoma This category is used for carcinomas that, because of their morphology, cannot be ascribed to any known cell type. 11. GERM CELL TUMOURS The germ cell tumours have their origin in primor- dial germ cells of the ovary. Two different tumours of domestic animals belong in this group, the dysger- minoma and the teratoma. In the first, the tumour cells fail to undergo further histogenetic differentia- tion, whereas in the teratoma, various somatic differ- entiation or maturation processes occur, resulting in the formation of two or more germinal layers and the presence of skin, muscle, fat, bone, nervous tissue, etc. Embryonal carcinomas have not been reported, although features have been observed in some tumours to indicate that they occur in domes- tic animals. A. Dysgerminoma (Fig. 4-7) Dysgerminomas are most frequently encountered in bitches and cats. They can be large and are usually solid, lobulated masses with areas of haemorrhage and necrosis. Metastases occur in about 10-20%4 of cases and evidence of hormonal secretion is rare. This tumour consists of a uniform population of large round or polygonal cells with lightly-staining cytoplasm, and it bears a close resemblance to the seminoma in the male. The nuclei are large and vesicular. Coarsely clumped chromatin is evenly scattered throughout the nuclei. Mitoses and giant cells are frequent. The cells are arranged diffusely or in islands and strands. Fibrous stroma varies in amount but is usually scarce. The tumour frequently contains perivascular or nodular lymphoid aggre- gates. Necrosis is frequent. Occasional large histio- cytes with clear cytoplasm may be scattered through- out the tumour giving a so-called " starry sky" appearance. B. Teratoma (Fig. 8-10) Teratomas are rare tumours that have been seen in all six species of domestic animal. They contain a mixture of normal and neoplastic tissues from two or three germ layers, and may be solid or cystic and contain hair, skin, cartilage, bone, teeth, or muscle. They may reach large sizes and may metastasize but are less malignant than their counterparts in women. A special form of cystic teratoma is the dermoid cyst, in which one or more cystic cavities are lined by epidermis and epidermal appendages that may pro- duce sebum, sweat, and hair, which accumulate in the cystic spaces. III. SEX CORD-STROMAL TUMOURS Sex cord/stromal tumours have also been known as gonadostromal or sex cord mesenchymal tu- mours. These terms were used to indicate the origin of granulosa and Sertoli-like tumours in sex cords and of thecomas in ovarian stromal cells. The classi- fication of these tumours depends on the predomi- nant cell type and pattern. Characteristic of the sex cord-stromal tumours is the frequency with which several cell types co-exist in the same tumour. Granulosa cell tumours may have Sertoli or lutein components. Luteomas can probably develop from either theca cells or granulosa cells. Many tumours in this group have the ability to produce steroid hormones (estrogen and-or progesterone) that may result in either nymphomaniac or virilizing effects on the animal. They represent the most frequent ova- rian tumour in all the domestic species studied except bitches, in which papillary tumours are equal- ly frequent. Granulosa cell tumours are often malig- nant in the cat and bitch, with more than half producing metastases in the former and approx- imately 20%4 in the latter. Luteomas, thecomas, and granulosa cell tumours with Sertoli pattern are usu- ally benign. A. Granulosa cell tumours (Fig. 11-16) This common tumour of all domestic animals is seen as a unilateral, often huge, lobulated, firm mass with a yellow-white cut surface, and often has cysts, haemorrhage, and/or necrosis. It consists of a uniform population of cells resembling normal gran- ulosa cells with lightly-staining cytoplasm and poorly delineated cell borders, and with eccentric round or ovoid nuclei having few or no mitoses. The cells may be arranged: (a) in a diffuse sarcomatous pattern; (b) in long strands or islands surrounded by septa of 15 213 214 S. W. NIELSEN ET AL. connective tissue; or (c) in a follicular pattern in which cells may be grouped around clear spaces or foci of proteinaceous material, resembling the Call- Exner bodies of granulosa cell tumours in man. These bodies occur particularly in small benign tumours. Granulosa cells may show differentiation in vari- ous directions and have areas with a Sertoli cell pattern or areas showing luteinization. Granulosa cell tumours of cats are usually malignant and have often shown clinical evidence of hyperestrogenism. In the bitch, cystic endometrial hyperplasia has been encountered. Some granulosa cell tumours have a pattern re- sembling that of Sertoli cell tumours of the testis and, since several transition states exist, it may be difficult to distinguish these from pure granulosa cell tu- mours. The Sertoli-like tumour consists of clear, fusiform, or tall triangular cells on basement mem- branes and arranged in a columnar or tubular pattern. The cytoplasm may contain lipid droplets and its borders are often indistinct. The nuclei are small and hypochromatic, and contain few or no mitotic figures. These tumours commonly lack detectable hormone production but they have the potential to become either estrogenic or androgenic. B. Thecoma (Fig. 17-19) This tumour consists of spindle- or star-shaped cells with poorly defined borders, often arranged in interlacing fascicles. The nuclei vary from ovoid to long or fusiform, and the cytoplasm is pale and foamy and may contain lipid droplets. This tumour is usually benign, and grows by expansion without meta- stasis. It may produce estrogen, especially in cows. C. Luteoma (Fig. 20-22) Luteomas are rare, but have been observed in cows, bitches, and cats. They can be large. The tumour is yellow-brown and consists microscopically of a uniform population of large, luteinized cells similar to corpus luteum cells. Two variations of luteoma exist in domestic animals: lipid cell tumour and Leydig-like tumour. The lipid cell tumour has been recognized in the cat. It consists of a uniform population of large, lipid-filled cells resembling those of the adrenal cortex, with small nuclei and well delineated borders. It has not been established whether the tumour arises from ovarian stroma cells or from accessory adrenal cortical tissue, which is occasionally found in the cat. A few cases of Leydig-like tumours have been found in domestic animals. The cells are uniform in size and shape, are polygonal, have well delineated borders, and have dark, granular cytoplasm with many lipid-filled vacuoles. The nuclei are small, ovoid, and hyperchromatic with small eccentric nucleoli and few mitoses. The fibrous stroma is usually delicate and contains many small vessels; in some tumours, it becomes thick and hyalinized and has a tendency to form the tumour cells into a pseudolobulated pattern. The tumour may have its cytoplasm completely filled with lipid and it may have an androgenic effect on the animal. IV. SOFT TISSUE TUMOURS These tumours have the same appearance as soft tissue tumours originating elsewhere in the body and should be classified accordingly.a The most common are vascular, fibrous tissue, and smooth muscle tumours. V. SECONDARY (METASTATIC) TUMOURS Metastases to the ovary are rare in domestic animals. The most frequently observed tumours with ovarian metastases are mammary, intestinal, and pancreatic carcinomas of the bitch and cat, uterine and intestinal carcinomas of cows, and lymphosar- comas of cats, bitches, sows, cows, and mares., VI. UNCLASSIFIED TUMOURS This term is used for benign and malignant tu- mours that cannot be placed in any of the above categories. VII. TUMOUR-LIKE LESIONS A. Adenomatous hyperplasia of rete ovarii This is a rare lesion, seen mostly in bitches, in which epithelial strands form gland-like structures in the centre of the ovary or below the capsule. Its significance as a possible preneoplastic lesion and its possible functional potential are unknown. B. Papillary hyperplasia of ovarian serosa Prolonged estrogenic stimulation induces papillary a For a classification of tumours of the soft (mesen- chymal) tissues see WEISS, E. Bulletin of the World Health Organization, 50: 101-110 (1974). b See also JARRErr, W. F. & MACKEY, L. J. Bull- etin of the World Health Organization, 50: 21-34 (1974). OVARY proliferation of the ovarian serosa; the lesion is usually bilateral. C. Vascular hamartoma Congenital anomalies of ovarian vessels are rare, but may occur in cows, sows, and bitches. They are seen as localized areas of tortuous arteries and veins surrounded by fibrous tissue. Thrombosis of the involved vessels is frequent and is usually followed by marked scarring and haemosiderosis. D. Ovarian cysts Cyst formation is common in the ovary of domes- tic animals, particularly in the bitch, sow, and cow. The cysts can develop from several different ana- tomical structures and histogenetic determination can be difficult, requiring multiple sectioning of the cyst wall followed by careful microscopic studies. Large and old cysts with thin atrophic walls are particularly difficult in this respect. The term " simple cyst " should be used if careful study of the cyst wall reveals only fibrous tissue. Graafian follicle cysts, which may be solitary or multiple, are the most frequent type in most species. They are particularly common and of great impor- tance in cows and sows, where signs of nymphoma- nia may be present. They have their origin in Graafian follicles that fail to rupture or to undergo atresia. They contain clear fluid and their size can vary a great deal. Small cysts may have layers of granulosa cells in the wall; larger ones may have a single layer of either cuboidal or flat cells, and some part of the cyst may have no recognizable granulosa cells. Luteinized cysts occur in mature follicles that fail to ovulate and undergo luteinization of the theca interna. A complete rim of luteal tissue lines the cyst. There is no ovulation bulge on the surface of the ovary and the cystic cavity is spherical. Cystic corpus luteum (Fig. 23). Ovulation occurs, but the area of rupture of the follicle closes prema- turely and traps fluid in the centre of the corpus luteum. An ovulation bulge is present and the cyst has an irregular contour. Subsurface epithelial (germinal) cysts (Fig. 24) are common in mares and aged bitches but are probably of greatest importance in the mare, where the ovary may be transformed into a honeycombed mass. They consist of many small inclusion cysts located in the ovarian cortex, which are probably of peritoneal and oviductal origin and are lined by cuboid or columnar epithelium. Cystic rete tubules (Fig. 25) occur in most species of domestic animal but most frequently in the bitch and cat. The rete tubules are located in the hilar portion of the ovary. As cystic distention of the rete tubules increases, the cortex of the ovary becomes compressed. The absence of smooth muscle in the cyst wall is a useful guide for distinguishing these cysts from cystic mesonephric tubules, which are surrounded by muscle. Parovarian cysts (Fig. 26) are single or multiple, measure from a few millimetres to a few centimetres across, and are present in the mesovarian tissue or in the mesosalpinx. The cysts originate from meso- nephric tubules, have clear fluid, and are lined by cuboidal cells. Smooth muscle surrounds the cyst. The anterior mesonephric tubules (epoophoron) are the mesonephric remnants that usually become cystic. These structures are located in the lateral pole of the ovary adjacent to the fimbriated portion of the oviduct. In the mare, the cysts may be 6-8 cm in diameter. 215