The ovaries – applied pathology

Dr Bindu K  BHMS,MD(Hom)
Each ovary measures about 35mm in length, 25mm in width and 18 mm in thickness.The ovary is almond- shaped, pearly gray due to a compact tunica albugenea and the surface is slightly corrugated. Before puberty ovaries are small. After menopause they atrophy and become shrunken and the grooves and furrows on the surface become well marked. The ovary is attached to the back of the broad ligament by a thin mesentry, the mesovarium. Laterally the ovary is related to the fossa below the bifurcation of the common iliac artery and ureter. Medially it is close to the fimbriae of the fallopian tube, which is stretch over it around ovulation. It is attached to the cornua of the uterus by the ovarian ligament. The infundibulo pelvic ligament is the outer border of the broad ligament and contains the ovarian vessels, nerves and lymphatics. The ovaries are not normally palpable during bimanual examination.

The ovary of the new born:
At term the foetal ovary measures 10 – 16 mm in length and it is situated at the level of the brim of the pelvis. If a section is taken through the ovary and examined histologically the following divisions can be recognized.
1. surface epithelium : – this is a single layer of cuboidal cells, which gives rise later to surface epithelium of the adult ovary, and which is morphologically continuous with the mesothelium of the peritoneum.
2. The sub epithelial connective tissue layer :- This layer gives rise to the tunica albuginea of the adult ovary and to the basement membrane beneath the surface epithelium.
3. The parenchymatous zone :- This area is the most important, as it contains the sex cells. It can be sub divided into three zones.
a) Immediately beneath the surface epithelium the sex cells are still grouped together in bunches to form nests.
b) Below this area the sex cells take the form of primordial follicles and are packed together without orderly arrangement.
c) In the deepest part of the parenchymatous zone, developing follicles can be seen.
4. The zona vasculosa :- This area contains the blood vessels which pass into the ovary from the mesovarium. It constitutes the medulla of the ovary, the other layers forming the cortex.

Malignant tumours of the genital tract account for one fifth of all cancers in women. Although the incidence of the ovarian cancer is lower than that of cervix and uterine endometrium, the mortality from ovarian carcinoma exceeds the combined mortality from cervical and endometrial carcinoma in the metropolitan cities of India. However in the country as a whole, carcinoma cervix continues to hold the premier position amongst all gynaecological cancers.
Ovarian tumour is not a single entity but a complex wide spectrum of diseases, involving a variety of histological tissues ranging from epithelial tissues, connective tissues, specialised hormone secreting tissues to germinal and embryonal tissues.
Unfortunately patients with ovarian tumours are often non specific, hence by the time ovarian malignancy is diagnosed, about two thirds of these have already become far advanced and the prognosis in such cases continues to be unfavourable. A high index of clinical suspicion and the assiduous skill with which the clinician pursues the diagnosis will go a long way in reducing the ravages from ovarian cancer.

Epidemiology :
Incidence :ovarian cancers account for about 5% of all gynaecological cancers in India, as against 15% observed in the west.
Racial factors:Higher among in the white population,as compared to the negroes in USA.I ncidence of ovarian carcinoma among Hispanics.and Asian women is half to one third of that observed among Caucasians.

Economic status
The incidence is higher among women from affluent classes, and the highly industrialized countries. This has been attributed to the higher animal fat content in their diets.

Environmental factors
Industrial pollutants have been implicated and chemical irritants like asbetos and talc have been identified to cause ovarian neoplastic disease.

Clinical observations
Ovarian cancer is associated with nulliparity, infertility, marked premenstrual tension,abnormal breast swellings, marked dysmenorrhoea, pelvic irradiation, and history of rubella and mumps.
It is well known that repeated gonadotropic stimulation of the ovaries and uninterrupted cycles of ovulation predisposes to cancer of ovary. Factors suppressing ovulation such as pregnancies , lactation , oral contraceptives , are known to be protective.

High risk factors:
Recognition of high risk factors include
1)family history of ovarian cancer
2) history of ovarian or breast neoplasm
3)history of abnormal ovarian function
4)presence of ovarian neoplasm in adolescent and perimenopausal women .
5)presence of a palpable enlarged ovary in post-menopausal is suspicious of ovarian cancer.

[major group]
A.Serous tumours.
B.Mucinous tumours
C.Endometrial tumours
D.Clear cell[mesonephroid tumours]
E,Brenner tumours
F.Mixed epithelial tumours.
G.Undifferentiated carcinoma.
H.Unclassified epithelial tumours.

A.Granulosa- stromal cell tumours.
B.Androblastomas: sertoli – Leydig cell tumours.


B.Endodermal sinus tumour.
C.Embryonal carcinoma.
G.Mixed forms.

B.Mixed with dysgerminoma or other germ cell tumours.





Histologically these tumours are intermediate between truly benign neoplasms and those with invasive characteristics.They account for 10 – 20% of all epithelial tumours.
Characteristics of Borderline Ovarian Tumour [Grade – o]
1.Patients have a high survival rate.
2.Tumours run a typical indolent course.
3.Spontaneous regression of peritoneal implant is known.
4.Diagnosis must be based exclusively on the examination of the ovarian tumour.
5.Multiple sections must be examined to exclude invasion.

1.Tumours of the surface epithelium.
Epithelial ovarian neoplasms arise from the mesoepithelial cells on the ovarian surface.They recapitulate the histology of the female genital tract.They constitute about 80% of all ovarian cancers.The most common histologic type is the papillary serous cystadenocarcinoma accounting for almost 50% of all epithelial tumours.Mucinous cystadeno carcinomas account for 12-15%,clear cell and endometrioid combined about 10% and the unspecified types,25-27% of cases.

a)Serous cystadenoma and cystadenocarcinoma.
These are amongst the commonest of cystic ovarian neoplasms, accounting for about 30% of all ovarian tumours.Out of these 60% are benign,15% borderline and 25% are malignant.
Serous cystadenomas occur in the third,fourth and fifth decades of life;malignant cystadenocarcinomas tend to occur more frequently with advancing age.In about half of the cases they are bilateral.apillary excrescences may be seen on the surface and with in the loculi.In cases of serous cystadenocarcinoma, spread to the peritoneal surface is known.Histologically the benign variety shows the cystic spaces, and lining of the tumour toconsist of tall columnar ciliated epithelium resembling the endosalpinx.The loculi contain a serous straw coloured fluid,which may be blood stained when malignant transformation occurs.Unless cellular atypia exceeds four cell layer thickness or stromal invasion, the tumour is classified as borderline.

b) Mucinous Tumours
These tumours are lined by epithelium resembling the endocervix.Formerly they were reffered to as pseudomucinous, as their contents are not chemically true mucin.The tumours are not infrequent, can grow to a large size, are often pedunculated, and may be associated with a dermoid cyst or a Brenner tumour.They are usually unilateral,only 5% are bilateral.The tumours are essentially benign, only 5-10% are malignant and 10-15% are of low maqlignant potential.
Mucinous tumours occur in middle aged woman.They have a glistening surface, and the cut section reveals loculi filled with mucinous contents.If the tumour ruptures, it may lead to formation of pseudo myxoma pritonei and show extensive adhesions.This condition may be associated with a mucocele of the appendix.

c) Endometrial tumour :
These tumours account for about 20% of all ovarian cancers. They are lined by a glandular epithelium resembling the endometrium. The tumours are of moderate size and are essentially solid with cystic areas in between. In 15% of cases ovarian endometriosis may co-exist.

d) Clear cell carcinoma :
it is an uncommon tumor of the ovary. It is composed of large cuboidal epithelial cells with abundant clear cytoplasm characteristically forming tubules, glands, small cystic spaces lined by clear cells showing large dark nuclei protruding into the lumen (hobnail cells).

e) Brenner tumour :
This is a solid tumour accounting for about 1 – 2 % of all ovarian neoplasms. On gross appearance, it resembles a fibroma of the ovary, its cut surface appears gritty and yellowish gray. It is generally unilateral, small to moderate size, essentially benign and having no endocrine function.
The tumour is generally seen in women around the age of menopause and causes post menopausal bleeding. Occasionally it may be associated with ascites and hydrothorax – pseudo Meig’s syndrome.
Histologically the tumour shows a background of fibrous tissue, interposed within it are nests of transitional epithelium (Walthad cell nests). These cells demonstrate a longitudinal groove resembling puffed wheat. This tumour may be associated with mucinous adenoma of the ovary.

Spread of epithelial tumours of the ovary
These tumours extend through the capsule and may be seeded on to the peritoneal surface, omentum, intestinal viscera and by trans-coelomic spread reach the subdiaphragmatic space. The ascitic fluid shows presence of clusters of tumour cells. the tumour cells may spread to the lymph nodes and metastasize to the liver, lungs, gastrointestinal tract and other areas. In over half of the cases that come to light, the opposite ovary is involved.

These accounts for about 15 – 20% of all ovarian tumours. The majority of tumours in this group are the benign cystic teratomas (about 90%), also called dermoids. Below the age of 20years, 60% of all ovarian tumours belong to this group and are almost invariably malignant growths.

a) Teratoma : All germ cell tumours show diffenciation principally along embryonic rather than extraembryonic pathways. These are grouped together as teratomas and divided into 3 categories.
i) Benign or mature eg: dermoid cyst.
ii) Immature (essentially malignant) eg: solid teratoma
iii) Monodermal or highly specialized eg: Struma ovarrii.
i) Dermoid cyst :- of all cystic tumours of the ovary, 5 – 10% are dermoids. Dermoid cysts are usually unilocular swelling with smooth surfaces, seldom attaining more than 15cm in diameter.

They contain sebaceous material and hair and the wall is lined in part by squamous epithelium which contains hair follicle and sebaceous glands. Teeth, bone, cartilage, thyroid tissue and bronchial mucous membrane are often found in the wall. Sometimes, the sebaceous material may be collected together in the form of small balls, and as many as 1000 sebaceous balls of this type have been counted in a dermoid cyst. The inner surface of the dermoid cyst is always irregular and contains what is called a ‘focus’ or ‘embryonic node’ from which hairs project and in which the teeth and bone are usually found. The nomenclature ‘dermoid cyst’ is inaccurate for in addition to ectodermal tissues, tissues from both the mesoderm and endoderm are usually found in some part of the tumour. Moreover, though squamous epithelium usually lines the cyst, columnar and transitional types are also found. It is extremely rare for pancreas or liver tissues and intestinal mucous membrane to be found in the wall of a dermoid. Dermoid cysts frequently arise in association with mucinous cystadenomas to form a combined tumour, part of which consists of a dermoid cyst while the rest has the characteristic structure of a mucinous cystadenoma. Perhaps as many as 40% of dermoid cysts are combined tumour of this kind. This association suggests that the origin of the two forms of ovarian tumours is related.

Multiple dermoid cyst in the same ovary are well recognized and it is often quite usual to find 2 -3 separate dermoids, extra – ovarian dermoid cysts arise occasionally in the lumbar region, in the uterovescical septum, in the parasacral region and in the recto vaginal septum. The combined tumours tends to arise in patients between the ages of 20 and 30, while simple dermoid cysts have a maximum age incidence between 40 and 50. the tumours may, however arise at any age. They are not infrequently bilateral, 12 – 15%.
Dermoid cysts are innocent ovarian tumours but epidermoid carcinoma occurs in 1.7% of all dermoids and sarcomatous changes have also been described. Usually a squamous celled carcinoma develops from the ectodermal tissues but mammary carcinomas and malignant thyroid tumours have been described.

ii) Solid teratoma of the ovary :- These tumours are very rare. They are mainly solid and cut surface has a peculiar trabeculated appearance. Almost invariably large loculi are found beneath the capsule. The solid part of the tumour contains cartilage and bone, while hair and sebaceous material are found in the cystic spaces. The solid area also contains plain muscle, brain tissue, glia, piamater and intestinal mucous membrane. The attempted formation of rudimentary eye has been described and even recognizable pattern of a foetus has been simulated. The so-called embryoma. Most solid teratomas of the ovary are malignant tumours because of sarcomatous change, but a fair proportion, probably about 20% are innocent.

iii) Struma ovarii :- This tumour consists of thyroid tissue similar to that of a thyroid adenoma. The tumour is solid, consisting almost entirely of thyroid tissue and should be clearly distinguished from a dermoid cyst with thyroid tissue in its wall. To the naked eye the tumour resembles a small pseudo-mucinous cystadenoma, but the material contained in the vesicle is colloid and gives reactions for iodine. Most of the tumours have been recorded. The histogenesis is supposedly a dermoid in which the thyroid tissue preponderates at the expense of other elements.
Carcinoid tumours of ovary :- it may be primary or metastatic tumour of the ovary, known as argentaffinoma. It occurs as a malignant change in a benign dermoid cyst and presents as a solid yellow tumour with the characteristic histological property of reducing silver salts being derived from the specialized Kultschitzky cells of the intestine. It produces 5-hydroxy tryptamine which causes attacks of flushing and cyanosis.

b) Endodermal sinus (yolk sac tumour) :
It is a rare tumour and the second most common of germ cell origin. It is thought to originate from a multipotential embryonal tissue as a result of selective defferenciation of yolk sac structures. This explains why the tumour is rich in alpha-fetoproteins and alpha-1- antitrypsin. Histologically, the tumour characteristically presents with pappillary projections composed of a central core of blood vessels enveloped by immature epithelium. Conspicuous intracellular and extracellular hyaline droplets present in all tumours. The alpha- fetoprotein contents can generally be stained by immuoperoxidase techniques. Most of these patients are children or young women, presenting with abdominal pain and a pelvic mass. The tumours are known to grow rapidly.

c) Choriocarcinoma:
Rarely seen in a pure form. Generally it is a part of a mixed germ cell tumour. Its origin as a teratoma can be confirmed in pre-pubertal girls, when the possibility of its gestational origin can be definitely excluded. The tumours are often very vascular.
Histologically they show a dimorphic population of syncytio-trophoblast and cytotrophoblasts. They secrete large quantities of human chorionic gonadotrophin which forms an ideal tumour marker in diagnosis and management of the tumour. The tumours are highly malignant, before they are recognised and diagnosed; they generally have metastasized by the blood stream to the lungs, brain, bones, and other viscera.

d) Embryonal cell carcinoma :
It is a rare tumour accounting for about 5% of all germ cell tumour. It generally occurs in prepubertal girls. It elaborates both alpha-fetoproteins and chorionic gonadotropins. It is known to be associated with the symptoms of precocious puberty and menstrual irregularities.

e) Dysgerminoma :
This tumour corresponds exactly to the seminoma of the testis and its incidence is one third that of the granulosa cell tumour. It usually arises in young women or in children, with an average incidence at the age of 20. the tumour is solid with a peculiar elastic rubbery consistence with a smooth, firm capsule. The cut surface is yellow or grey with areas of degeneration and haemorrhage. The size is variable, usually moderate; thogh large tumours have been described. They are usually unilateral, occasionally undergo torsion and may like all solid tumours, be associated with ascites. The tumour consists of large cells arranged in bunches or alveoli. The lumphocytes and giant cells are always found amongst the tumour cells. This appearance of large dark-staining nuclii with clear almost translucent cytoplasm and lymphocytic infiltration of the fibrous septa, is immeadiately diagnostic. The tumour is nutral and does not secrete either male or female sex hormones. A number of patients with a dysgeminoma of the ovary have been reported to show genital abnormality, with hypoplsia or absence of some part of the genital tract. It has been repoerted in pseudo-hermaphrodites. Such congenital abnormalities are not caused by the dysgeminoma and its removal has no beneficial effect upon them. The malignancy of dysgeminoma is similar to that of granulosa cell tumour and depends largely on the findings at laparotomy.

i) A unilateral tumour confined to one ovary is relatively benign.
ii) The presence of active invasion of pelvic viscera is naturally of grave importance though not hopless.
iii) The presence of extra pelvic metastases in the general peritoneal cavity and glands, omentum or liver renders the outlook hopeless. A fair estimate of the malignancy is 33 – 50% .

f) Mixed germ cell tumour :
These tumours contain two or more recognizable germ cell entities, eg: combination of dysgeminoma teratoma, endodermal sinus tumours and choriocarcinoma.

III. Sex cord stromal tumours :
These tumours originate either from the sex cord of the embryonic gonad (before the differenciation of the gonadal mesenchyme into male or female) or from the stroma of the ovary. Since theca cells are the source of ovarian steroids, many of these are functional and exert feminising effects. The embryonic sex cords may differenciate along the male line, giving rise to sertoli or Leydig cell tumours called androblastomas. These tumours are also referred to as mesenchymomas.

Tumours arising from primitive mesenchyme (mesenchymoma)
A) Feminising functioning mesenchymoma
a) Granulosa cell tumour:-are composed of cells closely resembling the granulosa cells of the graffian follicle .
clinical features:common tumours represent 10 % of all solid malignant ovarian tumours. Thgey can occur at any age and before and after menopause. The main clinical features depend upon the oestrogenic activity of the tumour and only the larger ones cause pain and abdominal swelling. Feminising tumours secreate oestrogen which the tumour has metabolised from progestrogen in the same manner as the normal ovary
i) when occuring before the puberty,a precocious puberty results with secondary sexual characteristics, hypertrophy of breast,external genetalia,pubic hair and myohyperplasia of the uterus. The endometrium shows an oestrogenic anovulatory pattern. Removal of the tumour causes regression of all these manifestations.

ii) when occuring in adult life, the oestrogenic effect is less remarkable than in the prepubertal stage. There is no change in rthe secondary sexual characteristics since these are already established. The effect on the endometrium is that of hyper oestrogenism in general,ie, an exaggerated proliferative pattern with cystic glandular hyperplasia. Thus there may be a super threshold level of blood oestrogen , leading to amenorrhea followed by prolonged bleeding. In fact ,the behaviour of the endometrium closely resembles that of metropathia haemorrhagica, another condition in which hyper oestrogenism occurs.

iii) In the post menopausal patients, the most remarkable feature is post menopausal bleeding. The secondary sexual characteristics are less affected though hypertrophy of the breast is sometimes seen. The uterus shows myohyperplasia and cyastic glandular hyperplasia exactly as in metropathia. Removal of the tumour causes a regression of all these symptoms and sometimes the additional symptoms of a second menopause.

Macroscopic features
The tumours vary in size from tiny to gross, the average being 10 cm in diameter. The shape is oval and consistence soft.T he cut surface is reticular or trabeculated with areas of interstitial haemorrhage and it often shows yellow areas.The outer surface is smooth and often lobulated.
The cells are arranged either in cords or trabeculae , and are often surrounded by structureless hyaline tissue, which resembles the glass membrane of an atretic follicle. Small call-exner bodies can usually be found in some part or other of the tumour. It will be remembered that these small cyst like spaces are a characteristic feature of graffian follicle.

Three histologic types of granulosa cell tumours are identified
a) An early undifferentiated form which consists of a solid mass of granulosa cells .
b) A trabecular form
c) A folliculoid type in which the granulosa cells are grouped around spaces filled with secretion.

Most granulosa cell tumours are encapsulated and appear to be clinically benign. This appearance of the gross specimen and the histological picture may both be misleading as judged by the subsequent recurrence of the tumour.This recurrence may be delayed for many years,long after the arbitrary five year period has passed.50% of granulosa cell tumours are malignant [A well differentiated folliculoid pattern is 10% malignant while an anaplastic, almost sarcomatous appearance is 65% malignant.]
The metastases are interesting, because the opposite ovary first becomes involved, then metastases develop in the lubar region and finally, secondary deposits become scattered in the mesentry, the liver and mediastinum.

Association Of Carcinoma Of The Endometrium With Granulosa Cell Tumours :- There is strong evidence that carcinoma of the endometrium may be associated with feminizing tumours of the ovary in post-menopausal women.It has been estimated that in 1/5th of oestrogenic ovarian tumours, an endometrial cancer will develop.A theca cell tumour is four times more commonly associated with endometrial cancer than the granulosa tumour.

b) Theca cell tumour
Seen rarely and usually arises after the menopause.It is nearly always unilateral and forms a solid mass.The cut surface is often yellow in colour and if stained selectively, lipoid material is characteristically present.The tumour consists of spindle-shaped cells reminiscent of an ovarian fibroma together with fatladen polyhedral cells which resemble the theca lutein cells of the Graffian follicle.The tumour is intensely oestrogenic and causes post menopausal bleeding. It is usually innocent, but malignant forms have been described.It has been shown recently that both granulosa cell tumours and theca cell tumours may show luetinization of their cells,with the result that progestrone is secreted and secretory hypertrophy can be demonstrated in the endometrium.

B. Viriilizing mesenchymoma [And other virilising tumours of the ovary]
a) Arrhenoblastoma.
Rare tumours which secrete androgens which secrete androgens which cause defeminization followed by masculinization.Women in the child bearing age may complain of altered body contours, flattening of breasts, scanty and irregular menstruation ending ultimately in amenorrhoea.Later signs of masculinization like increased hair growth on the face(hirsuitism) appear.Coarsening of the features, enlargement of the clitoris and even breaking of the voice may occur.Removal of the tumour can reverse the above features except voice change.Gross appearance is like that of other mesenchymomas.Generally only one ovary is affected.Its association with pregnancy has been reportede.The incidence of malignant transformation is rated to be higher than with feminizing tumours.
Histologically, the tumour reveals all grades of differentiation from the testicular adenoma showing perfectly formed seminiferous tubules to a sarcomatous anaplastic variety, wherein lipoid containing cells are seen.The diagnosis is usually made on the basis of the endocrine behaviour of the tumour.

b) Adrenal cortical tumours of the ovary:
These tumours have some resemblance to adrenal cortex when examined microscopically and have been called hypernephroma,masculinovoblastoma ,virilizing luteoma or clear celled tumour.Very rare tumours which are sometimes masculinizing.

c) Hilus cell tumour:
Rare.Arising from cells in the ovarian hilum especially in women past the menopause.One interesting feature of the hilus cell tumour is the presence of Reinke crystals in the cells, a distinguishing feature of the Leydig or interstitial cells of the testis.

d) Gynandroblastoma:
This tumour has the combined characteristic of the granulosa cell tumour and an arrhenoblastoma.

IV. Tumours arising from the connective tissue of the ovary.

a) Ovarian fibroma:
Of the innocent connective tissue tumours of the ovary,fibromas are the most common and comprises about 3% of ovarian neoplasms.Has no particular age incidence.The tumour is oval in shape with a smooth surface and large veins which are always noticebale in the capsule.The consistence is firm and harder than that of uterine myoma .The tumour frequntly undergoes degeneration so that cystic spaces are found towards the centre and calcareous degeneration is not uncommon. The tumours are usually about 15cm in diameter but they sometimes become much larger than this and weigh as much as 25kg.Torsion may occur with the larger tumours.Microscopical examination shows the tumour to be composed of a net work of spindle shaped cells which closely resemble the spindle cells of the ovarian cortex.The cellular pattern is strikingly uniform and there is no attempt at nuclear activity.The combination of an ovarian fibroma with ascites and hydrothorax, is referred to as meig’s syndrome.

Three types of fibromas are recognized.
1) surface papilloma on the ovary
2) small encapsulated fibroma ; Normal ovarian tissue can be seen at one pole of ovary.
3) fibroma replaces the ovary completely.

Rare.Many tumours labelled as sarcomas have been misdiagnosed histologically and were in reality granulose cell tumours or anaplastic carcinomas.Sarcomas arise most frequently after the menopause,particularly in multiparae.They give rise to multiple metases.Rhabdomyosarcoma of the ovary has been described.This is probably more accurately to be considered as one form of mixed mesodermal tumour.

Ovarian metastases are commonly from primary growths of the gastrointestinal tract,notably the pylorus,colon and rarely, the small bowel;they occasionally occur from the gall bladder and pancreas.They may also occur in late carcinoma of the breast,as seen in 30% of all autopsy material from breast cancer.Carcinomas of the corpus [10%] and cervix [1%] also metastasize to the ovary owing to the close relationship of their lymphatic drainage. Carcinomas of the corpus is 10 times more likely to metastasize to the ovary than that of the cervix.

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