Histomorphological Patterns of Ovarian Neoplasms with Special Emphasis on Estrogen Receptor & Progesterone Receptor Expression in Surface Epithelial Tumours

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DISSERTATION ON

HISTOMORPHOLOGICAL PATTERNS OF OVARIAN NEOPLASMS WITH SPECIAL EMPHASIS ON ESTROGEN RECEPTOR & PROGESTERONE RECEPTOR EXPRESSION IN SURFACE EPITHELIAL TUMOURS

Dissertation submitted to THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY in partial fulfilment of the requirement for the award of degree of

MD BRANCH – III PATHOLOGY

KARPAGA VINAYAGA INSTITUTE OF MEDICAL SCIENCES, MADURANTAGAM

THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY, CHENNAI, TAMILNADU.

APRIL 2016

DISSERTATION ON

HISTOMORPHOLOGICAL PATTERNS OF OVARIAN NEOPLASMS WITH SPECIAL EMPHASIS ON ESTROGEN RECEPTOR & PROGESTERONE RECEPTOR EXPRESSION IN SURFACE EPITHELIAL TUMOURS

Dissertation submitted to THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY in partial fulfilment of the requirement for the award of degree of

MD BRANCH – III PATHOLOGY

KARPAGA VINAYAGA INSTITUTE OF MEDICAL SCIENCES, MADHURANTHAGAM

THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY, CHENNAI, TAMILNADU.

APRIL 2016 CERTIFICATE

Certified that this dissertation entitled

“HISTOMORPHOLOGICAL PATTERNS OF OVARIAN

NEOPLASMS WITH SPECIAL EMPHASIS ON ESTROGEN

RECEPTOR & PROGESTERONE RECEPTOR EXPRESSION IN

SURFACE EPITHELIAL TUMOURS” is a bona fide work done by

Dr. R.Madhumittha, Post graduate student, KarpagaVinayaga Institute

of Medical Sciences, Madhuranthagam, during the academic year 2013 –

2016.

Dr.A.R. Chakravarthy MBBS, MD, DGO, Prof.Dr. T.Chitra, M.D., Dean, Hod&Professor of Pathology, Karpaga Vinayaga Institute of Medical KarpagaVinayaga Institute of Medical Sciences, Sciences, Madhuranthagam Tk, MadhuranthagamTk, Kancheepuram Dist-603308, Kancheepuram Dist-603308, Tamilnadu, India. Tamilnadu, India.

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled

“HISTOMORPHOLOGICAL PATTERNS OF OVARIAN

NEOPLASMS WITH SPECIAL EMPHASIS ON ESTROGEN

RECEPTOR & PROGESTERONE RECEPTOR EXPRESSION IN

SURFACE EPITHELIAL TUMOURS” submitted by me for the

Degree of M.D is the record work carried out by me during the period from August 2013 to September 2015 under the guidance of

Dr.A.B.Harke, Professor, Department of Pathology, Karpaga Vinayaga

Institute of Medical Sciences and has not formed the basis of any degree, diploma or fellowship titles in this or any other University or other similar Institution of Higher learning.

Place: Dr. R. Madhumittha,

Date: Post-graduate student in Pathology.

Signature of the guide Dr A.B.Harke, Professor, Department of Pathology, Karpaga Vinayaga Institute of Medical Sciences and Research Centre, Madhuranthagam

ACKNOWLEDGEMENT I feel words can‘t express my gratitude for all those lovely people who have always been there for me and have stood beside me in all the phases of my life. I express my very sincere thanks to Dr. R. ANNAMALAI, Managing Director, Karpaga Vinayaga Institute of Medical Sciences for his kind-heartedness & providing me with all the available facilities to carry out this thesis work. I could never thank enough Dr. A.R. CHAKRAVARTHY, Dean Karpaga Vinayaga Institute of Medical Sciences for his student friendly nature, support and encouragement. I would like to express my sincere thanks to my guide Dr.A.B.HARKE, Professor, Department of pathology, Karpaga Vinayaga Institute of Medical Sciences, for being a tremendous mentor and letting me have a glimpse of his unsurpassed knowledge. I would like to thank him for patiently correcting my writing and also motivating me throughout the writing of this thesis. His remarkable patience and calmness have been invaluable in making me understand the basics of this subject. I am grateful to thank Dr.T.CHITRA, Professor and Head of Department of Pathology, Karpaga Vinayaga Institute of Medical Sciences, for her constant encouragement and support, extended to me throughout the course. With her friendly attitude creates a comfortable atmosphere in the department. I would like express my gratitude to Dr.E.SARAVANAN, Associate Professor, and Department of Pathology for his encouragement and caring attention. I would like to use this opportunity to also thank Dr. S. KARTHICK, Dr. B. SHOBANA and Dr.R.VIMAL, Assistant Professor of Pathology Karpaga Vinayaga Institute of Medical Sciences for their advices and helping me at times when I needed them the most. In the three years of my post graduation, I have completely understood the meaning of famous saying ―A Friend in need is a Friend indeed‖. I would like to thank my colleague and my juniors for their extreme warmth and care towards me and the infinite support they have given me. A very special thanks to all the lab technicians Mrs. DAISY, Mrs.JAYANTHI, Miss. DARWIN and other non teaching staffs for providing me with everything essential for my thesis and without which it would have remainded incomplete. I would like to thank Obstetrics & Gynaecology department for their help & constant support. Last but not least, I would like to convey my regards to my Dad who is my role model & hero; my Mom who is seeing me from heaven and my Brother and Sister for their blessings and warmth for that I have achieved what I wanted. I would like to end the acknowledgement with thanks to the almighty God.

CONTENTS

Sl.No CONTENTS Page No

1 Introduction ………………………….… 1

2 Aim and objectives …………………….. 3

3 Review of literature ……………………. 4

4 Methodology ………………..………….. 48

5 Results ………………………………… 49

6 Discussion ……………………………… 80

7 Conclusion ……………………………... 94

8 Annexures

9 Bibliography

Introduction

The ovaries are a couple of tiny organs in the female pelvic cavity situated on both the sides of the uterus, suspended in the pelvic cavity by the mesovarium, which is attached to the broad ligament1.

In US the estimated number of new cases & deaths of ovarian tumors in

2015 is 21,290 & 14,180 respectively. One of 70 of women develops some type of tumors in the ovary in her lifetime. Ovarian neoplasm represents the 6th most common malignancy, fourth leading cause of death due to cancers in women and second most common site for female genital tract & is seen usually after 3 rd decade of life. The incidence of ovarian neoplasms varies in different parts of the world. The difference is also noted in the type of ovarian cancer seen in Western countries & Asian continents. Surface epithelial tumors being more common in the former and germ cell tumors in the latter2-4, 7.

The survival rate is less than 50% because the screening test has not been developed & the disease is also not very symptomatic and hence called as silent killer3. However they are treatable tumors because of sensitivity to anticancer therapies5,6.

Estrogen and progesterone receptor expression in surface epithelial type are useful for selecting women suffering from ovarian cancers to improve their therapeutic response and also their prognosis7.

Ovarian neoplasms are difficult to diagnose using simple techniques like smears, biopsy/ curettage in an early stage as it is possible in other tumors of cervix and body of the uterus. So it poses a difficult diagnostic challenge in early diagnosis.

The aim of the study is to estimate the incidence rate, histomorphological patterns & clinical correlation.

AIMS & OBJECTIVES

1. To characterize ovarian tumors based on gross and histopathological

findings.

2. To study the incidence of ovarian neoplasms.

3. To study the age-related occurrence of the same.

4. To carry out ER & PR status of surface epithelial tumors wherever

possible.

REVIEW OF LITERATURE

EMBRYOLOGY

The embryonic development of the ovary begins in an undifferentiated stage. The ovary develops from the gonadal ridge, a bulging from the surface of the coelomic cavity. The ridges are located one on each side of the midline between the dorsal mesentery & mesonephros. Eventually, the tissue of these two ridges forms the two almond-shaped structures.

First the mesodermal cells at the surface of the developing ovary differentiate into a layer of epithelial cells covering the organ. In other sites in the coelomic cavity, surface cells differentiate into thinner mesothelial cells that line the peritoneal cavity. Second, beneath the covering epithelium, cords of cells similar to the covering cells appear among the stromal cells. This is reminiscent of the development of epithelial glands and a commonly held view is that cords of cells that appear in the cortex represent the down growth from the surface epithelium. Third, at the same time when developing cords of cells are seen, primordial germ cells make their appearance in the cortex along with the cells of the cords. It was earlier believed that primordial germ cells are from these epithelial cells. However, it became established that the primordial germ cells originate in the endoderm of the yolk sac from which they migrate to the developing ovary and move into its substance at the same time when cords are forming in the cortex. The female germ cells that migrate to the ovaries and gain entrance to their stroma are called oogonia. There are 2 millions of these in both the ovaries at birth, but by puberty large numbers get degenerated so that only 40, 000 remain9.

ANATOMY:

Ovaries are a pair of nodular bodies situated on either side the uterus closer to the lateral pelvic wall, attached to the broad ligament of the uterus posteriorly and behind & below to the uterine tubes. It is connected to the uterine cornua by the utero-ovarian ligament, to the broad ligament by the mesovarium & lateral pelvic wall by the Infundopelvic ligament 1,10.

WEIGHT & SIZE:

The size of each ovary is 4x2x1cm and average weight is 5-8 Gms during the reproductive age group and during menopause they shrink to half/even lesser.

EXTERNAL FEATURES:

Each ovary has two surfaces-lateral & medial, two poles-upper/tubal poles & lower/uterine pole. The ovary also has two borders-anterior & posterior. The ovarian parenchyma has two distinct zones- an outer cortex and inner medulla1.

BLOOD SUPPLY:

The ovaries are supplied by arteries coming from the main stem of abdominal aorta & are named as an ovarian artery. It divides into two branches one into the mesovarium which supplies the ovary and another branch

continues into the uterine broad ligament, below the tube and supplies the same. Venous supply: At the hilus, veins meet where they form the pampiniform plexus and after coursing along the ovarian arteries they drain into IVC on the right side &on left side it drains into left renal vein1.

LYMPHATICS:

Similar to the venous drainage, the lymphatics also emerges from the hilus, which travels through mesovarium & drains into Para-aortic group of lymph nodes & others drain into , common iliac, external & internal iliac, interaortic and inguinal group of lymph nodes10.

NERVE SUPPLY:

Nerve innervation is by ovarian plexus which arises from aortic, renal & hypogastric plexuses. They have both sympathetic (T10, T11) and parasympathetic nerve supply (S2, S3, S4).

HISTOLOGY

The ovaries are covered externally by a single layer of low cuboidal cells called as germinal epithelium. Underneath this epithelium, there is a dense connective tissue known as tunica albuginea. The stroma of the ovary is divided into outer cortex/peripheral zone which is composed of different stages of follicles and an inner medulla with numerous blood vessels which supply the cortex.

Primordial germ cells in the ovary are covered by a single layer of epithelial cells known as the primordial or primary follicle. At the 3rd month of foetal life, the covered oogonia develop into larger cells termed as primary oocytes.

During puberty, each primary follicle in the ovary consists of primary oocyte around 25-30μm in diameter surrounded by a single flattened follicular epithelium, in which the whole follicle measures about 40µm in diameter. The primary oocyte has a large eccentrically placed nucleus & dispersed fine granular chromatin with a prominent nucleolus.

The cells of primary follicle proliferate by mitotic division and form layers of cuboidal cells known as granulosa cells that surround the oocyte

(primary).

The corona radiata is formed by single layer of granulosa cells. A thick membrane is formed between the oocyte and the corona radiata known as the

Zona pellucida. Next to the follicular cells, the stromal cells differentiate into theca interna layer.

With further growth of the follicles, fluid accumulates between the granulosa cells forming a cavity, surrounding the oocyte called as the antrum.

So when antrum appears in the follicle, it is called as the secondary follicle.

Then the granulosa cells form a hillock called as cumulus oophorus.

The granulosa cells and the theca cells are separated by a thin basement membrane. The inner most cellular layer with many capillaries is known as theca interna & outer fibrous layer with minimal vasculature is theca externa.

For the development of the follicle, two most important hormones involved are the FSH & LH.

Initially, the ovarian follicles are small, but as they enlarge it becomes bigger in size, by not only reaching the surface but also form a bulge at this situation. As a result, the stroma & the theca becomes stretched and become thinner and at the same time, the cell of cumulus oophoricus is loosened due to the accumulation of fluid in between them. The follicle ultimately ruptures and sheds the ovum from the ovary & this stage is known as ovulation. After this stage, the remaining follicles convert into corpus luteum.

The fate of corpus luteum depends on whether the fertilization of ovum taking place or not, if the ovum is fertilized and pregnancy results, this type of corpus luteum persists for 3-4months secreting progesterone which is essential for the maintenance of pregnancy. And if the ovum is not fertilized, corpus luteum persists for the remaining ovarian cycle secreting progesterone. At the end, it degenerates and converted into a mass of fibrous tissue known as corpus albicans11.

Classification of ovarian tumors8 - (Modified).

The classification by WHO in 1973 has been revised and a detailed classification has been brought in 2003. The recent classification has changes in the epithelial group i.e., transitional group, sex cord stromal group and germ cell type which include a number of mono dermal teratoma variants.

Surface epithelial-stromal tumors

 Serous

 Mucinous

 Endometrioid

 Clear Cell

 Transitional Cell

 Squamous Cell

 Mixed Epithelial

 Undifferentiated & Unclassified

Sex Cord-Stromal Tumors

 Granulosa Cell Tumors

 Thecoma-Fibroma

 Sertoli-Stromal Cell

 Sex Cord-Stromal Tumors Of Mixed Or Unclassified Cell Types

 Steroid Cell Tumors

Germ Cell Tumors

Primitive Germ Cell

 Dysgerminoma

 Yolk Sac Tumor

 Embryonal Carcinoma

 Polyembryoma

 Non Gestational Choriocarcinoma

Biphasic / Triphasic Teratoma

 Immature Teratoma

 Mature Teratoma

Monodermal Teratoma & Somatic Type Associated With Dermoid Cyst

Germ cell sex cord-stromal tumors

 Gonadoblastoma

 Mixed Germ Cell-Sex Cord-Stromal Tumor

Tumors of rete ovarii

Miscellaneous tumors

Tumor like conditions

Lymphoid & hematopoietic tumors

Secondary tumors

Pathophysiology:

It occurs due to the dedifferentiation of the cells overlying the ovary, at ovulation time they are incorporated into the ovary & proliferate. Ovarian cancer typically spreads to peritoneum & omentum. They spread by local, lymphatic, intraperitoneal, hematogenous & transdiaphragmatic route. The most common route is an intraperitoneal one which occurs along peritoneal fluid collection & at the sites of stasis. Even though the hematogenous route is unusual in the initial stage of the disease3.

With recent advances of immunohistochemical & molecular genetics, there is a new paradigm for pathogenesis & origin.

It includes two categories: type 1 & type 2. In the former, it is indolent

& stage 1 presentation which develops from borderline tumors & endometriosis with a specific mutation of KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA,

ARIDIA and PPPR1A and stable genetically. In type 2, there is aggressive & advanced stage presentation and develops from intraepithelial carcinoma in fallopian tubes with TP53 mutation &, in addition, they have BRCA mutation.

The so fallopian tube is the source of low grade (from papillary tubal hyperplasia) & high-grade serous carcinomas (from STIC). With another theory stating that is due to dislodgement of normal tubal epithelium from

fimbrial end on the site of rupture, where ovulation has taken place resulting in inclusion cyst that may undergo malignant transformation.

Endometrioid & clear cell tumors originate from a non-ovarian

Mullerian type of tissue &widely accepted that they arise from endometriosis due to retrograde menstruation. Origin of the mucinous & transitional tumor is not still well established. Transitional epithelial nests are located in para ovarian tissue & are situated at the tubo-peritoneal junction. These nests are now blamed to be the precursor for origin of transitional cell tumor.

Thus by taking the concern of origin of ovarian carcinogenesis from ovary to fallopian tubes, the preventive measures like salpingectomy with conservation of ovary which was not seriously thought in the past may play role in reducing the burden as well as preservation of hormonal function & fertility12.

Risk factors:

It is the disease of developed & industrialized countries women where parity is low13.

Regardless of their age, most of the women are prone for neoplasms of ovary but as they become older, chances of neoplasms are comparatively higher. The most important risk factor is the family history of ovarian & breast cancer mainly the latter with BRCA1 & BRCA2 positive inherited mutation.

Smoking tobacco is associated with mucinous cancer and obesity also

increases the risk of ovarian cancers. Pregnancies, use of OCPs, tubal ligation, hysterectomy & salphingectomy reduce the risk14.

Reproductive factors: Research says that there is a strong relation between a number of ovulation & likelihood of cancer. The chances are on higher side especially, early puberty, late menopause; first child birth after the

30s, nulliparity14.The medical conditions with increased association are pelvic inflammatory disease, diabetes & endometriosis.

Familial syndromes:

There is increased cancer risk in lynch syndrome II due to inherited mutations that degrade the self-repair capability of DNA15. Twelve percentages of patients develop ovarian cancer & 40% patients develop uterine cancer.

Other syndromes associated are Meigs syndrome, Gorlin syndrome, Pseudo

Meig‘s syndrome, PTEN hamartoma tumor syndrome, Peutz-Jeghers syndrome, Cushing syndrome & MUTYH-associated multiple polyps3,16.

Other causes included are asbestos, ionizing radiation & talcum powder by the International Agency for Research on Cancer (IARC). But Meta-analysis shows it is because of erroneous inclusion with ovarian cancers in some studies& lack of association with it 17-22.

Incidence:

One of 70 women develop some type tumors in the ovary in her lifetime7. Most of the ovarian tumors are benign which accounts for 80% &

occurs in the younger age group between 20 to 45 yrs, borderline occurs slightly in older age group & malignant tumors are predominant in older age. It accounts for 3% of overall cancers in women. In the dispersion of all tumors of an ovary, serous cystadenocarcinoma accounts for about 47%23.

In south India, the accurate occurrence of ovarian tumors is not known but it is the one of the commonest cancer among Indian females and at presentation the cancer is already at an advanced stage24. In Japan and Asian countries the incidence rate is 2–6.5 new cases per 100,000 females/ year 25. In

Asian countries, Pakistan has the highest rate & also among south Asian countries inclusive of Srilanka, India, Bhutan & Bangladesh it is proportionately numerous in Pakistan 26&27. In US the estimated number of new cases & deaths in 2015 is 21,290 & 14,180 respectively14.Ninety-five or more than that of cancers of ovaries can be diagnosed as one of five histological patterns in descending order as follows: high-grade serous, clear cell, endometrioid, mucinous & low grade serous carcinomas. Even with advanced treatment modalities inclusive of surgery & chemotherapy, the 5-year survival rate is only 30%28-32.

SURFACE EPITHELIAL TYPE

In 1929, Taylor was first one to describe the subset of epithelial ovarian tumors that he termed as semi malignant, which had favorable outcome than do other ovarian cancers, but they were not separately classified by FIGO

3 and WHO until the early 1970s . They are heterogeneous neoplasms which are primarily divided depending upon the cell type into serous, endometrioid, mucinous, transitional, clear cell and squamous cell tumors. Furthermore depending on the degree of cellular proliferation, atypia of nuclei, and the presence or absence of stromal invasion it is subdivided into benign, borderline (intermediate), and malignant

(carcinoma) 33,34.

The Pathophysiology of surface epithelial tumor is already reviewed.

Benign serous tumors

They account for two- thirds of benign ovarian neoplasms and also dominate the ovarian serous tumors.

Macroscopically, a unilocular / multilocular cyst filled with clear fluid.

Microscopically benign surface epithelial tumors are divided into 4 subcategories which are as follows:

Cystadenomas:

The epithelial lining is pseudostratified, tubal like epithelium with elongated or rounded nuclei.

Adenofibromas show solid structure on cut section grossly. Microscopically they are highly cellular fibrous stroma with scattered glands or papillae.

Cystadenofibromas are grossly solid and cystic. Microscopically they show fibrous stroma with cystically dilated glands.

Surface papillomas show single or multiple papillary projections on the surface of usually a normal sized ovary and fibrosis of the stroma resembling cystadenofibroma & microscopic adenofibroma35.

Atypical Proliferative Serous Tumors/Borderline Serous tumours

Fifty five percentage of APST are bilateral36.

Grossly they show fine friable exuberant papillary projections inside & outside the cyst.

Serous carcinomas: They present in an advanced stage with stage II /III with bilateral involvement. Macroscopically they are solid &cystic with pink soft friable areas, necrosis and hemorrhage. The microscopically they can be differentiated based on following morphological features:

MORPHOLOGICAL FEATURES OF SEROUS OVARIAN

NEOPLASMS35

Microscopic Benign APST MPSC MPSC, Serous features serous non- Invasive carcinoma neoplasm invasive Atypia -/+<10% + >10% + + + Stratification & +, Usually detachment of -/+<10% + May be >/=10% + cells Micropapillary - +, < 5mm +, > /5mm + May be Invasion of - - - + + stroma (NOTE: - : Absent, +: present & =: equal)

Peritoneal Implants: APSTs usually are associated with two types of implants, Invasive & Noninvasive (Desmoplastic/Epithelial) implants. Among women with APST, thirty one percentages (78% of patients with implants) of women have noninvasive & nine percentages (28% of cases with implants) have invasive implants.

Psammoma bodies: It is especially seen in a female genital tract with special emphasis on serous tumors of ovary in spite of benign/borderline/malignant.

They are well circumscribed, calcified laminated structures. When abundant they are termed as psammoma carcinoma35.

R I Cameron. et.al, reported a first case report of uterine serous carcinoma which metastasized to both ovaries with abundant Psammoma bodies not associated with epithelial components which was due to secondary to local factors from the tumor37.

Mucinous tumors:

The name mucinous is by the epithelial lining with basally placed nuclei with prominent mucin filled cells resembling endocervix or intestinal type & less often with argentaffin cells and rarely Paneth cells38.Cystadenomas,

Atypical proliferative mucinous tumors & Carcinoma – intraepithelial & invasive are primary ovarian tumours. There are also metastatic mucinous tumors mostly from GIT & low-grade mucinous tumors of appendiceal origin.

Mucinous cystadenoma

It comprises 13% of benign ovarian epithelial neoplasms. A unilocular

/multilocular cyst typically unilateral with a smooth & thick capsule filled with gelatinous material. With two patterns, 80% are intestinal types remaining being an endocervical type35.

Atypical Proliferative Mucinous Tumor

In 2003, Borderline ovarian tumor conference established three terms; mucinous tumor of low malignant potential/ atypical proliferative mucinous tumor/mucinous borderline are synonymous &the term tumor of low malignant potential is least favoured39&40.

An enlarged sized ovarian mass with multiple locules filled with mucin material. The cyst lined by stratified, proliferative gastrointestinal-type of lining with tufting & villoglandular /papillary pattern, nuclear atypia & absence of stromal invasion. APMT with an intraepithelial carcinoma (non-invasive type) display marked epithelial overgrowth & atypia which has an excellent prognosis with the survival rate of 95-100% 39, 41-45.

APMT with micro invasion, there is a haphazard growth of smaller glands & nests <5mm in greatest dimension. Mucinous tumor associated with pseudomyxoma peritonei (PMP) is an uncommon condition (5%) characterized by an accumulation of mucin in peritoneal cavity which undergoes fibrosis forming adhesions. This condition is associated especially metastatic in origin. The cystic neoplasms of mucinous variety occasionally contain 3 types of mural nodules like a true sarcoma, sarcoma-like mural nodule and foci of anaplastic carcinoma35.

Invasive mucinous carcinoma: Grossly resemble APMT; microscopically there are confluent crowded glands with back to back cribriform & haphazard stromal invasion. Two patterns of stromal invasion; an expansile and destructive pattern invading 3mm in two linear dimensions / >10mm2 in an area.

It is associated with KRAS mutation with MUC2, 3, 17 & CDX1,

CDX2 & LGALS4. It should be differentiated from metastatic mucinous tumors which are commonly bilateral, smaller nodular surface, extra-ovarian involvement & extensive lymphovascular invasion35, 46-48.

ENDOMETRIOID TUMORS

It constitutes 15-20% of cancers of an ovary. The majority of this category is malignant, endometrioid adenofibromas & atypical proliferative endometrioid tumors are unusual16&35.

Endometrioid adenofibroma (Benign)

An unusual tumor with a median age of 57yrs & mean diameter size of

10 cm, grossly they have a honeycomb appearance. The dominant pattern is adenofibroma or cystadenofibroma with epithelial elements arranged in branching tubular glands and cyst, the lining is tall columnar with oval nuclei

containing coarse chromatin and small nucleoli, the cytoplasm is basophilic or amphophillic35.

APET (Atypical proliferative endometrioid tumor)

It constitutes 0.2% of epithelial tumors35. In a recent study published by

Roth L M.et al, in 30 cases out of which 63% had endometriosis & remainder had endometrial hyperplasia/carcinoma associated with the tumor49. It shows two characteristic patterns; adenofibromatous & glandular/papillary. There is a proliferation of epithelium which lacks stromal support & mild atypia, not beyond 5mm with squamous metaplasia.

Endometrioid carcinomas: It is so named because of its pattern resemblance to uterine endometrial adenocarcinoma. A destructive infiltrative growth exceeding >5mm, where the glands are arranged back to back, similar to uterine malignancy where there are villoglandular/tubular glands composed of stratified epithelial cells35. Other variants include, EC with squamous differentiation, secretory, ciliated variant, sertoliform endometrioid CA & with rare varieties include undifferentiated neuroendocrine component50, adenoid cystic, basaloid and oxyphilic variants.

IHC-Epithelial membrane antigen, CK7 (97%) and CK20 (13%) show positivity with other markers B72.3, OC-125, Vimentin & CEA35.

Clear cell tumors

Earlier it was known as Mesonephroma because of its mesonephric origin. The vast majority of the tumors are clear cell carcinomas & accounts for

8.5% of overall ovarian malignancies.

Clear cell adenofibroma (Benign)

It is one of the rare forms. Macroscopically, a honey-combed cyst with firm rubbery stroma (Parvilocular). Microscopically tubular glands lined by one or two layers of peg-like/ hobnail cells with clear cytoplasm due to glycogen content. In a study of 1000 consecutive epithelial cases, there was no such condition encountered 35.

Atypical proliferative clear cell tumors (APCCT)

It comprises 0.2% of epithelial tumors. Microscopy findings are similar to the endometrioid adenofibroma but with more crowded glands, atypia, nucleoli and mitotic activity 3/10HPF. Sometimes it may be difficult to distinguish it from carcinoma, because in the malignancy; invasion may not be well defined. So practice helps us by staging and furthermore chemotherapy benefits the patient if there is doubt in the diagnosis 35.

Clear cell carcinomas

They accounts for 5% of cancers in ovary. It is the one of the neoplasm of an ovary to be associated with paraneoplastic hypercalcemia (2-10%) and

vascular thrombotic events (18-46%). In a study from Australia, about 27% of cases with CCC had thromboembolic episode compared to other types of neoplasms in ovary51-53.

They are solid & cystic tumor with a diameter of 13-15cm. microscopically there are three patterns-solid with adenofibromatous component, papillary & tubulocystic54.The cells are large with clear cytoplasm with hyaline globules with hobnail appearance .They are always high grade with poor prognosis. It mimics high-grade serous carcinomas, YST, dysgerminoma & struma ovarii. They can be distinguished with the panel of markers like WT1, ER, HNF-1β, AFP and TTF 35.

Brenner tumors

Meyer in 1932 introduced the term Brenner tumor for the ovarian neoplasm which was first described by Brenner in 1907.It accounts for 10% of epithelial variety, 1.5 to 2.5 % of all ovarian tumors & the benign form is common than atypical proliferative or malignant. It is named as transitional because of its resemblance to urothelium. It has multiple layers of cells with ovoid nucleus & grooves. Age of presentation for Benign is < 50 yrs;

Borderline 50-59 yrs & above 60 yrs for a malignant & transitional cell at 56 years29. They may cause postmenopausal bleeding due to endometrial hyperplasia35.

Benign Brenner tumors

They are 2 cm or smaller, may exceed up to 10 cm, well circumscribed with a hard or fibromatous, gray-white or yellow solid cut surface.

Microscopically, show sharply demarcated epithelial nests in a dense fibrous stroma. Occasionally the cystic nest will be lined by endocervical mucinous epithelium and it is then called as Metaplastic Brenner tumor.

Atypical Proliferating Brenner tumor (APBT)

Intermediate Brenner are larger than benign & cystic in nature measuring 10-28cm. They show friable papillary/ polypoid masses in the cyst lumen with an adjacent benign component being more solid & fibrous.

Microscopically, an intracystic papillary component is present, composed of a transitional type of epithelium resembling noninvasive papillary transitional cell neoplasm (low grade) of the urinary tract. Proliferative type resembles grade 1,2 of papillary Urothelial TCC & low malignant potential as grade 3 of papillary Urothelial TCC by some authors 35.

Among fifty reported cases of APBTs, 1 had local recurrence & no convincing evidence of malignant behaviour55.

Malignant Brenner tumor

They range up to 25 cm in size. They are solid & cystic in nature and cystic component may show friable polypoidal mural nodules. Hemorrhage & necrosis may be prominent & have foci of gritty calcifications. It also shows a

component of benign / proliferating Brenner tumor. The nuclei show marked atypical features & increased mitosis with a stromal invasion.

If there is no underlying component of Benign / Proliferating Brenner then the tumor should be designated as Transitional Cell Carcinoma (TCC) of

Ovary and poorly differentiated with central necrosis.

Positive for keratin, EMA, CK 7, CEA, Chromogranin, neuron specific enolase &negative for CK 20, steroidogenic enzymes . In TCC of the urinary tract, CK 20 is positive which distinguishes from the ovarian TCC35.

The other neoplasms associated are Mucinous Cystadenomas, Fibroma-

Thecoma, Serous Cystadenofibroma and Serous Papillary & Adenofibroma.

Walthard cell rest: Sometimes the Pathologists find cohesive groups of cells in the ovarian stroma which resemble Urothelial epithelium which can be misinterpreted as Brenner tumor.

Squamous tumors

Benign squamous tumors

It is known as epidermoid cyst which is very rare comprising of

<1% of surface epithelial type56. Nearly half of the tumors show contralateral teratoma /monodermal teratomas or foci of Brenner with squamous metaplasia/ metaplastic change in endometriosis on further sampling35.

Squamous cell carcinoma

It accounts for 0.5% of neoplasms in the ovary, usually presents in late stage & death occurs in a period of one year. Invasive SCC in ovary is either; mature teratoma undergoing malignant transformation or metastasis from a cervix or endometrioid carcinoma with the squamous component which can mimic the same35.

Mixed epithelial tumors:

The criterion is any combination of above epithelial types, at least two components comprising at least 10%. Most commonly serous & endometrioid occur together16, 35.

Undifferentiated carcinoma:

It is categorized by when there are no readily identifiable features of differentiation of the cells. There are four types which as follows, cell small cell carcinoma of hypercalcemic & pulmonary type, non-small neuroendocrine and undifferentiated NOS. Out of the four types first one is more common than other three types. Before making a diagnosis, it is very important to exclude metastasis from lung35.

Carcinosarcoma (MMMT):

The Carcinosarcoma of the ovary is not as much as common in endometrium & it is not the collision tumor but rather a poorly differentiated carcinoma with metaplastic sarcomatous elements.

Sex cord – stromal tumors

They account for 5 – 12% of overall OTs. They are functioning tumors of the ovary. They arise from the stromal cells of the ovary which are specialized in steroid hormone production with endocrine manifestations. There are two theories which hypothesize the origin of sex cord-stromal tumors.

They arise from the mesenchymal part of the genital ridge or mesonephric and coelomic epithelium. There is no well-defined cause for granulosa type of neoplasms despite the fact of the chromosomal abnormality and abnormal autocrine & endocrine signals. Coelomic & mesonephric epithelium participates in the formation of sex cords which is widely accepted theory now.

While diagnosing the sex cord – stromal tumor, thorough sampling, an age of the patient, clinical details, immunohistochemical profile are of great importance. Triad of markers like calretinin, epithelial membrane antigen & inhibin are helpful in evaluating the sex cord stromal tumors. Inhibin & calretinin are specific positivity while EMA show negativity.

The mutation in FOX L 2 plays the role in sex cord tumors35.

Granulosa cell tumor: There are two types – Adult & Juvenile granulosa cell tumor.

Adult granulosa tumor accounts for 1 % of all ovarian malignancies and more common than juvenile category. It affects pre & postmenopausal aged circle and is one of the estrogen secreting cancers.

Gross: It can be compact or cystic in nature. On opening the compact tumor it appears gray-white / yellow due to the presence of lipid; sometimes they are soft or firm. Cross section of the cyst may be multilocular or unilocular.

Microscopy: It shows theca cells, granulosa cells & fibroblasts arranged in diffuse, micro follicular, macro follicular, insular, cords to trabeculae, solid tubular, sarcomatoid, watered silk, gyriform & pseudo papillary pattern. The peculiar finding is numerous Call-Exner bodies.

Two types of granulosa cell tumor can be differentiated as follows35:

Age Nuclear Incidence Gross Pattern Luteinization group features Solid Immature Round Juvenile 50% Before & follicles darker Frequent GCT Prepubertal 30 yrs cystic with mucin nuclei Mature Nuclei follicles & pale, Adult After <1% Solid occasional angulated Infrequent GCT 30yrs call-exner with bodies grooves

Fibroma

It accounts for 6% of all ovarian tumors which predominantly occurs in perimenopausal age group & hormonally inactive16. Grossly they are solid with firm gray-white cut surface & occasionally with cystic changes. Under light microscopy, spindle-shaped cells arranged in interlacing bundles & storiform pattern with little mitosis.

Cellular fibroma & fibrosarcoma may exist rarely. In the former there is mild atypia with mitosis being <3/10HPF &the latter condition is extremely rare where there is pronounced mitosis & nuclear pleomorphism57.

Thecoma

A hormonally active tumor with mainly estrogen manifestations and bilaterality in 3% of cases 58,59.

Grossly it reveals solid yellow mass & microscopically shows round to oval, lipid-laden theca cells in a fibromatous stroma which are positive for inhibin and Oil red O.

Variants:

 Luteinized thecoma: Clusters of an eosinophilic cell with large round

nuclei typically occurs in the younger age group with additional

androgenic features 16.

 Sclerosing stromal tumor: Average age of presentation is 27yrs

typically showing ill-defined cellular pseudo lobules separated by

stroma which can be mistaken for Krukenberg tumor60.

Sertoli -Leydig cell tumors

It occurs in younger age group & present with androgen manifestations.

Some are nonfunctioning, while some present with estrogenic presentation61. A nodular mass with an average diameter of 10cm, yellow-orange to a red-brown cut surface with the central scar is what we see on gross morphology.

Histologically they resemble developing testis with 5 patterns;

 Well differentiated with tubular pattern composed of Sertoli & Leydig

cells separated by fibrous stroma,

 Intermediate form composed of Leydig cells with abortive tubules which

resemble an embryonic testis,

 Sarcomatoid variant of spindle cells with trabecular arrangement,

 Heterologous elements which seen in 25% cases and

 Retiform pattern.

Most often they are benign with malignancy being a rarity62-64.

SEX CORD –STROMAL TUMORS, MIXED FORM

 SCTAT: An intermediate form between sertoli cell & granulosa cell

tumor, usually small & incidental associated with PJ syndrome.

Histologically they show well-circumscribed ring shaped tubules with a hyalinized material. The individual cells have pale cytoplasm with

elongated nuclei 16.

 Gynandroblastoma: Rare form which show both granulosa-theca cell

and Sertoli-Leydig cell patterns.

Steroid cell tumors: It is otherwise known as lipid cell tumor. Steroid cell tumors are of 3types:

a) Stromal luteoma: It is rarely androgenic & lack crystals of Reinke65.

b) Hilus cell tumors: They are mainly androgenic & show Reinke crystals.

Post-menopausal women are victims for this tumor. However they are

benign in nature.

c) Steroid cell type (Not otherwise specified): A malignant & typically

androgenic and mitosis being > 2/HPF with areas of necrosis, large cell

size & nuclear atypia 16, 66.

Germ cell tumors of ovary

It has number of histologically various types of tumours & is derived from the primitive germ cells located in the embryonic gonad35. The concept of this tumor as distinct type of neoplasms of gonads has been evolved over the last several decades based on: a) The neoplasms which has common histogenesis, b) Relatively frequent presence of histologically various neoplastic contents

within the same tumor, c) The presence of extragonadal neoplasms located along the line of

migration of the primitive germ cells from the wall of the sac to the ridge

of gonads and

d) The notable homology between the various tumors in the male and the

female66.

Telium’s histogenesis of GCTs67

Germ cell

Seminoma Tumors of totipotential

Embryonal carcinoma

Extra Embryonic Structures Embryonic; ecto, endo & mesoderm

Endodermal Sinus Tumor Choriocarcinoma Teratoma

Germ cell tumors account for approximately 15-20% of all ovarian

tumors. Ninety-five percent of tumors are mature cystic teratomas and

remainders are malignant. Of benign ovarian neoplasms, dermoid cysts account for one-third and malignant germ cell cancers account for approximately 3% of all ovarian cancers especially in Western countries. During the first two decades, it accounts for two-third of cancers of ovary and common in blacks where surface epithelial type is uncommon68.

I). Primitive germ cell tumors

1. Dysgerminoma:

Grossly they have average diameter of 15 cm with firm solid & smooth

nodular surface. The cut section is homogenous, fleshy and appears

tan/white69.

Microscopically, neoplasm is similar to Seminoma, tumour of testis

which is composed of islands, aggregates or even uniformly arranged

large cells surrounded by connective tissue stroma containing

lymphocytes. The individual cells are oval/round with vesicular nucleus

& well-defined cytoplasmic borders with clear slightly granular

eosinophilic cytoplasm35.

2. Yolk sac tumor

Gross: A Unilateral tumor which are round/oval/globular in shape with

a capsule. On sectioning it is solid, but there may few cystic areas

containing gelatinous fluid. Microscopy: The following patterns may be

observed: microcystic or reticular, endodermal sinus, solid, alveolar–

glandular, poly vesicular vitelline, myxomatous, papillary, macrocystic,

hepatoid, and glandular or primitive endodermal (intestinal).

The hallmark of the tumor is Schiller-Duval bodies & these formations

are known to recapitulate the so-called endodermal sinuses of rat

placenta71, 72. These structures resemble superficially immature renal

glomeruli & are also designated as glomerulus-like structures, sinuses of

Duval and endodermal sinuses.

3. Embryonal Carcinoma:

It is the least differentiated form & differentiates either into somatic or

extra-embryonic structures forming yolk sac or trophoblastic structures.

It is a malignant & locally aggressive tumor which metastasizes earlier

in its course. Mostly it is a component of mixed GCTs. Grossly a gray-

white, solid & slightly granular tumour with foci of necrosis/hemorrhage

in large sized tumours.

Microscopically it shows two patterns; (i) Primitive undifferentiated

form: There is a solid aggregate of epithelial-like cells which are large

polygonal cell with large prominent central vesicular or hyperchromatic

nucleus and ample amount of cytoplasm. (ii)Differentiated form: Cells

are the proper epithelial type which line clefts like spaces & form

papillae35.

4. Polyembryoma

It is one of the rare germ cell tumors comprising of many embryoid

bodies which resembles morphologically normal presomite embryos. Grossly they are very large tumors- almost fill the abdominal cavity &

invades the surrounding structures. On sectioning, it appears solid with

hemorrhagic & necrotic foci.

Microscopy: The tumor shows numerous embryoid bodies which have

endodermal lining on one side & ectodermal lining on another side with

an amniotic cavity, embryonal disk & yolk sac elements73-75.

5. Non Gestational Choriocarcinoma

The pure form is rare. It is usually a component of mixed germ cell

tumor.

Gross: Usually unilateral. They have solid gray-white areas with foci of

hemorrhage & necrosis. It varies according to the component present.

Microscopy: They show 2 types of cells: Cytotrophoblast situated

centrally & syncytiotrophoblast arranged peripherally in solid

aggregates.

6. Mixed GCTs

It accounts for only 10% of germ cell tumor. Any combination of the

tumor can occur, but the most common combination is dysgerminoma

with yolk sac tumor35.

II). Biphasic/ triphasic teratoma

1. Immature teratoma

A malignant tumor which accounts for <1 % of ovarian teratomas76. It is

composed of derivatives of all 3 germ cell layers with immature /

embryonal structures.

Gross: A unilateral tumor with size of 9 to 28 cm, solid or solid & cystic.

The cut section appears as a variegated & lobulated mass with

trabeculations.

Microscopy: It consists of immature/primitive tissue from all 3 germ cell

layers with a mature component. Neuroectodermal derivatives are most

common immature element arranged in rosettes, masses/tubules.

Grading is done as per proposal put by AFIP approved by WHO. It is

done depending on the amount of immature neuroectodermal components

in a single slide77, 78.

Grade 1: Amount of immature neuroectodermal tissue occupying < 1 LPF

under 4 x objective.

Grade 2: Amount of immature neuroectodermal tissue 1- 3 LPF.

Grade 3: Amount of immature neuroectodermal component >3 LPF.

2. Mature teratoma a) Mature solid teratoma

It is an uncommon tumor; affects children & young adults. Grossly, it is

large, solid & unilateral. Microscopy: Tumor is made up of mature tissues

which are derived from all 3 germ layers arranged in orderly manner35. b) Mature cystic teratoma/Dermoid cyst : It is the most common type of

teratoma of the ovary & affects infancy to an old age group of people.

Gross: The size varies from very small to larger size i.e. 0.5 cm to 40 cm.

Tumor appears round/oval/ globular with a glistening & smooth surface.

Cut section reveals unilocular cyst composed of hair & fatty material with

a small solid elevated mass---Rokistansky protuberance. It should be

sampled carefully because it contains a variety of tissues.

Microscopy : Cyst wall lined by stratified squamous epithelium

sometimes bronchial/gastro intestinal epithelium & underlying tissue

derived from all the 3 germ cell layers of ectoderm, endoderm &

mesoderm in a organoid orderly arrangement in which ectodermal tissue

is predominant pattern.

It may undergo a malignant transformation which accounts for only 2% &

uncommon79.

Squamous epithelium is the most common component which undergoes

malignant transformation to squamous cell carcinoma.

2-11% of ovarian mature cystic teratoma has been associated with the

mucinous tumor. c) Fetiform teratoma (homunculus): Phalanges, long bones, parts of the rib

cage, loops of intestine & even fetus like structures are seen in the solid

area of the cystic teratoma. So when these structures are seen it is known

as Fetiform teratoma80. d) Monodermal teratoma & somatic type of tumors which is associated

with dermoid cysts. a) Struma ovarii

Benign: An uncommon tumor which accounts for only 3% of ovarian

teratoma. The thyroid tissue is the most common component and accounts

for 5-20%. Grossly a unilateral & mostly associated with mature cystic

teratoma81-83. Size is <10 cm with smooth external surface. The cut

surface appears light tan, glistening thyroid tissue.

Microscopy: It is composed of variously shaped acini which are

monolayerd columnar or flattened epithelium filled with colloid.

Variants include cystic with clear cells, oxyphilic, signet ring, cord-like

arrangement & hypercellular.

Hypercellular variant i.e. with crowded follicles without features of

malignancy is known a Proliferative struma ovarii. TTF-1 and

Thyroglobulin are diagnostic immunohistochemical markers for the

tumor.

Malignant

Malignancy in struma ovarii is uncommon and accounts for 3% of struma

ovarii. The malignant neoplasm most commonly involved is papillary

carcinoma35. b) Carcinoid group

It can be primary or metastatic. In primary, there are 4 types: Insular,

trabecular, Strumal &Mucinous.

Macroscopically, in primary carcinoids the tumors are firm, solid with tan

or yellow cut surface. In metastatic type it is bilateral, multinodular with

the presence of peritoneal metastasis. Mucinous carcinoids have a high

risk of metastasis.

Microscopy – the tumor cells are arranged in confluent nodules separated

by fibrous septa (Insular pattern), ribbons (Trabeculae pattern), and

tubules lined by columnar cells with goblet cells (Mucinous pattern) 35.

Strumal carcinoids have features of both carcinoids & struma ovarii.

Individual cells are polygonal to round nuclei with salt & pepper

chromatin with clear to eosinophilic cytoplasm. Synaptophysin &

chromogranin and TTF-1 &

CK 7 positivity in carcinoid & strumal components respectively84.

Monodermal teratoma with neuroectodermal differentiation

Tumor appears cystic & or solid with 3 types of histological patterns—

Differentiated, primitive and anaplastic varieties. IHC: Glial Fibrillary Acidic

Protein positivity is seen in differentiated & anaplastic types.

Twenty five cases of primary neuroectodermal tumors of ovary have been reported by Kleinman.et al85.

Monodermal teratoma with vascular tissue

It is composed entirely / predominantly immature vascular tissue.

Tumor size varies & appears smooth, soft, solid, gray pink with areas hemorrhage.

It shows vascular spaces (small) in aggregates lined by immature endothelial cells with loose, dense to fibrous connective tissue. CD 31, CD 34, Factor 8 differentiates immature pericytes from heamangiopericytoma35.

Monodermal teratoma with sebaceous differentiation

It is a rare condition. Most often they are cystic with necrotic & chessy material

& sometimes solid yellow / tan mass.It consists of sebaceous adenoma, basal cell carcinoma with sebaceous differentiation & sebaceous carcinoma.

Epidermoid cyst, melanocytic tumour, mucinous tumour of germ cell origin and benign cystic retinal anlage tumor are other types Monodermal teratomas86.

IV. Germ cell sex cord – stromal tumor

a. Gonadoblastoma: An uncommon tumor most commonly seen in

gonadal dysgenesis and involvement of both ovaries in 40% of cases,

seen especially in phenotypic females but can also occur in phenotyped

males & associated with endocrine abnormalities. The size of the tumor

varies from microscopic up to 8 cm; solid mass & on cutting have tan /

white appearance with areas of calcification.

Microscopically: Solid nests of cells composed of large germ cells &

small sex cord cells with calcifications surrounded by connective tissue

which contain Leydig / luteinized cells.

IHC: Germ cells show positivity for CD 117, OCT 4, SALL 4 & PLAP.

Sex cord elements reveal positive reaction for Cytokeratin, Vimentin &

Inhibin. The hyalinized material is detected by antibody to laminin69.

b. Mixed germ cell – sex cord stromal tumor

These tumors are not associated with endocrine abnormalities. Initially,

Gonadoblastoma was included in this section, but now Gonadoblastoma

is different from this entity.

Grossly; A large mass with one side involvement of the ovary which is

weighing 100 grams to more than 1kilograms 50 grams & firm with a

smooth capsule.

Microscopically: It has four patterns comprising of cords / trabeculae,

tubules devoid of the lumen, scatter collection of germ cells surrounded by sex cord elements & pattern similar to sex cord tumor with annular

tubules. There is no nesting pattern and here the germ cells & sex cord

elements are intermixed35.

Tumors of rete ovarii

There are varied benign (adenoma, cystadenoma & cystadenofibroma) & malignant (adenocarcinoma) lesions which arise from rete ovarii which is present in the ovarian hilus. The cystadenoma may be functioning due to steroid cells at the periphery.

Miscellaneous tumors

Small cell carcinoma: In those 2 subtypes, hypercalcemic is associated with para endocrine hypercalcemia & composed of small cells & pulmonary type which resemble pulmonary small cell carcinoma of neuroendocrine-type.

Mesothelial tumors may be confined to the surface or the hilus of the ovary8.

Hydatiform mole has hydropic chorionic villi with the formation of cisterns. A neoplasm resembles Wilms tumor of the kidney. Myxoma, a benign mesenchymal tumor composed of a bland nucleus with abundant basophilic ground substance. Soft tissue tumors of the ovary, which may be benign or malignant & typically present same features as in other locations. Other rare types include hepatoid carcinoma which resembles hepatocellular carcinoma which is extremely rare and should be differentiated from metastatic HCC.

Adenoid cystic carcinoma of salivary gland resemblance which is again an unusual variant & they usually lacks Myoepithelial differentiation87-89.

Tumor-like conditions

Luteoma of pregnancy- Multiple or single nodule composed of lutein cells with more eosinophilic cytoplasm which is seen at the end of pregnancy.

Stromal hyperthecosis- There is hyperplasia of ovarian stromal cells with luteinized stromal cells, in stromal hyperplasia, the proliferation of only stromal cells without luteinized cells. Fibromatosis: Non-malignant proliferation of collagen producing stroma of ovary. Massive ovarian edema composed of edema fluid.

Lymphoma & leukemia

There are primary/secondary lymphoproliferative or hematopoietic neoplasm of ovaries.

Plasmacytoma: Localized growth pattern with plasma cell proliferation of plasma cells identical to plasma cell myeloma.

Secondary tumors of ovary:

It arises mainly from Gastro intestinal tract, colon & stomach known as

Krukenberg tumor. The main characteristic findings include bilaterality, small superficial multiple nodules, vascular invasion, desmoplastic reaction, extensive extra ovarian invasion & non-specific clinical findings8.

Immunohistochemistry review

Surface epithelial tumors

All the primary epithelial tumors express CK7 positive and most of them are CK20 & CDX2 negative, with an exception of mucinous tumor of intestinal type. If any primaries are CK7 negative, metastasis or the rare type of primary of the epithelial variant has to be taken into consideration. Estrogen and progesterone receptors are expressed in 50% of cases and p53 in 30-50% of cases90-93.

TYPE OF TUMOR MOST USEFUL MARKER/ANTIBODY94 SEROUS TYPE CK7 & WT1 MUCINOUS TUMORS CK7, CK20 ENDOMETRIOID TUMORS CK7, CK20, CDX2, Cytokeratin Cocktail, EMA, Inhibin

CK7, CK20, Hepatocyte Nuclear Factor-1β, WT1, CLEAR CELL CARCINOMA EMA, Glypican-3, Alpha-Fetoprotein, CD10

BRENNER AND TRANSITIONAL CK7, CK20, WT1 CELL TUMORS

CK, EMA, CK7, CD56, Synaptophysin, OTHER EPITHELIAL TUMORS Chromogranin, WT1.

Sex Cord–Stromal Tumors

It can be either positive or negative for Cytokeratin & almost always EMA negative. Inhibin is a relatively specific marker for sex cord–stromal tumors.

Calretinin is a more sensitive, but less specific marker for sex cord–stromal tumors than Inhibin. Other markers for which includes are CD56, WT1, and

SF-1.

CK, EMA, Inhibin, GRANULOSA CELL TUMORS Calretinin, CD99 Inhibin, Calretinin, FIBROMA,THECOMA,AND RELATED TUMORS CD56 SERTOLI-LEYDIGCELL TUMOR, SERTOLI CELL TUMOR, CK, EMA, Inhibin, SCTAT, STEROID&LEGDIGCELL TUMOR. Calretinin

Germ Cell Tumors In most types of malignant germ cell tumors, PLAP can be positive, but it also can stain the epithelial neoplasms. For malignant germ cell tumors cytokeratin,

AE1/AE3 and EMA are negative.

DYSGERMINOMA CK, EMA, PLAP, CD117, Oct-4, D2-40, hCG CK AE1/AE3, CK7, EMA, Alpha Fetoprotein, YOLK SAC TUMOR Glypican-3 EMBRYONAL CARCINOMA CK AE1/AE3, EMA, CD30, Oct-4 CHORIOCARCINOMA CK AE1/AE3, hCG TERATOMAS Depends on Specific Type of Teratoma Germ cells stain for placental alkaline phosphatase, GONADOBLASTOMA CD 117 & OCT-4; for sex cord cells, Vimentin, cytokeratin, and inhibin95-99.

METASTATIC TUMORS: Colon & rectal adenocarcinoma frequently metastasize & mimic endometroid

& mucinous adenoCA. The triads of markers for metastatic ovarian tumours are CK7, CK20, and CDX2.

Sometimes serous type which involves the ovary & peritoneal surfaces, raise the possibility of mesothelioma.

CR, CK5/6, Ber-EP4, MOC-31, ER & WT1 differentiate the two conditions, where the first three markers positive & next three negative for mesothelioma94.

Estrogen & progesterone receptors on SETs

With the development of molecular genetics & immunological methods like

IHC & FISH, hormone receptors are now introduced for the outcome prediction of female cancers such as breast, endometrium & cancers of ovary100.

ER & PR are a member of the nuclear family; they are the group of proteins in the cells, which are activated by the hormone estrogen-17β-estradiol

& progesterone respectively.

Estrogens have 2 classes: ER α & β each encoded by a different gene

ESR1 &ESR2, implicated in breast, ovary, endometrium, colon & prostate. PR has 2 classes: A & B encoded by PGR gene located on chromosome 11q22.

Normally during the menstrual cycle, in the first 14 days there is a growth of follicles, the follicular cells possess a FSH receptor which is the principal circulating hormone responsible for the maturation of the ovarian follicles and stimulates the theca interna cells to produce androgenic steroid precursors and they are converted into estrogen by the granulosa cells. At the midcycle, estrogen peaks & after ovulation, the ovary enters the luteal phase with LH surge, which transforms the granulosa & theca cells into granulosa lutein cells & theca lutein cells, respectively. Then the ovulated follicle is transformed into corpus luteum which secretes estrogen & progesterone11. But the recent study states that both the hormones with its receptors are involved in the process of tumor genesis of ovaries. It is involved by the disruption of the cell cycle, apoptosis & DNA repair. Estrogen plays a pivotal role in the proliferation of ovarian surface epithelial cells by promoting its growth & inhibiting the apoptosis with additional combined genotoxic & mitogenic activity101, 102.

Hogdall EV.et al states that more than benign & borderline, in malignant tumors they are expressed higher, frequency of ER expression-positive OCs are increased with higher FIG0 staging and PR positivity in higher histological grade103.

In a study reported by Weiva Sieh.et al assessed ER & PR status among nearly 3,000 women with invasive epithelial ovarian cancer and found that tumor ER and PR are prognostic markers for endometrioid and high-grade serous ovarian cancers104.

With the aid from higher ER &PR receptor levels, alone or in combination point a favourable outcome for patients with OC7.

Factors affecting prognosis

With the above discussion every different cancer of the ovary are the separate disease. The accepted prognostic factors include FIGO stage, Histologic type, tumor grade, Clinico-surgical parameters with residual disease after debulking surgery, with or without ascites and age. Of this staging is the most important independent factor105-107. The 5 yr survival rate for stage 1is 60-80%, 45-60% for stage 2, 15% for stage

3 and less than 10% for stage 4.

Among various histological types, there is different survival rate though it is not an independent factor. Ploidy is related to stage & it is an independent prognostic factor. Stage 3 & 4 has aneuploidy of 60-80% compared to stage 1&

2 with Ploidy of 45-60%16.

S-phase fraction cells with other proliferative markers parallel with

Ploidy & >10% denotes aggressiveness108.109.

CA 125 above 35U/ml is present in 80% of ovarian cancers & it can be measured in ascitic fluid with newer markers like soluble tumor necrosis factor is seen >84% of the cancers & also serves to monitor the patients110.

Research on oncogenes & antioncogenes has aroused their role in the genesis of tumor & several other genes are of prognostic significance, the work is still considered investigational111.

Methodology

A detailed retrospective & prospective study of 70 ovarian neoplasms was done from August 2012 to July 2015, taking into account the relevant clinical data. In the retrospective study the available H& E slides & paraffin blocks of the ovarian tumors, in the department were studied from August 2012 to July 2013 and the data was retrieved from the record files of the pathology department.

In the prospective study, every excised surgical specimen of ovarian tumor from August 2013 to July 2015 was included. All cystectomy, oophorectomy & total abdominal hysterectomy with bilateral or unilateral salphingo- oophorectomy were included in the present study. Exclusion criteria set during the present study was to exclude all those patients having abdominal masses due to causes other than ovarian tumors. Thorough grossing was done

& multiple representative sections were taken & the tissue was processed by routine histological techniques & subjected for hematoxylin & eosin stain. In certain surface epithelial tumors, ER & PR status was also found out by doing

IHC study.

The nature of ovarian tumor was categorized based on WHO

Classification, 20038.

The analysis of data accumulated was done by descriptive statistics.

RESULTS

TABLE -1: Morphological type Of Ovarian Tumors

Types No of cases Percentage Benign 61 87.14% Borderline 2 2.86% Malignant 7 10.00% Total 70 100%

CHART 1 - MORPHOLOGICAL TYPE OF OVARIAN TUMORS

2.86% 10%

87.14% BENIGN BORDERLINE MALIGNANT

During the present study from August 2012 to July 2015, seventy consecutive cases of ovarian tumors were processed in our laboratory, of which 61 were benign (87.14%), 2 were borderline (2.86%) and 7 cases were malignant

(10%).

TABLE -2: Frequency distribution of various Classes of Ovarian tumors

Different classes of ovarian No. of classes Percentage tumors Surface epithelial 58 82.86% Germ cell tumor 10 14.29% Sex cord stromal tumor 02 2.86% Total 70 100%

CHART 2 - FREQUENCY DISTRIBUTION OF VARIOUS CLASSES OF OVARIAN TUMORS

2.86% 14.29%

82.86% SURFACE EPITHELIAL

GERM CELL TUMOUR

Out of 70 ovarian tumors, 58 were surface epithelial tumors (82.86%), 10 were germ cell tumors (14.29%) and 2 were sex cord stromal tumors (2.86%).

All the ovarian tumors encountered in the present study were primary ovarian tumors. There was no secondary ovarian tumor encountered during the present study.

Primary ovarian tumors were broadly divided into three categories based on

WHO Classification as shown in above table 2.

Table-3: Frequency of different classes of benign ovarian tumors

Benign tumors Number of cases Percentage Surface epithelial 51 83.61% Germ cell tumors 09 14.75% Sex cord stromal tumors 01 1.64% Total 61 100%

Chart - 3 : FREQUENCY OF DIFFERENT CLASSES OF BENIGN OVARIAN TUMORS. 1.64% 14.75%

83.61%

Surface epithelial

Germ cell tumours

Sex cord stromal tumours

Out of 61 benign tumors 51 were surface epithelial tumors (83.61%), 9 were

Benign Germ cell tumors (14.75%) and 1 were sex cord stromal tumors

(1.64%).

Table -4: Frequency of different classes of malignant ovarian tumors

Malignant tumors Number of cases Percentage

Surface epithelial 05 71.43%

Germ cell tumors 01 14.29%

Sex cord stromal tumors 01 14.29%

Total 07 100%

CHART - 4 : FREQUENCY OF DIFFERENT CLASSES OF MALIGNANT OVARIAN TUMORS

14.29% 14.29%

71.43%

SURFACE EPITHELIAL

GERM CELL TUMOURS

SEX CORD STROMAL TUMOURS

Out of 7 malignant tumors, 5 were surface epithelial type, 1 were germ cell tumor and 1 sex cord stromal tumor.

Table -5: Histopathological distribution of benign ovarian tumors

Percentage Percentage among total Name of tumor No among benign ovarian tumors(n=70) type(n=61) Serous cystadenoma 40 65.57% 57.14% Mucinous cystadenoma 10 16.39% 14.29% Brenner tumor 1 1.64% 1.43% Mature cystic teratoma 8 13.11% 11.43% Struma ovarii 1 1.64% 1.43% Fibrothecoma 1 1.64% 1.43% Total 61 100% 87.14%

Chart - 5 : HISTOPATHOLOGICAL DISTRIBUTION OF BENIGN OVARIAN TUMORS

1.64% 13.11% 1.64% 1.64%

65.57% SEROUS CYSTADENOMA MUCINOUS CYSTADENOMA BRENNER TUMOUR 16.39% MATURE CYSTIC TERATOMA STRUMA OVARII FIBROTHECOMA

Among the 61 benign tumors, the serous tumor (65.57%) was the commonest followed by mucinous (16.39%) and mature cystic teratoma of the ovary

(13.11%).

Table -6: Histopathological distribution malignant ovarian tumors

% among total (n=7) malignant Name of tumor No tumors Serous cystadenocarcinoma 03 42.86% Mucinous carcinoma 01 14.29% Endometroid carcinoma 01 14.29% Granulosa cell tumor 01 14.29% Mixed germ cell tumor 01 14.29% Total 07 100%

CHART - 6 : HISTOPATHOLOGICAL DISTRIBUTION MALIGNANT OVARIAN TUMORS 14.29% 14.29% 42.86%

SEROUS CYSTADENOCARCINOMA 14.29% MUCINOUS CARCINOMA 14.29% ENDOMETROID CARCINOMA GRANULOSA CELL TUMOUR MIXED GERM CELL TUMOUR

Out of 7 malignant tumors, 3 were serous cystadenocarcinoma (42.86%), 1 each consists of Mucinous carcinoma (14.29%), endometroid adenocarcinoma

(14.29%), mixed germ cell tumor (14.29%) and Granulosa cell tumor

(14.29%).

Table -7: Frequency subtypes of benign surface epithelial ovarian neoplasms % of tumors among % among total Name of tumor No benign surface ovarian type(51) neoplasms(70) Serous type 40 78.43% 57.14% Mucinous cystadenoma 10 19.61% 14.29% Brenner tumor 1 1.96% 1.43% Total 51 100% 72.86%

(Note : % ---Percentage)

CHART -7 : FREQUENCY SUBTYPES OF BENIGN SURFACE EPITHELIAL OVARIAN NEOPLASMS

1.96% 19.60%

78.43% SEROUS TYPE MUCINOUS CYSTADENOMA BRENNER TUMOUR

Among the benign surface epithelial tumors, serous tumors were highest

(78.43%), followed by mucinous tumors (19.61%) and one was benign Brenner

(1.96%).

Table-8: Frequency subtypes of borderline surface epithelial neoplasms

Name of tumor No Borderline mucinous tumor 01 Proliferating brenner tumor 01 Total 02

CHART-8: FREQUENCY SUBTYPES OF BORDERLINE SURFACE

EPITHELIAL NEOPLASMS

100% 90% 80% 50% 70% 60% 50% 40% 30% 50% 20% 10% Proliferating brenner 0% tumour Frequency subtypes of borderline surface Borderline mucinous epithelial neoplasms tumour

Out of 70 cases of tumors of ovary, only 2 borderline tumors were detected

(2.86%) and noted as surface epithelial type, one was borderline mucinous and other being proliferating brenner tumor.

Table-9: Frequency subtypes of malignant surface epithelial neoplasms

% among % out of total malignant Nature of lesion No. malignant type ovarian neoplasms (n=7) (n=5) Serous 03 60% 42.85% cystadenocarcinoma Mucinous carcinoma 01 20% 14.29% Endometroid carcinoma 01 20% 14.29% Total 05 100% 71.43%

(Note: %-Percentage)

CHART - 9 : FREQUENCY SUBTYPES OF MALIGNANT SURFACE EPITHELIAL NEOPLASMS 20%

20% 60%

SEROUS CYSTADENOCARCINOMA MUCINOUS CARCINOMA ENDOMETROID CARCINOMA

Among malignant surface epithelial type, serous cystadenocarcinoma was the commonest, followed by 1 each case of mucinous & endometrioid carcinoma

The most SETs are serous & mucinous varieties. In this study, serous tumors constitutes 43, wherein 40 (93%) were benign & 3 (7%) were malignant and whereas in 12 mucinous tumors, 10 (83.33%) being benign & 1(8.33%) &

1(8.33%) of borderline & malignant respectively.

Thus the surface epithelial type is the most common despite benign/ borderline/ malignant.

Table-10: Frequency of GCTs.

NO of cases Total & Type of GCTs BENIGN MALIGNANT Percentage Mature cystic teratoma 08 (80%) - 08(80%) Struma ovarii 01 (10%) - 01(10%) Mixed Germ cell tumor - 01 (10%) 01(10%) Total 09 (90%) 01 (10%) 10(100%)

CHART - 10 : FREQUENCY OF GERM CELL TUMORS. 10% 10%

MATURE CYSTIC TERATOMA 80% STRUMA OVARII MIXED GERM CELL TUMOUR

Among the germ cell tumors, mature cystic teratoma was the commonest one

(80%).

Table -11: Frequency of sex cord stromal tumors

No of cases

NO & Type of tumor Benign Malignant PERCENTAGE Granulosa cell tumor - 01 (50%) 01 (50%) Fibrothecoma 01 (50%) 01 (50%) Total 01 (50%) 01 (50%) 02 (100%)

CHART - 11 : FREQUENCY OF SEX CORD STROMAL TUMORS 50% 40% 30% 50% 50% 20% 10% 0% GRANULOSA CELL TUMOUR FIBROTHECOMA

In the present study only two sex cord stromal tumors - one Fibrothecoma and one Granulosa cell tumor, were observed.

Granulosa cell tumor observed in the present study was associated with simple endometrial hyperplasia which is commonly seen in this condition.

Table -12: Frequency of ovarian neoplasms in different age group.

Classification

Age Surface epithelial Germ cell Sex cord Total group(yrs) tumor tumor stromal tumor

Upto 20 yrs 3 (4.29%) 03(4.29%) 21-30yrs 9 (12.86 %) 3 (4.29%) 12(17.14%) 31-40yrs 20 (28.57%) 3 (4.29%) 23(32.86%) 41-50yrs 15 (21.43%) 1 (1.43%) 1 (1.43%) 17(24.29%) 51-60yrs 8 (11.43%) 3 (4.29%) 1 (1.43%) 12(17.14%) >60yrs 3 (4.29%) 03(4.29%) Total & 10 58 (82.86%) 2 (2.86%) 70(100%) percentage (14.30%)

Chart -12: FREQUENCY OF OVARIAN NEOPLASMS IN DIFFERENT AGE GROUP.

>60yrs 4.29% 1.43% 51- 4.29% 60yrs 11.43% 1.43% 41- 1.43% 50yrs 21.43%

31- 4.29% 28.57% 40yrs Sex cord stromal 21- 4.29% tumour 30yrs 12.86% Germ cell tumour

Upto Surface epithelial 20 yrs 4.29% tumour

0% 10% 20% 30%

Only under the age group of 31-40 years, the maximum number of ovarian tumors(n=23) has been found, followed by 41 -50 years of age group which accounted 17 number of cases.

Fifteen tumors were found in the age group upto thirty years, out of which 12 were surface epithelial type and 3 were germ cell tumors.

In total, 55 cases were found upto 50 years of age group.

Surface epithelial tumors were spread from 1st decade to more than 6th decade of life.

Germ cell tumors were found in the age group of 21 to 60 years.

Table -13:Frequency of individual benign neoplasms in different age group

Age group (yrs) Diagnosis Upto 20 21-30yrs 31-40yrs 41-50yrs 51-60yrs >60yrs Total (%) yrs Serous 2 (3.28%) 7(11.48%) 14(22.95%) 10(16.39%) 6(9.84%) 1(1.64%) 40(65.57%) cystadenoma Mucinous 1 (1.64%) 2(3.28%) 3 (4.92%) 2(3.28%) 2(3.28%) - 10(16.39%) cystadenoma Brenner - - 1 (1.64%) - - - 01(1.64%) tumor Mature cystic - 2(3.28%) 3 (4.92%) - 3(4.92%) - 08(13.11%) teratoma Struma ovarii - - - 1 (1.64%) - - 01(1.64%) Fibrothecoma - - - - 1(1.64%) - 01(1.64%) Total 3(4.92%) 11(18.03) 21(34.43%) 13(21.31%) 12(19.67%) 1(1.64%) 61(100%)

Chart -13:FREQUENCY OF INDIVIDUAL BENIGN NEOPLASMS IN DIFFERENT AGE GROUP

1.64% >60 YRS 0 0 51-60 0 0 1.64% YRS 0 41-50 4.92% 0 4.92% YRS 0 3.28% 31-40 0 1.64% FIBROTHECOMA YRS 0 3.28% 21-30 3.28% STRUMA OVARII 4.92% YRS 3.28% 1.64% MATURE CYSTIC 9.84% UPTO 20 16.39% TERATOMA 22.95% BRENNER TUMOUR YRS 3.28% 11.48% MUCINOUS 0% 5% 10% 15% 20% 25% CYSTADENOMA

Most common age group in this entity (Benign) was 31-40 years

Table-14:FREQUENCY OF INDIVIDUAL MALIGNANT NEOPLASMS

IN DIFFERENT AGE GROUP.

Age group(yrs) Diagnosis Upto 51- >60y 21-30 yrs 31-40yrs 41-50yrs Total (%) 20 yrs 60yrs rs Serous cystadeno - - 01(14.29%) 02(28.57%) - - 03(42.86%) carcinoma Mucinous - - - 01(14.29%) - - 01(14.29%) carcinoma Endometroid - - - 01(14.29%) - - 01(14.29%) adenocarcinoma Mixed germ cell - 01(14.29%) - - - - 01(14.29%) tumor Granulosa cell - - - 01(14.29%) - - 01(14.29%) tumor Total - 01(14.29%) 01(14.29%) 05(71.43%) - - 07(100%)

Chart-14: FREQUENCY OF INDIVIDUAL MALIGNANT NEOPLASMS IN DIFFERENT AGE GROUP

>60 yrs

51-60… 14.29% 41-50… 14.29% 14.29% Granulosa cell tumour 28.57% Mixed germ cell tumour 31-40… 14.29% Endometroid adenocarcinoma 21-30… 14.29% Mucinous carcinoma Upto … Serous cystadeno carcinoma 0% 10% 20% 30%

Maximum numbers of malignant cases were found in the age between 41-50 years and for all aged personals, benign tumors were more common than malignant.

Table -15: SITE OF INVOLVEMENT

Laterality Site Number of cases (%) Right 33 (47.14%) Unilateral Left 32 (45.71%) Bilateral 05 (7.14%) Total 70 (100%)

CHART - 15 ; SITE OF INVOLVEMENT

7.14% 47.14%

45.71% UNILATERAL RIGHT

UNILATERAL LEFT

BILATERAL

There were 65 (92.86%) unilateral cases and 5 (7.14%) bilateral cases in our study.

Table -16: DISTRIBUTION OF BENIGN AND MALIGNANT TUMORS IN ONE OR BOTH OVARIES

Diagnosis Bilateral Unilateral Total · Benign Serous cystadenoma 2 (3.28%) 38 (62.30%) 40 (65.57%) Mucinous cystadenoma 1 (1.64%) 9 (14.75%) 10 (14.39%) Brenner tumor - 1 (1.64%) 1 (1.64%) Mature cystic teratoma - 8 (13.11%) 8 (13.11%) Struma ovarii - 1 (1.64%) 1 (1.64%) Fibrothecoma - 1 (1.64%) 1 (1.64%) Total 03(4.92%) 58(95.08%) 61 (100%) · Malignant Serous cystadenocarcinoma 2 (28.57%) 1 (14.29%) 3 (42.86%) Mucinous carcinoma - 1 (14.29%) 1 (14.29%) Endometroid - 1 (14.29%) 1 (14.29%) adenocarcinoma Mixed germ cell tumor - 1 (14.29%) 1 (14.29%) Granulosa cell tumor - 1 (14.29%) 1 (14.29%) Total 02 (28.57%) 05 (71.43%) 07 (100%)

Chart 16 (a): DISTRIBUTION OF BENIGN TUMORS IN ONE OR BOTH OVARIES BENIGN

1.64% Fibrothecoma 0 1.64% Struma ovarii 0 13.11% Mature cystic teratoma 0 1.64% Brenner tumour 0 14.75% Mucinous cystadenoma 1.64%

Serous cystadenoma 62.30% 3.28% Unilateral

0% 10% 20% 30% 40% 50% 60% 70% Bilateral

CHART 16 (B) : DISTRIBUTION OF MALIGNANT TUMORS IN ONE OR BOTH OVARIES MALIGNANT

14.29% Mixed germ cell tumour 0

14.29% Endometroid adenocarcinoma 0

14.29% Mucinous carcinoma 0 14.29% Serous cystadenocarcinoma 28.57% Unilateral 0% 5% 10% 15% 20% 25% 30% Bilateral

In 65 unilateral cases, 33 were right sided and 32 were left sided.

Right side & left side involvement was almost equal.

There were 5 bilateral tumors in the present study, 2 being benign serous cystadenoma, 1 mucinous cystadenoma and 2 serous cystadenocarcinoma.

All others were unilateral tumors.

Table -17: Frequency Of Nature - Benign Ovarian Tumors. Diagnosis Cystic Solid Mixed Total Serous cystadenoma 40 (65.57%) - - 40 (65.57%) Mucinous cystadenoma 10 (16.39%) - - 10 (16.39%) Brenner tumor - - 1 (1.64%) 01 (1.64%) Mature cystic teratoma 8 (13.11) - - 08 (13.11%) Struma ovarii 1 (1.64%) - - 01 (1.64%) Fibrothecoma - 1 (1.64%) - 01 (1.64%) Total 59 (96.72%) 01 (1.64%) 01 (1.64%) 61 (100%)

CHART -17: FREQUENCY OF NATURE - BENIGN OVARIAN TUMORS

70% 65.57%

60%

50%

40%

30%

20% 16.39% 13.11% 10% 1.64% 1.64% 1.64% 0 0 0 0 0 0 0 0 0 0 0 0 0% Cystic Serous Mucinous Brenner Mature cystic Struma ovariiFibrothecoma cystadenoma cystadenoma tumour teratoma Solid Mixed

Majority of tumors in benign groups were cystic (96.72%).

In borderline variety, one each was solid & cystic-mixed (proliferating brenner) and the other being cystic (borderline mucinous).

Table -18: Frequency Of Nature Of Malignant Ovarian Tumors Diagnosis Cystic Solid Mixed Total Serous cystadenocarcinoma - 1 (14.29%) 2 (28.57%) 03(42.86%) Mucinous carcinoma 1 (14.29%) - - 01(14.29%) Endometrioid - - 1 (14.29%) 01(14.29%) adenocarcinoma Mixed germ cell tumor - 1 (14.29%) - 01(14.29%) Granulosa cell tumor - 1 (14.29%) - 01(14.29%) Total 01(14.29%) 03(42.86%) 03(42.86%) 07(100%)

CHART -18: FREQUENCY OF NATURE OF MALIGNANT OVARIAN TUMORS 30% 28.57%

25%

20% 14.29% 14.29% 14.29% 14.29% 14.29% 15%

10%

5% 0 0 0 0 0 0 0 0 0 0%

CYSTIC

SOLID

MIXED

The malignant ovarian tumors were solid (42.86%) and mixed (42.86%) apart from a single case of cystic (14.29%) mucinous carcinoma.

In this group, solid & mixed tumors were common.

Table -19: Clinical Presentation Of The Cases In Present Study

Clinical symptoms Number of cases Percentage Mass / abdomen(MPA) 27 38.57% Irregular bleeding(IB) 21 30.00% Pain abdomen(PA) 17 24.29% Mass descending P/V(MDPV) 04 5.71% Primary infertility(IB) 01 1.43% Total 70 100%

CHART -19: CLINICAL PRESENTATION OF THE CASES IN PRESENT STUDY 5.71% 1.43% 38.57% 24.29% Mass / abdomen(MPA)

Irregular bleeding(IB)

Pain abdomen(PA)

Mass descending P/V(MDPV) Primary infertility(IB) 30.00%

Most of the cases clinically presented with mass per abdomen (38.57%) followed by irregular bleeding per vaginum (30%) and pain abdomen

(24.29%).

One case was associated with primary infertility and the remaining was presented with mass descending per vaginum.

Table -20: Clinical Symptoms In Benign Ovarian Neoplasms

Benign Clinical presentation Diagnosis Total & IB MPA PA MDPV INF percentage Serous 15 12 (19.67%) 09 (14.75%) 3(4.92%) 1(1.64%) 40(65.57%) cystadenoma (24.59%) Mucinous 3(4.92%) 4(6.56%) 3(4.92%) - - 10(16.39%) cystadenoma Brenner 1(1.64%) - - - - 1(1.64%) tumor Mature cystic - 2(3.28%) 5(8.20%) 1(1.64%) - 8(13.11%) teratoma Struma ovarii 1(1.64%) - - 1(1.64%)

Fibrothecoma - 1(1.64%) - - 1(1.64%)

Total 20(32.79%) 19(31.15%) 17(27.87%) 04(6.56%) 1(1.64%) 61(100%)

CHART -20: CLINICAL SYMPTOMS IN BENIGN OVARIAN NEOPLASMS

0 0 Fibrothecoma 1.64% 0 0 0 Struma ovarii 1.64% 0 1.64% Mature cystic teratoma 8.20% 3.28% 0 0 0 Brenner tumour 0 0 1.64% 0 0 Mucinous cystadenoma 4.92% 6.56% 4.92% INF 1.64% 4.92% MDPV Serous cystadenoma 14.75% 19.67% PA 24.59% MPA 0% 5% 10% 15% 20% 25% 30% IB

Most of the benign tumours presented with irregular bleeding, MPA & pain abdomen.

TABLE -21: CLINICAL SYMPTOMS IN BORDERLINE TUMORS

Diagnosis PA MPA IB MDPV INF Total Borderline mucinous tumor - 1 (50%) - - - 1 (50%) Proliferating brenner tumor - 1 (50%) - - - 1 (50%) Total - 2 (100%) - - - 2 (100%)

CHART -21: CLINICAL SYMPTOMS IN BORDERLINE TUMORS

Proliferating brenner tumour 50%

Borderline mucinous tumour INF 50% MDPV IB 0% 20% MPA 40% 60% PA

Both the borderline tumors presented with mass per abdomen.

TABLE -22: Clinical Symptoms In Malignant Tumors

Malignant PA MPA IB MDPV INF Total

Serous cystadenocarcinoma - 3 (42.86%) - - - 3 (42.86%) Mucinous carcinoma - 1 (14.29%) - - - 1 (14.29%) Endometrioid adenocarcinoma - 1 (14.29%) - - - 1 (14.29%)

Mixed germ cell tumor - 1 (14.29%) - - - 1 (14.29%)

Granulosa cell tumor - - 1 (14.29%) - - 1 (14.29%)

Total - 06(85.71%) 01(14.29%) - - 7 (100%)

CHART -22: CLINICAL SYMPTOMS IN MALIGNANT TUMORS

Granulosa cell tumour 0 14.29% Mixed germ cell 0 tumour 14.29% Endometrioid 0 adenocarcinoma 14.29%

Mucinous carcinoma 0 14.29% INF Serous MDPV 0 42.86% cystadenocarcinoma IB MPA 0% 10% 20% 30% 40% 50% PA

In malignant cases, mass per abdomen (85.71%) was a common finding.

Granulosa cell tumor presented with irregular bleeding.

Table -23: Histomorphological Pattern Of Ovarian Tumors

Diagnosis Number of cases Percentage Serous cystadenoma 40 57.14% Mucinous cystadenoma 10 14.29% Brenner tumor 01 1.43% Mature cystic teratoma 08 11.43% Struma ovarii 01 1.43% Fibrothecoma 01 1.43% Borderline mucinous tumor 01 1.43% Proliferating brenner tumor 01 1.43% Serous cystadenocarcinoma 03 4.29% Mucinous carcinoma 01 1.43% Endometrioid adenocarcinoma 01 1.43% Mixed germ cell tumor 01 1.43% Granulosa cell tumor 01 1.43% Total 70 100%

CHART -23: HISTOMORPHOLOGICAL PATTERN OF OVARIAN TUMORS

1.43%

4.29%

1.43%

1.43% 1.43%

Serous cystadenoma

Mucinous cystadenoma 11.43% Number of cases Brenner tumour

= 70 Mature cystic teratoma

57.14% 1.43% Struma ovarii

Fibrothecoma 14.29% Borderline mucinous tumour Proliferating brenner tumour Serous cystadenocarcinoma

Out of 70 cases of clinical suscipicion, CA 125 was done in 24 cases of which

5 showed higher value than normal.

However, out of 5, one each turned out to be malignant- serous cystadenocarcinoma and borderline brenner tumor. In remaining 3 cases one was benign serous cystadenoma, one mucinous cystadenoma & one

Fibrothecoma.

TABLE -24: ER & PR expression in Surface Epithelial Tumors (n=33). HPE ER- ER- ER+PR ER+PR SN Age HPE Diagnosis ER PR No PR- PR+ - + 1 50 621/13 Endometrioid adenocarcinoma - - 1

2 50 817/13 Papillary serous adenocarcinoma + - 1

3 46 223/13 Mucinous carcinoma - - 1

Invasive high grade serous 4 45 615/15 + + 1 carcinoma 5 37 030/15 Borderline mucinous tumor - + 1

6 40 264/15 Serous cystadenoma + + 1

7 35 1165/14 Mucinous cystadenoma - - 1

8 30 864/14 Mucinous cystadenoma - - 1

9 32 501/13 Serous cystadenoma - - 1

10 40 085/15 Serous cystadenoma + - 1

11 48 279/15 Mucinous cystadenoma + + 1

12 60 431/15 Serous adenofibroma - + 1

13 50 847/14 Papillary serous cystadenoma - - 1

14 33 314/13 Serous cystadenoma - - 1

15 40 594/13 Serous cystadenoma - - 1

16 34 347/13 Bilateral mucinous cystadenoma - - 1

17 20 400/13 Right mucinous cystadenoma - - 1

18 65 679/13 Left mucinous cystadenoma - - 1

19 23 023/13 Left Serous cystadenoma + + 1

20 45 121/13 Right Serous cystadenoma + + 1

21 45 262/13 Papillary Serous cystadenoma + + 1

22 50 344/13 Serous cystadenoma + + 1

23 39 360/13 Serous cystadenoma + + 1

24 35 372/13 Serous cystadenoma + + 1

25 45 415/13 Serous cystadenoma + + 1

26 40 476/13 Serous cystadenoma + + 1

27 55 528/13 Serous cystadenoma + + 1

28 31 542/13 Serous cystadenoma - + 1

29 55 579/13 Serous cystadenoma - - 1

30 49 723/13 Serous cystadenoma - - 1

31 42 074/14 Serous cystadenoma - - 1

32 20 282/14 Serous cystadenoma - - 1

33 46 287/14 Serous cystadenoma - - 1

TOTAL 16 3 2 12

"+" 14 15 "-" 19 18

IHC in present study showed, ER positivity in 14 & PR positivity in 15 surface epithelial tumors.

ER positivity (n=14) was seen in 13 serous tumors & one mucinous tumor. Out of 13 serous tumors 11 were benign serous tumors & 2 serous cystadenocarcinoma and the sole mucinous tumor was mucinous cystadenoma.

PR positivity (n=15) was seen in 13 serous tumors & 2 mucinous tumors. Of the 13 serous tumors, 12 were benign serous tumor & one serous cystadenocarcinoma. Two mucinous tumors included, one mucinous cystadenoma & one borderline mucinous tumor.

Sixteen surface epithelial tumors were both ER & PR-ve, which included 9 serous cystadenomas, 5 mucinous cystadenomas, one mucinous carcinoma & one endometroid carcinoma.

ER-ve & PR positivity was seen in 3 cases, i.e., 2 serous cystadenoma & one borderline mucinous tumor.

ER+ve & PR negativity was seen in 2 cases, which includes one serous carcinoma & one serous cystadenoma.

TABLE -25: Correlation Of Receptors With Age

AGE <40yrs 40-50yrs >50yrs

ER positive n=14 3 (21.43%) 10 (71.43%) 1 (7.14%)

PR positive n=15 5 (33.33%) 8 (53.33%) 2 (13.33%)

CHART -25: CORRELATION OF RECEPTORS WITH AGE

71.43% 80% 70% 53.33% 60% 50% 33.33% <40yrs (n=14) 40% 21.43% 40-50yrs (n=09) 30% 13.33% >50yrs (n=7) 20% 7.14% 10% 0% ER n=14 PR n=15

ER & PR expression was predominantly seen in 40-50yrs.

Table -26: Expression of Estrogen & Progesterone receptors in SETs

Serous Mucinous Endometrioid Receptor evaluation P value tumors(24) tumors(8) tumors(1) ER-ve PR-ve (n=16) 9 (37.50%) 6 (75.00%) 1 (100%) -

ER-ve PR+ve (n=3) 2 (8.33%) 1 (12.50%) - -

ER +ve PR-ve (n=2) 2 (8.33%) - - -

ER+ve PR+ve(n=12) 11 (45.83%) 1 (12.50%) - 0.0001

CHART -26: Expression of Estrogen & Progesterone receptors in SETs 100% 100%

90% 75.00% 80% 70% 60% 45.83% 50% 37.50% 40% 30% 12.50% 12.50% 20% 8.33% 8.33% 10% 0 0 0 0 Serous tumors(24) 0% ER-PR- (n=16) ER- PR+ (n=3) ER + PR- (n=2) ER + PR +(n=12) Mucinous tumors(8)

P value was calculated using CHI Square Test by considering the actual & expected/average range

ER & PR expression was higher in serous tumors (45.83%) than mucinous tumors (12.50%).

Table -27: Expression Of ER & PR In Morphological Types Of Sets.

TYPE OF SURFACE Nature of No. of cases where No.of.ER & EPITHELIAL TUMORS tumor IHC was done. PR positive Benign 22 10 Serous (24) Borderline - - Malignant 02 01 Benign 06 01 Mucinous (8) Borderline 01 - Malignant 01 - Benign - - Endometroid (1) Borderline - - Malignant 01 -

CHART -27: EXPRESSION OF ER & PR IN MORPHOLOGICAL TYPES OF SETS.

10 10 9 8 7 6 5 4 3 2 1 1 Benign 1 0 0 0 0 0 0 Borderline 0 Serous (24) Mucinous (8) Endometroid (1) Malignant

Benign serous tumors showed ER & PR positivity in 45.45% cases (10/22).

Out of two malignant serous tumors, one showed ER & PR positivity (50%).

Among 6 benign mucinous tumors, only one showed both ER & PR positivity

(16.66%). The sole malignant mucinous tumor observed in the present study turned out to be ER & PR negative.

Similarly the sole endometroid adenocarcinoma encountered in the present study was negative for ER & PR.

(i)

(ii)

(iii)

(iv)

(v)

(vi)

(vii)

Fig-1: Serous Cystadenoma

(viii)

(ix)

(x)

(xi)

(xii)

(xiii)

DISCUSSION

Ovarian tumors are the most appealing neoplasms in terms of origin, clinical presentation and malignant potentiality. Therefore, it aroused curiosity & difficulties to pathologists and clinicians regarding their abnormal contents & histogenesis. So a detailed study of morphological patterns of ovarian tumors is needed for planning the treatment modality and to assess the prognosis.

The present study was carried on 70 consecutive cases of various types of ovarian neoplasms. The main aspects considered in present study are the histomorphological findings made out by light microscopic examination and also by using special stains wherever required, the incident rate of the ovarian tumors in different age groups and to carry out Immunohistochemistry especially in surface epithelial types.

INCIDENCE:

Out of 70 cases, 61 were benign (87.14%), 2 borderline (2.86%) and the remaining 7 cases were malignant (10%). The present study data was in correlation with Nital.et al22, Summyia Farooq.et al7, A Pradan.et al114 and

Vaddatti.et al113. In the last reference the total number of cases were more

(n=278).

TABLE -1: COMPARATIVE ANALYSIS OF NATURE OF OVARIAN

TUMORS

Kanthik Summyia A. GG Type of Nital.et Vaddatti.e R Jha. et Present ar S.N.et Farooq.et Pradan. Swamy. tumor al22 t al113 al116 study al112 al7 et al114 et al115

Benign 66(79.5%) 55(78.57%) 217(78.05%) 108(75%) 66(79.5%) 86(71.6%) 135(83.9%) 61(87.14%)

Border 02(2.4%) 01(1.42%) - 05(3.48%) 02(2.4%) 4(3.3%) - 02(2.86%) line

Malignant 15(18%) 14 (20%) 61(21.95%) 31(21.52%) 15(18%) 30(25.1%) 26(16.1%) 07(10%)

Total 83(100%) 70(100%) 278(100%) 144(100%) 83(100%) 120(100%) 161(100%) 70(100%)

In Vaddatti.et al113 study, there were no borderline tumors encountered.

Kanthikar.S.N.et al112 took both non-neoplastic (75) & neoplastic lesions (70).

In the latter lesions, 55 (78.57%) were benign, 1 borderline & 14 (20%) being

malignant.

Ameena Asraf et.al117 also studied the relative frequency & histomorphological

pattern of ovarian masses; they took only oophorectomy specimens of both

neoplastic (127) &

non-neoplastic lesions (85) of the ovary. In neoplastic lesions there were 82

(64.57%) benign cases & 45 (35.43%) malignant cases.

By comparing the incidence of nature of ovarian tumors with other studies,

irrespective of the total number of cases, the benign lesions were more

common followed by malignant conditions and borderline tumors were the

least common (2.4%).

Age

All the ovarian tumors were observed between the age group 10-80 years,

finding similar to Nital.et al22, Kanthikar S N.et al112, A Pradhan .et al114,

Vaddatti.et al113, Ameena Asraf.et al117 & R Jha.et al116. The youngest patient

was 10 years old & oldest was 75 yrs, both of them presented with serous

cystadenoma. 31-40yrs of age group showed maximum number of cases.

However, the rate of incidence peaks as the age advances.

31-40 yrs age group was the one where benign ovarian tumors mainly fell,

which is parallel to Vaddatti.et al113 & R Jha.et al116. The mature cystic

teratomas were seen betwixt 21-60 yrs age group.

Malignancies specifically glimpsed among 41-50 yrs congruent to Vaddatti.et

al113 & R Jha.et al116.

Clinical presentation

Most of the patients presented with Mass per abdomen (38.57%) followed by irregular bleeding per vaginum (30%), pain abdomen (24.29%) & mass descending P/V in 4cases (5.17%). One case was associated with primary infertility (1.43%). In Nital.et al22, Kanthikar.et al112 & A Pradhan.et al114 studies, also the most common presentation of patients was mass per abdomen.

In benign lesions, irregular bleeding/ vaginum, mass per abdomen & pain in abdomen were the most commonly observed presentation accounting for

32.79%, 31.15% & 27.87% respectively.

In borderline & malignant conditions, lump in the abdomen was a common finding.

Site of involvement

Unilateral involvement was more common than bilaterality. Out of 70 cases, unilateral involvement was observed in 65 cases while 5 were bilateral.

Amongst unilateral cases, 33 were right sided & 32 were left sided making the incidence almost equal.

Two benign serous cystadenoma, 1 mucinous cystadenomas and 2 serous cystadenocarcinomas were bilateral.

Thus, unilateral involvement was more common than bilateral one, coinciding with other findings of Nital.et al22, Kanthikar S.N.et al112 & A Pradhan.et al114.

TABLE -2: COMPARATIVE INCIDENCE OF SITE OF INVOLVEMENT Nital.et Kanthikar A Pradhan.et Site Present study al22 S.N.et al112 al114 Unilateral 78% 78.18% 72% 92.86% Bilateral 22% 21.82% 28% 7.14%

In our study right & left side, participation showed close numbers, but in

Nital.et al22 & A Pradhan.et al114 left side was more common than the right side.

In Vaddatti.et al113study, commonest bilateral tumor was benign serous tumor & serous cystadenocarcinoma. Similar findings were also noted in present

study. However R Jha.et al116 quoted findings other way round and showed

bilaterality as commonest observations in malignant tumors, but the overall site

of involvement supported our study by being unilateral is common than

bilateral tumors.

Gross pathology

Size: The largest tumor was mucinous cystadenoma 22x20x15 cm & smallest

was serous cystadenoma 3x1.8x1cm.

The greater numbers of benign lesions were cystic & malignancies were solid

& mixed, this goes in agreement with findings of Nital.et al22, Kanthikar S N.et

al112 & A Pradhan.et al114.

The benign lesions with cystic consistency were 59 in number (96.72%), while

one (1.64%) was solid & the other one was mixed (1.64%). In malignancies,

majority were solid (42.86%) & mixed (42.86%).

TABLE-3: COMPARATIVE ANALYSIS OF GROSS PATHOLOGY Benign Borderline Malignant Studies Cystic Solid Mixed Cystic Solid Mixed Cystic Solid Mixed Kanthikar S 66.67% 13.30% 28.80% - - 1.42% - 42.85% 55% N.et al112 A Pradhan.et 42.10% 4.80% 32.50% 2.60% - - - 8.40% 9.60% al114 Present study 96.72% 1.64% 1.64% 2.86% - - 14.29% 42.86% 42.86%

Morphological patterns: TABLE -4: COMPARATIVE INCIDENCE OF MORPHOLOGICAL

TYPES OF OVERALL OVARIAN TUMORS

Kanthi Ameena GG Ovarian Nital.et kar Summyia Pradhan A R Jha. et Present Vaddatti.et Ashraf.et Swamy.et tumors al22 S.N.et farooq.et al7 .et al114 al116 study al113 al117 al115 al112

Surface 39(46.9%) 67.14% 100(69.44%) 237(85.25%) 39(46.9%) 67(52.76%) 74(61.6%) 84(52.2%) 58(82.26%) epithelial Germ cell 38(45.7%) 22.85% 32(22.22%) 27(9.72%) 38(45.7%) 55(43.31%) 2(21.7%) 68(42.2%) 10(14.29%) tumors Sex cord stromal 03(3.6%) 5.71% 09(6.25%) 11(3.95%) 03(3.6%) 04(3.15%) 14(11.7%) 05(3.1%) 2(2.86%) tumors

Metastatic 03(3.6%) 4.28% 03(2.09%) 03(1.08%) 03(3.6%) 01(0.78%) 06(5.0%) 04(2.4%) - tumors

Total 83(100%) 100% 144(100%) 278(100%) 83(100%) 127(100%) 120(100%) 161100%) 70 (100%)

In present study, only primary ovarian tumors were detected and there were no

metastatic tumors. Among the histological type, the commonest type of ovarian

neoplasm seen in present study was surface epithelial type (82.26%), followed

by germ cell tumors (14.28%) and sex cord stromal tumors, which showed

minimal incidence (2.86%). Our finding is comparable to the observations

quoted in several other studies i.e. 67.14%, 22.85% & 5.17%--- 69.44%,

22.22% & 6.25% -- 85.25%, 9.72% & 3.95 in Kanthikar S.N.et al112,

Summyia farooq.et al7 & Vaddatti.et al113respectively. GG Swamy et.al115 also

showed similar frequency. Many other studies like Nital.et al22, A Pradhan .et

al114, Ameena ashraf.et al117 & R Jha.et al116, as shown in above table although

showed surface epithelial type as more common than other types, it is noticed

that the germ cell tumors were also equally common. In present study,

however, the GCTs are comparatively less common than surface epithelial

tumors.

TABLE -5: COMPARATIVE ANALYSIS OF COMMON BENIGN TUMORS Summyia A Nital.et Vaddatti.et Ameena Benign tumors farooq.et Pradhan Present study al22 al113 ashraf.et al117 al7 .et al114 Surface epithelial 31(47%) 75 190 (7.56%) 31(47%) 43 51(83.61%) type Germ cell tumors 33(50%) 28 19 (8.75%) 33(50%) 48 09(14.75%) Sex cord stromal 2(3%) 5 8 (3.69%) 02(3%) 1 01(1.64%) tumors Total 66(100%) 108 217(100%) 66(100%) 82 61(100%)

The common benign tumor encountered in present study was surface epithelial type followed by GCTs. Sex cord stromal tumor was least common comparatively. Similar results were seen in Summyia farooq.et al7 &

Vaddatti.et al113 as shown in the above table. The reverse results were seen in

Nital.et al22, A Pradhan.et al114 & Ameena ashraf.et al117, where benign germ cell tumors were common than benign surface epithelial type but again sex cord stromal tumors were least common in all the above studies which are in concordance with our study.

In our study, comparing the nature of the tumors, borderline tumors were least detected(n=2), both being in the category of surface epithelial neoplasms, which is similar to Nital.et al22, Kanthikar.et al112, Summyia farooq.et al7, A

Pradhan.et al114, GG Swamy.et al115.

TABLE -6: COMPARATIVE ANALYSIS OF COMMON

MALIGNANT TUMORS

Malignant Summyia A Pradhan Ameena Nital.et al22 Vaddatti.et al113 Present study tumors farooq.et al7 .et al114 ashraf.et al117 Surface 12 47 06 05 20 34 epithelial (80%) (77.05%) (40%) (71.43%) Germ cell 05 08 05 01 4 7 tumors (33%) (13.11%) (33%) (14.29%) Sex cord 01 03 1 01 4 3 stromal tumors (7%) (4.92%) (7%) (14.29%) 03 03 03 Metastatic 3 1 - (20%) (4.92%) (20%) 21 61 15 07 Total 67 45 (100%) (100%) (100%) (100%)

In the present study, among the malignant tumors, the most common type was

surface epithelial type followed by germ cell & sex cord stromal tumors.

Nital.et al22, Summyia.et al7, Vaddatti.et al113, A Pradhan.et al114 & Ameena

ashraf.et al117 also encountered the similar results.

No metastatic tumors were encountered in our study

Irrespective of benign, borderline or malignant, surface epithelial tumors were

the most ovarian tumors observed in the present study.

Histopathology: Surface epithelial type: Amongst the surface epithelial tumors, serous subtype was more common than

mucinous subtype despite of benign, borderline or malignant nature.

TABLE -7: COMPARATIVE ANALYSIS OF BENIGN OVARIAN

TUMORS IN SETs

% among total benign % among total ovarian Studies Name of tumor tumors tumors Serous tumor 64.48% 50.72% Vaddatti.et Mucinous cystadenomas 21.66% 16.90% al113 Brenner type 0.92% 0.72% Serous tumor 65.57% 57.14% Present study Mucinous tumor 16.39% 14.29% Brenner tumor 1.64% 1.43%

(Note: % ---Percentage)

TABLE -8: COMPARATIVE ANALYSIS OF MALIGNANT OVARIAN TUMORS IN SET

% among total % among total Studies Name of tumor malignant tumors ovarian tumors

Serous tumor 49.18% 10.79% Mucinous type 21.30% 4.48% Vaddatti.et Endometrioid type 3.28% 0.73% al113 Clear cell type 1.64% 0.36% Brenner type 1.64% 0.36% Serous cystadenocarcinoma 42.86% 4.29% Present Mucinous carcinoma 14.29% 1.43% study Endometrioid 14.29% 1.43% adenocarcinoma

In R Jha.et al116 study, 78.9% of serous tumors were benign & 21.1% were

malignant, similarly 77.8% of mucinous tumors were benign neoplasms while

22.2% were malignancies analogous to present study, in serous 93% were

benign & 7% were malignant. In Nital.et al22 study alike of our study among

mucinous tumors 12(80%) were benign, 1(6.7%) borderline & 2(13.3%)

malignant. In present study, out of 12 mucinous tumors, 10 (83.3%) were benign, 1(8.3%) borderline & 1(8.3%) was malignant.

The present study highlights the occurrence of serous tumors (in spite of benign/malignant) as the most common as compared to mucinous tumors. This observation correlates with many other studies like Nital.et al22, Vaddatti.et al113, Summyia Farooq.et al7, Ameena Ashraf.et al117 & GG Swamy.et al115.

Benign Brenner tumor observed in the present study was an incidental finding coinciding with the findings in literature35. It enacts 1.43% of all ovarian tumors. Proliferating Brenner was also accounted for the same percentage as above.

Among overall benign lesions serous tumors were also the commonest ones.

There were 3 serous cystadenocarcinoma, one endometrioid adenocarcinoma & one mucinous carcinoma. Serous cystadenocarcinoma had an incidence of

4.29% of overall OTs. Endometrioid accounted for 1.43% of entire ovarian neoplasms.

Serous over rides other subtypes of SETs.

Germ cell tumors:

Germ cell tumors were noticed as the second most common type of ovarian tumor in present study. Teratoma, 8/10 (80%), was the most common amongst the GCTs in this study akin to other studies like Nital.et al22 & A Pradhan.et al114.

Mature cystic teratoma ranked the third most common tumor in present study

(11.43%).

R Jha.et al116 & Vaddatti.et al113 found similar observations 65/68 and 18/27 respectively.

TABLE -9: COMPARATIVE INCIDENCE OF TERATOMA

Studies No. or % of teratoma Nital.et al22 92.1% A Pradhan.et al114 92% R Jha.et al116 65 Vaddatti.et al113 18 Present study 8(80%)

In present study, there was one struma ovarii, an uncommon ovarian teratoma, which accounted for 1.43% of all ovarian tumors and coincides with findings in literature with an incidence as 3% 35. In Nital.et al22 & Vaddatti.et al113 research, struma ovarii comprised one case of overall ovarian teratomas.

The incidence in Vaddatti.et al113 study also showed only 0.36% of all ovarian tumors.

The only Mixed Germ cell tumor observed in the present study showed components of immature teratoma (70%) and yolk sac tumor (30%). It represented 1.43% of all OTs.

Sex cord stromal tumors

In present study, 1 benign (Fibrothecoma) and 1 malignant (granulosa cell tumor) sex cord stromal tumors were observed which accounted for 1.43% each, of all ovarian tumors.

These findings are in close proximity to Nital.et al22 which also showed only 3cases and

R Jha.et al116 study which showed1/4 sex cord stromal tumor.

ER & PR expression

Both, the hormones with its receptors are involved in the process of tumor genesis of ovaries. It is involved by the disruption of the cell cycle, apoptosis &

DNA repair101, 102.

In present study, ER & PR were positive more in serous tumors compared to other SETs like mucinous tumors and endometroid adenocarcinoma, corresponding with the results of Summyia Farooq et.al7, Hugo Arias-Pulido.et al118 & Sylvia.et al119.

TABLE -10:COMPARATIVE INCIDENCE OF ER & PR EXPRESSION IN SURFACE EPITHELIAL TUMORS ER & PR HugoArias-Pulido.et al118 Summyia Farooq.et al7 Present study expression Serous Mucinous Serous Mucinous Serous Mucinous

ER-PR- 12 (18.5%) 15 (62.5%) 17(48.57% 13(86.6%) 09(37.50%) 06 (75.00%)

ER-PR+ 09 (13.9%) 04 (16.7%) 5(14.28%) 1(6.67%) 02 (8.33%) 01 (12.50%) ER+PR- 15 (23.1%) 03 (12.5%) 0 0 2(8.33%) - ER+PR+ 29 (44.6%) 02 (8.35) 13(37.14%) 1(6.67%) 11 (45.83%) 01 (12.50%)

In Summyia Farooq.et al7 study, the more number of ER & PR positive cases were seen in >50 years of age group accounting for 75%; Sylvia.et al119 study also quoted similar finding. However in the present study more number of ER & PR positive cases was seen in 41-50 yrs of age group.

Amongst serous tumors, Summyia Farooq.et al7 found estrogen receptor expression in 8 malignant tumors, one borderline and 4 benign tumors and progesterone receptor expression in 11 malignant, one borderline and 6 benign serous tumor. In mucinous tumors, they found ER expression in only 1 malignant tumor and PR expression in 1 borderline & 1 malignant tumor.

In the present study, among serous tumors, estrogen receptors were expressed in 2 malignant & 11 benign tumors and progesterone receptors were expressed in 1 malignant & 11 benign tumor.

In mucinous tumors, ER was expressed in 1 benign tumor & PR in 1 benign and 1 borderline tumor.

Thus to conclude, ER & PR expression is higher in serous tumors than in mucinous tumors.

The numbers of borderline & malignant tumors in the present study were less as compared to other studies & hence cannot hypothesize regarding the different level of ER & PR expression in benign versus borderline & malignant tumors.

Conclusion

A retrospective & prospective analysis of 70 consecutive ovarian tumors was done in department of pathology, Karpaga Vinayaga Institute of Medical

Sciences from August 2012 to July 2015. A comprehensive analysis of the data obtained, suggested the following:

1. Benign ovarian tumors (87.14%) were more common than malignant

tumors (10%). Surface epithelial class of tumors (82.86%) was the most

common type amongst overall ovarian tumors while Germ cell tumors

(14.29%) ranked second.

2. Benign surface epithelial tumors (83.61%) were the most common

tumors amongst all benign tumors and malignant surface epithelial

tumors (71.43%) were the most common malignant tumors.

3. In germ cell variety of tumors, benign mature cystic teratoma (80%)

was the most common one.

4. Taking into account all morphological patterns, serous cystadenoma

(57.14%) was the most common benign type and serous

cystadenocarcinoma (4.29%), the most common malignant tumor.

5. Considering the age, the maximum number of cases was found in the

reproductive age group, with a maximal number of benign tumors

(34.43%) in 31-40yrs age group and malignant tumors (71.43%) in 41-

50yrs of age group. 6. The majority of cases presented with mass per abdomen, but other

symptoms like pain abdomen, irregular bleeding & mass descending PV

were also observed.

7. Bilaterality was commonly observed in surface epithelial tumors.

8. Grossly, benign tumors were mostly cystic in nature while malignant

tumors were predominantly solid & mixed.

9. Serous tumors (91.67%) showed higher ER & PR expression than

mucinous tumors (8.33%).

ANNEXURE –I

DATA COLLECTION FORM

NAME:

AGE:

IP NUMBER:

CHIEF COMPLAINTS:

MENSTRUAL HISTORY:

OBSTETRIC HISTORY:

PER ABDOMEN / PER SPECULUM EXAMINATION/PER VAGINAL FINDINGS:

ULTRASOUND FINDINGS:

TUMOUR MARKERS:

CLINICAL DIAGNOSIS:

TYPE OF SPECIMEN: ASCITIC FLUID:

GROSS FINDINGS:

HISTOPATHOLOGICAL FINDINGS:

HISTO PATHOLOGICAL DIAGNOSIS: ER & PR:

ANNEXURE -II TNM Staging of ovarian tumours

Stage I-Growth limited only to the ovaries.

Ia. To one ovary, no ascites, no tumour on the surface & with intact capsule.

Ib. Both ovaries, no ascites. No tumour on the external surface, intact capsule.

Ic. Either of the above, with tumour on the surface of the ovaries, with ruptured capsule/ with ascites present containing malignant cells/ peritoneal washings.

Stage II- Growth involving one/both ovaries extension to the pelvis.

IIa. Extension/ metastasis to the uterus.

IIb. Extending to other pelvic tissues.

IIc. Either Stage IIa /IIb but with tumour on surface of the ovaries/ with capsule rupture/ with ascites/ with malignant cells/ with positive peritoneal washings.

Stage III. Tumour involvement with one or both ovaries with peritoneal implants out of the pelvis & / positive retroperitoneal or inguinal nodes.

Superficial metastasis in the liver qualifies the stage 3.

IIIa. Grossly limited to the pelvis with negative nodes, but histologically confirmed seedling of the abdominal peritoneal surfaces.

IIIb. Involving one or both sides of ovary, with histological confirmed implants on the abdomino peritoneal surface, not exceeding 2 cm, with negative nodes.

IIIc. Implants of the abdomen greater than 2cm & / + retroperitoneal or inguinal nodes. Stage IV. Both or one ovary involvement with distant metastasis. If effusion of the present, then positive cytological findings should be there, to say it as stage

IV and parenchymal liver metastases equals this stage.

Note: +Present.

ANNEXURE -IIIA

Staining procedure

Hematoxylin & eosin staining method

1. Sections -under water

2. Staining with Harris Hematoxylin for 2-3 minutes

3. Washed with running tap water

4. Differentiated in 1% acid alcohol

5. Wash and bluing was done with running tap water

6. Counter stained with aqueous eosin for 2 minutes

7. Dehydrated with absolute alcohol (2-3 changes)

8. Clearing was done 2-3 changes of xylene

9. Mounted using Dibutyl phthalate polystyrene xylene (Dpx)

Results: Nucleus-blue & cytoplasm-pink.

ANNEXURE -IIIB

Pas staining method

1. Oxidized wit periodic acid for 5 mins

2. Rinse in several changes of distilled water.

3. Sections were covered with Schiffs reagent for 30 mins.

4. Rinse in running tap water for 5-10 mins

5. Nuclear staining-Harris Hematoxylin.

6. Cover slip

Mucins stained magenda red.

ANNEXURE -IV

Immunohistochemistry method

1. Sections were taken on APES (Aminopropyltriethoxysilane) coated

slide and the slide is kept in incubator for 1 hour before the

procedure.

2. Deparaffinisation

 Xylene I- 5 mins

 Xylene II-5 mins

 Absolute alcohol I -5 min

 Absolute alcohol II- 5 min

 90% alcohol -5min

 80% alcohol-5min

3. Antigen retrieval – by using pressure cooker (15-18mins).TRIS

EDTA buffer withpH-9 was used.

4. Slides were cooled for 15 mins.

5. Hydrogen peroxide block step -10 mins.

6. Wash buffer-2 changes for 3 mins.

7. A drop of ready to use primary antibody(ER & PR) were added to

the slides. Incubate for 30 mins at room temperature in a humid

chamber.

8. Wash buffer-2 changes for 3mins each.

9. Apply a drop of ready to use secondary antibody HRP for 10 mins

at room temperature. 10. Wash slides in wash buffer for 2 changes-3 mins each.

11. DAB Chromogen -3mins

12. Wash slides in distilled water for 3 minute to stop the reaction.

13. Counter stain lightly with harris hematoxylin(5 mins)

14. Mount the slide with DPX (Diethyl Phthalate Xylene).

Note: Breast carcinoma slides were run along with the slides of ER & PR to act as control slides.

ANNEXURE V

Abbreviations SET- Surface epithelial tumours APST- Atypical proliferative serous tumor APMT- Atypical proliferative mucinous tumour APET-Atypical proliferative endometrioid tumours APBT-Atypical proliferative brenner tumour APCCT-Atypical proliferative clear cell tumor CCC-Clear cell carcinomas CA-125- Cancer/Carcinoma antigen PA- Pain abdomen MPA-Mass per abdomen IB-Irregular Bleeding MDPV-Mass descending per vaginum INF-infertility ER-Estrogen receptor PR-Progesterone receptor n –number WHO-World health organization BRCA (1) & (2)-Breast cancer OCPs-Oral contraceptive pills HNPCC-Hereditary non polyposis colon cancer PTEN-Phosphatase and tensin homologue MUTYH-mutY homologue DNA-Deoxyribonucleic acid US-United states FIGO-International federation of gynaecological and obstetrics GCT-Germ cell tumour KRAS- Kristen rat sarcoma viral oncogene BRAF- Murine sarcoma viral oncogene homologue B ERBB2-erb-b2 receptor tyrosine Kinase 2 CTNNB1-Catenin (Cadherin associated protein ) beta-1 PIK3CA- alpha Phosphatidylinostiol-4,5-bisphosphate 3-kinase, catalytic subunit ARIDIA-AT rich interactive domain 1A TP53-Tumour protein P53 MPSC-Micropapillary serous carcinoma CDX1 & 2-Caudal type homeobox1&2 LGALS4-Lectin, Galactoside-Binding, Soluble 4 EC-Endometrioid carcinoma CA- Carcinoma CK- Cytokeratin OC-Ovarian carcinoma OTs-Ovarian tumours CEA- Carcino embryogenic antigen YST- Yolk sac tumour WT1- Wilms tumour1 HNF-1β-Hepatocyte nuclear factor-1-beta AFP-Alpha Feto Protein TTF-Thyroid transcription factor TCC-Transitional cell carcinoma EMA-Epithelial membrane antigen MMMT- Malignant mixed mullerian tumour SCC- Squamous cell carcinoma FOX L2-Forkhead box L2 HPF-High power field LBF-Low power field SCTAT-Sex cord stromal tumour with annular tubules IHC- Immunohistochemistry CD 117-Cluster of differentiation OCT4-Octamer –binding transcription factor 4 SALL4-Spart –like transcription factor 4 PLAP-Placental alkaline phosphatase HCC-Hepatocellular carcinoma SF-1-Steriodogenic factor 1 hCG - Human Chorionic Gonadotrophin FISH-Florescent in situ hybridization NOS-Not otherwise specified PJ- Peutz jeghers syndrome

ANNEXURE VI

LIST OF TABLES

TABLE. DESCRIPTION OF TABLE'S NO’S. Table 1 MORPHOLOGICAL TYPE OF OVARIAN TUMORS

Table 2 FREQUENCY DISTRIBUTION OF VARIOUS CLASSES OF OVARIAN TUMORS

Table 3 FREQUENCY OF DIFFERENT CLASSES OF BENIGN OVARIAN TUMORS

Table 4 FREQUENCY OF DIFFERENT CLASSES OF MALIGNANT OVARIAN TUMORS

Table 5 HISTOPATHOLOGICAL DISTRIBUTRION OF BENIGN OVARIAN TUMORS

Table 6 HISTOPATHOLOGICAL DISTRIBUTRION OF MALIGNANT OVARIAN TUMORS FREQUENCY SUBTYPES OF BENIGN SURFACE EPITHELIAL OVARIAN Table 7 NEOPLASMS Table 8 FREQUENCY SUBTYPES OF BORDERLINE SURFACE EPITHELIAL NEOPLASMS

Table 9 FREQUENCY SUBTYPES OF MALIGNANT SURFACE EPITHELIAL NEOPLASMS

Table 10 FREQUENCY OF GERM CELL TUMORS

Table 11 FREQUENCY OF SEX CORD STROMAL TUMORS

Table 12 FREQUENCY OF OVARIAN NEOPLASMS IN DIFFERENT AGE GROUP

Table 13 FREQUENCY OF INDIVIDUAL BENIGN NEOPLASMS IN DIFFERENT AGE GROUP FREQUENCY OF INDIVIDUAL MALIGNANT NEOPLASMS IN DIFFERENT AGE Table 14 GROUP Table 15 SITE OF INVOLVEMENT DISTRIBUTION OF BENIGN AND MALIGNANT TUMORS IN ONE OR BOTH Table 16 OVARIES Table 17 FREQUENCY OF NATURE - BENIGN OVARIAN TUMORS.

Table 18 FREQUENCY OF NATURE OF MALIGNANT OVARIAN TUMORS

Table 19 CLINICAL PRESENTATION OF THE CASES IN PRESENT STUDY

Table 20 CLINICAL SYMPTOMS IN BENIGN OVARIAN NEOPLASMS

Table 21 CLINICAL SYMPTOMS IN BORDERLINE TUMORS

Table 22 CLINICAL SYMPTOMS IN MALIGNANT TUMORS

Table 23 HISTOMORPHOLOGICAL PATTERN OF OVARIAN TUMORS

Table 24 ER & PR EXPRESSION IN SURFACE EPITHELIAL TUMORS (n=33).

Table 25 CORRELATION OF RECEPTORS WITH AGE

Table 26 EXPRESSION OF ESTOGEN & PROGESTERONE RECEPTORS IN SETS

Table 27 EXPRESSION OF ER & PR IN MORPHOLOGICAL TYPES OF SETs.

LIST OF CHARTS

CHART NAME OF CHARTS NOS CHART 1 MORPHOLOGICAL TYPE OF OVARIAN TUMORS CHART 2 FREQUENCY DISTRIBUTION OF VARIOUS CLASSES OF OVARIAN TUMORS CHART 3 FREQUENCY OF DIFFERENT CLASSES OF BENIGN OVARIAN TUMORS CHART 4 FREQUENCY OF DIFFERENT CLASSES OF MALIGNANT OVARIAN TUMORS CHART 5 HISTOPATHOLOGICAL DISTRIBUTRION OF BENIGN OVARIAN TUMORS CHART 6 HISTOPATHOLOGICAL DISTRIBUTRION OF MALIGNANT OVARIAN TUMORS FREQUENCY SUBTYPES OF BENIGN SURFACE EPITHELIAL OVARIAN CHART 7 NEOPLASMS CHART 8 FREQUENCY SUBTYPES OF BORDERLINE SURFACE EPITHELIAL NEOPLASMS CHART 9 FREQUENCY SUBTYPES OF MALIGNANT SURFACE EPITHELIAL NEOPLASMS CHART 10 FREQUENCY OF GERM CELL TUMORS CHART 11 FREQUENCY OF SEX CORD STROMAL TUMORS CHART 12 FREQUENCY OF OVARIAN NEOPLASMS IN DIFFERENT AGE GROUP CHART 13 FREQUENCY OF INDIVIDUAL BENIGN NEOPLASMS IN DIFFERENT AGE GROUP FREQUENCY OF INDIVIDUAL MALIGNANT NEOPLASMS IN DIFFERENT AGE CHART 14 GROUP. CHART 15 SITE OF INVOLVEMENT CHART DISTRIBUTION OF BENIGN TUMORS IN ONE OR BOTH OVARIES 16(a) CHART DISTRIBUTION OF BENIGN TUMORS IN ONE OR BOTH OVARIES 16(b) CHART 17 FREQUENCY OF NATURE - BENIGN OVARIAN TUMORS. CHART 18 FREQUENCY OF NATURE OF MALIGNANT OVARIAN TUMORS CHART 19 CLINICAL PRESENTATION OF THE CASES IN PRESENT STUDY CHART 20 CLINICAL SYMPTOMS IN BENIGN OVARIAN NEOPLASMS CHART 21 CLINICAL SYMPTOMS IN BORDERLINE TUMORS CHART 22 CLINICAL SYMPTOMS IN MALIGNANT TUMORS CHART 23 HISTOMORPHOLOGICAL PATTERN OF OVARIAN TUMORS CHART 24 ER & PR EXPRESSION IN SURFACE EPITHELIAL TUMORS (n=33). CHART 25 CHART-25: CORRELATION OF RECEPTORS WITH AGE CHART 26 CHART-26: EXPRESSION OF ESTOGEN & PROGESTERONE RECEPTORS IN SETS

CHART 27 CHART-27: EXPRESSION OF ER & PR IN MORPHOLOGICAL TYPES OF SETs.

LIST OF FIGURE’S

Figure No’s Description of Figure's

Figure 1 Serous Cystadenoma

Figure 2 Mucinous cystadenoma Figure 3 Mature cystic teratoma

Figure 4 Struma ovarii

Figure 5 Fibrothecoma

Figure 6 Borderline Mucinous tumour

Figure 7 Proliferating brenner tumour

Figure 8 Granulosa cell tumour Figure 9 Serous Cystadenofibroma with calcifications Mucinous Cystadenoma showing cyst lined by tall columnar Figure 10 epithelium with apical mucin Figure 11 Incidental Benign brenner tumour with nests of transitional cells. Benign mature cystic teratoma showing squamous epithelium, keratin flakes & adnexal Figure 12 structures Figure 13 Struma ovarii showing thyroid follicular structures filled with colloid in the ovarian stroma Figure 14 Fibrothecoma showing spindle shaped cells with theca cells

Figure 15 Borderline mucinous tumour showing stratification, tufting with mild atypia of the nucleus.

Figure 16 Proliferating brenner tumour showing broad stratified urothelial cells Figure 17 Serous cystadenocarcinoma showing nests of tumour cells invading the fibrous stroma

Figure 18 Mucinous carcinoma showing mucin filled glands invading the stroma.

Endometrioid carcinoma with back to back arrangement of the Figure 19 glands with stratification of the epithelial cells Mixed germ cell tumour with YST component & immature Figure 20 teratoma showing microcystic & tubular pattern Granulosa cell tumour showing call exner bodies & tumour cells Figure 21 with nuclear grooves Figure 22 Borderline Mucinous tumour-PAS Stain: Mucin positive.

Figure 23 Mucinous Carcinoma- PAS Stain: Positive for mucin

Figure 24 ER positive in Serous Cystadenocarcinoma

Figure 25 PR positive in malignant serous tumour

ANNEXURE VIII Master chart

CLINICAL PRESENTATION INVESTIGATIONS S. CLINICAL GROSS No AGE HPE No HPE DIAGNOSIS ER & PR DIGNOSIS FINDINGS

TUMOUR ASCITIC COMPLAINTS P/V FINDINGS USG MARKER FLUID

Mass/ abdomen Unilocular cyst filled with Left fornix-cystic Left Serous ER & PR 1 23 with pain X 2 Left ovarian cyst _ _ Left Ovarian cyst 023/13 clear mass felt. cystadenoma Positive weeks. fluid.Size:9X7X3.5cm.

Excessive bleeding Anteverted , uterus Multiple fibroid Fibroid uterus with Unilocular cyst filled with Right Serous ER & PR 2 45 PV during 16 weeks size,right uterus with right _ _ umblical hernia and 121/13 clear fluid.Size:5X4X3cm. cystadenoma Positive periodsX 1 year fornix cyst felt. ovarian cyst right ovarian cyst.

Right ovarian mass- Right Serous pap Cervix flushed with intracystic papillary borderline Mass per abdomen vaginal wall. uterus Complex excrescenes. areas No malignant Bilateral ovarian malignancy/low 3 40 with painX 2 weeks could not be felt bilateral ovarian _ 242/13 .(14X10X8cm)Left ovarian _ cells . cyst. malignant potential & with vomiting. separately & pelvic cyst. mass-solid & cystic areas Left papillary mass 20 wks. with papillary structures cystadenocarcinoma (16X10X9cm) Uterus 10-12 Unilocular cyst with Irregular heavy fibroid uterus weeks with Fibroid uterus and paillary excrescences filled Right papillary serous ER & PR 4 45 bleeding since X 2 with right _ _ 262/13 posterior and right right ovarian cyst. with clear cystadenoma Positive yrs. ovarian cyst. fornix cyst felt. fluid.Size:5X4X3.5cm. Mass per abdomen with pain X 1 PER/ABDOMEN- Multiloculated cyst filled Left ovarian Left Mucinous ER & PR 5 46 month with Ditension with _ _ Left ovarian mass 223/13 gelatinous material. neoplasm. carcinoma Negative abdominal mass palpable. Size:6X4.5X3.2cm. distension. Pain in left lumbar Cervix, uterus Left adnexal Unilocular cyst filled with Left Serous ER & PR 6 33 region radiating to anteverted with left _ _ Left adnexal cyst. 314/13 cyst. clear fluid.Size:6X3X1 cm cystadenoma Negative anterior aspect. adnexal cystic mass 6 cm. Cervix, uterus Bulky uterus Unilocular cyst filled with Excessive bleeding anteverted 8-10 Left serous ER & PR 7 50 with left ovarian _ _ Fibroid uterus/AUB. 344/13 clear fluid PV X 15 days weeks, left fornix cystadenoma Positive cyst. .Size:4X3.5X1.5cm cystic lesion. Right ovarian Irregular cycles Bilateral adnexal Cervix, uterus cyst(6X7X5cm) and Left with lower Bilateral simple mass with Bilateral mucinous ER & PR 8 34 anteverted, bulky _ _ 347/13 ovarian cyst abdominal pain X ovarian cyst. dysplastic changes cystadenoma Negative mass in both fornix. (5X4X3cm),multiloculated 12 yrs in pap smear. filled mucoid material. Cervix ,uterus Fibroid uterus Unilocular cyst filled with Increased bleeding anteverted,8-10 with bilatral Fibroid uterus with Left serous ER & PR 9 39 _ _ 360/13 straw coloured PV X 15 days. weeks, left fornix - renal calculi and left ovarian cyst. cystadenoma Positive fluid.Size:5X3X2cm. cystic lesion. left ovarian cyst. Mass/ abdomen Cystic mass 4X3 Unilocular cyst filled with Left serous ER & PR 10 35 with pain X 2 Left ovarian cyst _ _ Left ovarian cyst 372/13 cm in left fornix. clear fluid.Size:7X6X5cm. cystadenoma Positive weeks Lower abdominal PER/ABDOMEN- mass with pain X 2 Cystic mass 18 Unilocular cyst filled with Right ovarian Right mucinous ER & PR 11 20 weeks.With weeks ,side to side _ _ Right ovarian cyst 400/13 clear cyst cystadenoma Negative giddiness & mobility,lower fluid.Size:12X10X9.5cm dysmenoorhea. margin made out. Excessive bleeding Cervix anteverted P/V X 3 Fibroid uterus Uniocular cyst filled with ,uterus 12 weeks Fibroid uterus with Left serous ER & PR 12 45 months.With lower with left ovarian _ _ 415/13 straw coloured size & left fornix left ovarian cyst. cystadenoma Positive abdominal pain X 3 cyst. fluid.Size:5X4.5X3.2cm. cystic lesion. days.

Mass/abdomen Left fornix-cystic CA-125 No malignant Unilocular cyst filled with Left serous ER & PR 13 40 Mesentric cyst Left ovarian cyst 476/13 with pain X 1 week lesion Normal cells . clear fluid.Size:10X9X8cm. cystadenoma Positive

Unilocular cyst filled straw Mass/abdomen Right fornix-cystic Right ovarian Right serous ER & PR 14 32 Normal _ Right ovarian cyst 501/13 coloured with pain X 5 days mass cyst cystadenoma Negative fluid.Size:9X7X3.5cm.

Unilocular cyst filled with Bleeding P/V X 15 Uteru bulky,Right Right ovarian AUB with right Right serous ER & PR 15 55 _ _ 528/13 clear days fornix-fullness cyst ovarian cyst cystadenoma Positive fluid.Size:5.5X4X3cm.

Excessive bleeding Lower abdominal Unilocular cyst filled with Fibroid with right Fibroid with right Right serous ER Negative & 16 31 during menses X 2 mass,right fornix _ _ 542/13 clear complex cyst ovarian cyst cystadenofibroma PR Positive months fullness. fluid.Size:10X9X7.5cm. Mass/abdomen Multiloculated cyst filled Left fornix cystic Left serous ER & PR 17 55 with pain on & off Left ovarian cyst _ _ Left ovarian cyst 579/13 yellow coloured mass cystadenoma Negative X 3 months fluid.Size:9X6X4cm. Pain abdomen on Unilocular cyst filled with Right fornix cystic Right ovarian Right serous ER & PR 18 40 right side X 4 _ _ Right ovarian cyst 594/13 brownish mass cyst cystadenoma Negative weeks material.Size:5X4X2 cm. Unilocularcyst filled with Mass/ abdomen Complexovarian pultaceous Right fornix soft Right ovarian cyst? Right benign mature 19 33 with pain X 1 mass suggestive _ _ 598/13 material8X7X5cm with _ mass. Dermoid cyst. cystic teratoma month of dermoid cyst. small solid gray white area. Pain abdomen with Size:15X9.5X7cm,cut Left adnexal mass Left ovarian No malignant ? Left malignant Left endometrial ER & PR- 20 50 mass & distension 621/13 surface-solid & cystic of 6X 4 cm mass cells . ovarian mass Adenocarcinoma Negative X 4 months areas. Mass/abdomen X Mass felt through Unilocular cyst filled 1 monthwith fornix,movement of Right ovarian CA 125- PERITONEA pultaceous material & Right benign mature 21 60 Ovarian tumour. 636/13 _ dysuria & burning cervix not cyst 30.39U/ml L FLUID hair.Size:11X8X4cm with cystic teratoma micturition. transmitted to mass focal small solid area. Post menopausal Uterus 12 weeks , Multiloculated cyst filled Left ovarian CA 125- Left mucinous ER & PR 22 65 bleeding X 2 antevered mobile _ Left ovarian mass. 679/13 with mucinous mass. 35.45 U/ml cystadenoma Negative months left fornix mass. material.Size:9X7X6cm.

Excessive bleeding Cervix , uterus Size:11.5X10X7cm with Right ovarian CA 125- DUB with right Right granulosa cell 23 43 PV with abdominal irregular anteverted _ 693/13 solid and microcystic _ mass. 11.74 U/ml ovarian mass. tumour pain X 4 months ,bulky ,right fornix areas. mass. Bleeding PV 15 uterus anteverted 6 days with lower weeks size AUB with fibroid Unilocular cyst filled with Left serous ER & PR 24 49 Cystitis _ _ 723/13 abdominal pain X deviated to right uterus. clear fluid.Size:5X4X3cm. cystadenoma Negative 4days. side. Right ovarian mass (11X9X8cm) & .Left Lower abdominal Malignant Right & left Papillary Bilateral fornix-solid Ovarian mass with ovarian mass ER Positive & 25 50 mass with pain X 2 Bilateral ovarian _ _ 817/13 serous Adeno to cystic mass DM (12X7X4.5cm )-solid & PR Negative months mass carcinoma cystic with papillary excrescences. Pain abdomen X 3 Cervix mid months with loss of Multiloculated cyst filled poition,uterus CA 125-51 Left mucinous 26 44 appetite & Left ovarian cyst _ Left ovarian cyst. 878/13 with mucinous _ aneveted,mass in U/ml cystadenoma epigastric material.Size:6X5X4cm. left fornix. discomfort. Abdominal PER ABDOMEN- distension X 1 year Abdomen Malignant CA 125 38 Size:22X18X12cm with ? Malignant ovarian Left proliferating 27 65 with abdominal distended with neoplastic U/ml:CEA- _ 069/14 solid & cystic areas with _ tumour. brenner tumour pain & mass X 1 mass in abdomen ovarian mass. 18 paillae. month. of 32 weeks. Continuous AUB with Unilocular cyst filled with Right fornix cystic Right ovarian Right serous ER & PR 28 42 bleeding PV X 1 _ _ hypothyroidism & 074/14 clear fluid .size:1.7cm with lesion. cyst cystadenoma Negative month anemia. remanant ovary-4X2X1cm. Bleeding P/V X 2 Left ovarian Size:5X4X2cm-solid & Left benign brenner 29 40 Left adnexal cyst _ _ DUB 186/14 _ months lesion cystic areas. tumor Primary infertility Right fornix cystic Poly cystic Unilocular cyst filled with Right serous ER & PR 30 20 & anxious to _ _ Primary infertility. 282/14 lesion. ovaries. clear fluid.Size:6X5X4cm. cystadenoma Negative conceive. Increased bleeding PV during Bulky uterus,right Fibroid uterus Multilocular cyst filled Fibroid uterus right Right serous ER & PR 31 46 periodsX 2 years fornix cystic lesion with right _ _ 287/14 withclear ovarian cyst. cystadenoma Negative with lower felt. ovarian cyst. fluid.Size:8X7X6.5cm. abdominal pain. Increased bleeding PV X Left fornix mass Menoorhagia for 3months with 7x7 cm,firm & non Left ovarian Multiloculated cyst clear Left serous 32 35 _ _ evaluation with left 297/14 _ dysmenorrhea & tender mobile cystic lesion. fluid 5X4X2 cm. cystadenoma ovarian cyst. white discharge PV mass. x 1 year. Lower abdominal Right fornix Right ovarian Unilocular cyst filled with Right Serous 33 24 pain & vomiting X fullness, cystic _ _ Right ovarian cyst. 302/14 _ cyst. clear fluid.Size:7X9X2cm. cystadenoma 1 month mass of 6X6 cm. Mass descending Procidentia with Cervix lying outside Bilateral PV x 9 years with bilateral Unilocular cyst filled with introitus with hydrourteroneph CA 125-49 Left serous 34 55 difficulty in _ hydronephrosis 316/14 straw coloured _ cystocele & rosis with left U/ml. cystadenoma micturition & stress with left ovarian fluid.Size:6X5X0.5cm. rectocele. ovarian cyst. incontinence. cyst. Cervix lying outside Mass descending Prolapsed with cystocele & P/V with difficulty uterus with non III Degree UV Unilocular cyst filled with Right serous 35 75 rectocele uterus _ _ 380/14 _ in passing urine X complex right prolapse clear fluid.Size:9X8X6cm. cystadenoma retroverted fornices 4 yrs adnexal cyst. free. Lower abdominal Mass Unilocular cyst filled with Left ovarian Left serous 36 26 mass with pain X 1 corresponding to _ _ Left ovarian cyst. 437/14 straw coloured _ cyst. cystadenoma month. 20 weeks. fluid.Size:11X8X4cm. Mass descendind PV x 3 years with Prolapsed uterus 111 degree UV Multilocular cyst filled with Right ovarian Right serous 37 44 stress incontinence with cystocele & _ _ prolapse with 489/14 mucinous _ cyst. cystadenoma & frequency of urethrocele. ovarian cyst. fluid.Size:16X17X2cm. micturition . Mass/abdomen Excoriation in Unilocular cyst filled with with lower external genitalia, Right ovarian CA 125 clear fluid & few papillary Right papillary serous 38 30 _ Ovarian cyst 494/14 _ abdominal pain X 1 Cervix , uterus cyst 11.41 U/ml projections cystadenofibroma month retroverted .Size:;9X7X4cm.

Lower abdominal Anterior fornix Left adnexal Multilocular cyst filled with CA125 10 Complex left Left mucinous 39 30 mass with pain X 5 fullness present lesion - 531/14 mucinous _ U/ml ovarian mass cystadenoma months mass 11X7 cm. 10X7.5X12.2 cm material.Size:14X10X6cm. Lower abdominal pain with pus from Unilocular cyst filled Right fornix cystic Right ovarian Right serous 40 34 umblicus & _ _ Right ovarian cyst. 537/14 withclear _ mass of 7x6 cm. cyst. cystadenoma backache X 1 fluid.Size:4.2X3X1.5cm. week. Mass descending Unilocular cyst filled with Uterus retroverted Prolapsed 111 degree UV P/V with difficulty sebaceous material,one Left mature cystic 41 60 atrophic, leftfornix uterus with left - - prolapse with left 568/14 _ in passing urine X firm area,grey teratoma mass felt . ovarian mass. ovarian mass. 4 months white.Size:3.5X2X1cm. Fullness in anterior Large intra fornix, right lateral abdominal mass fornix ,mobile , just above the Unilocular cyst with Mass/abdomen Peritoneal inclusion Left papillary serous 42 23 mixed consistency, bladder? Thin - _ 574/14 papillary _ with pain X 2 days cyst/ Hydatid cyst cystadenofibroma Tenderness +, walled cyst projections.Size:9X6X1cm. mass 18 weeks with? High size. density fluid. Unilocular cyst with hair Pain abdomen X 2 Solid to cystic mass and mucus material with Right mature cystic 43 38 Ovarian mass _ _ Right ovarian mass 609/14 _ months in the right fornix one small firm gray area teratoma .Size:4X4X2cm. Multiloculated cyst cyst Pain abdomen with Cystic lesion in the Right Ovarian filled with mucinous Right mucinous 44 55 abdominal mass X _ _ Right ovarian cyst. 612/14 _ right fornix. cyst material. Size: cystadenoma 3 weeks 22X20X15cm. Uterus retroverted, Irregular bleeding bulky, close to Complex left DUB with fibroid Multiloculated cyst with P/V with left sided uterus on left side adnexal cystic CA 125 – 45 45 _ and left dermoid 749/14 brownish Left struma ovarii _ abdominal pain X 1 cystic mass 8X6 mass probably 9.43U/ml cyst. material.Size:8X4X2cm. month. cm felt in anterior & ovarian dermoid. left fornix. Malignant right Size:15X13X9.5cm-solid Mass of 18 weeks ovarian tumour Pain abdomen X 2 CA125 No malignant Malignant ovarian and microcystic areas with Right mixed germ cell 46 27 in anterior & probably of 786/14 _ months 12.68U/ml cells. tumour greywhite gelatinous tumour posterior fornices mucinous material. carinoma. Large cystic Lower abdominal Multilocular cyst with clear right adnexal pain X 3 months Cystic mass7x7 cm CA 125- Dermoid cyst with ? fluid with papillary Right papillary serous ER & PR 47 50 mass with _ 847/14 with in anterior fornix. 12.2 U/ml. Fibroid. excrescences.Size:6X3X3 cystadenoma Negative papillary mass/abdomen. cm. excrescences. Pain abdomen Unilocular cyst with Cystic mass in the Left ovarian Left mucinous ER & PR 48 30 more on left side X _ _ Left ovarian cyst. 864/14 mucinous left fornix. cyst. cystadenoma Negative 1 week material.Size:5X3X1cm. lower abdominal Right fornix Bilateral ovarian CA 125- Bilateral ovarian Multilocular cyst with clear Right serous 49 38 _ 911/14 _ pain 3 months. fullness. cyst. 9.9U/ml. cyst. fluid.Size:5X2X0.5cm. cystadenoma Continuous Cystic mass 8x8 bleeding X 7 days Left ovarian CA 125- Unilocular cyst with clear Left serous 50 40 cm in anterior _ Left ovarian cyst. 923/14 _ with epigastric cystic lesion. 6.32 fluid.Size:9X7X2cm. cystadenofiro,a fornix. pain. Lower abdominal Complex Left ovarian cyst Unilocular cyst filled with pain and ovarian cyst- Left serous 51 31 Left fornix fullness. _ _ with cervical 1016/14 clear fluid. _ menorrhagia 3 ?Serous cystadenoma erosion. Size:6X5.5X1cm. months. cystadenoma.

Multiloculated cyst with Lower abdominal Cystic swelling Rightcomplex CA 125 < Right complex Right mucinous ER & PR 52 35 - 1165/14 mucinous pain X 2 days. 6X4cm in R fornix. ovarian cyst 4 U/ml ovarian cyst cystadenoma Negative material.Size:8X6X0.3cm.

Large cystic Abdominal mass 28 weeks ovarian Multiloculated cyst filled Anterior fornix lesion likely of CA 125- Left serous 53 55 with pain X 2 _ mass/?mesentric 1135/14 with clear _ fullness. ovarian/mesen 14.74U/ml cystadenoma months cyst. fluid.Size:21X17X10cm. tric cyst. Multiple joint pain Unilocular cyst filled with Left adnexal X 10 days and Fullness in left & CA 125- clear fluid and shows Left papillary serous 54 55 cyst with internal _ Left adnexal cyst. 1067/14 _ abdominal pain X anterior fornix. <4U/ml papillary excrescences. cystadenofibroma debris. 15 days. Size:11X9X3cm. Pain abdomen X Right fornix ?Serous Ascitic fluid- Multiloculated cyst with CA 125- Right borderline ER Negative & 55 37 15 days with mass,firm to cystic cystadenoma of no malignant Ovarian mass 030/15 mucinous 11.15U/ml mucinous tumour PR Positive giddiness. of 10x9 cm. right ovary cells. material.Size:14X10X7cm. Right ovarian cyst(8X6X4cm) -unilocular Bilateral ovarian CA 125- Left papillary and Menorrhagia X 1 Right fornixcystic DUB witj bilateral cyst with clear fluidand ER Positive & 56 40 cyst with bulky 9.8U/ml: _ 085/15 Right serous year mass 6X6 cm. ovarian cyst. Left ovarian cyst PR Negative uterus . AFP-1.9 cystadenoma (5X5X4cm)-unilocular cyst with papillary structures. Ovaarian mass:size:14X12X5cm.Ext Abdominal pain Cervix,since mass ernal surfacelobulated, with mass palpable CA 125- No malignant ? Malignant ovarian Right fibrothecoma of 57 55 felt in anterior & ? Ovarian mass 121/15 smooth, cut surface- _ per abdomen X 1 326.9 U/ml cells tumour ovary right fornix. homogenous,yellowish, month gray brown and firm to hard. PER/ABDOMEN- abdominal Right adnexal AFP-5.30 Mass/abdomen Multiloculated cyst with distension with cystic lesion ng/ml:β Right serous 58 10 with pain X 10 _ Right ovarian cyst. 211/15 clear fluid with few firm _ cystic mass 15X12 probably ovarian HCG < cystadenoma days areas.Size:11X9X1cm. cm in umblical & orgin. 200. hypogastrium.

Cervix Menorrhagia with posterior wall Fibroid uterus with irregular,uterus 10- Unilocular cyst with clear Left serous 59 47 lowback ache X 6 fibroid with left _ _ rectocele and left 263/15 _ 12 weeks,left fornix fluid.Size:9X7X2cm. cystadenoma months ovarian cyst. ovarian cyst. cystic mass felt.

Cervix Hypertrophied, Anterior wall AUB with fibroid Excessive bleeding Unilocular cyst with clear Right serous ER & PR 60 40 uterus retroverted, fibroid with Right - - and right ovarian 264/15 P/V 10 days fluid.Size:5X3X0.2cm. cystadenoma positive bulky & right fornix ovarian cyst. cyst. cystic lesion felt. Cervix mid position, uterus Bulky uterus Unilocular cyst filled with Excessive bleeding Fibroid uterus with Left mucinous ER & PR 61 48 anteverted,left with fibroid and - - 279/15 gelatinous P/V X 15 days left ovarian cyst. cystadenoma Positive fornix cystic lesion left ovarian cyst. material.Size:7X5X2cm felt. Unilocular cyst filled with Right ovarian cystic Right fornix Right adnexal pultaceous material and Lower abdominal CA125- teratoma with Right mature cystic 62 60 fullness, size could mass wit renal 302/15 hair with focal solid gray _ pain X 1 month 8.82U/ml systemic teratoma not be made out. calculi. white solid hypertension. area.Size:8X6X5cm. Right ovarian cyst Lower abdominal measuring(9X5X3cm) and pain with Bilateral cystic Bilatral ovarian CA 125- Bilateral ovarian left ovarian Bilateral serous ER Negative & 63 60 _ distension /mass X mass cyst 22.78 U/ml mass 431/15 cyst(8.5X4X4cm),both adenofibroma PR Positive 1 month multiloculated cyst filled with clear fluid. Unilocular cyst filled with Pain abdomen X 2 Left fornix0solid to pultaceous material and Left mature cystic 64 28 Left ovarian cyst _ _ Left ovarian cyst 483/15 _ weeks. cystic mass hair with focal small solid teratoma gray area.Size:8X7X5cm. Multilocular cyst filled with Mass per abdomen Left fornix-cystic Benign Mucinous Left mucinous 65 40 _ _ 489/15 mucinous _ & pain X 1month lesion mucinous neoplasm cystadenoma material.Size:16X17X2cm. Unilocular cyst filled with Abdominal painX 2 Right fornix-cystic Right ovarian Right twisted Right serous 66 25 _ _ 521/15 clear _ weeks lesion cyst ovarian cyst cystadenoma fluid.size:3X1.8X1cm. Unilocular cyst filled Abodominal pain X Right fornix soft Right ovarian Right ovarian sebum & hair with focal Right mature cystic 67 40 _ _ 583/15 _ 2months mass. dermoid cyst . dermoid cyst small solid teartoma. area.Size:8X7X5cm Right invasive high Abdominal mass & Right fonix fixed Right ovarian CA 125- No malignant Malignant ovarian Solid gray white ER & PR 68 45 615/15 grade carcinoma of painX3 month solid mass neoplasm 224U/ml cells tumour mass.Size:3X2X1cm Positive ovary Unilocular cyst filled Pain abdomen X 2 Rght fornix:cysic Right ovarian rRght papillary serous 69 30 _ _ Right ovarian cyst 664/15 yellow coloured _ weeks. mass. cyst cystadenoma fluid.Size:7X6X3cm. Unilocular cyst filled with Pain abdomen X 2 Left fornix soft seum & hair with focal Left mature cystic 70 23 Left ovarian cyst _ _ Left ovarian cyst 694/15 _ months cystic lesion small solid teratoma area.SIZE:7X5X4cm

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