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INTRODUCTION 1. Ovarian tumour is one of the major gynaecological disease and is a frequent site for primary and metastatic tumours. Due to its complex structure, primary ovarian neoplasm are of diverse histological types. Ovarian cancer accounts for 25% of all gynaecologic malignancies and 3rd commonest cause of death due to

malignancies of female genital tract in western world1. Ovaries are subjected to monthly endocrine and traumatic insult during ovulatory cycle and prime site for tumour genesis. The primary and secondary carcinoma of ovary are frequent with variety of pathologic pattern, which is seen in all ages2. Histological classification of ovarian tumours along with clinical stage forms an integral part of evaluation of optimum mode of therapy. AIM 2. To present a case of Ovarian Carcinoma, study the various histomorphological features of the ovarian tumours and their pattern of occurrence in relation to age and type diagnosed at in last one year.

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CASE STUDY 3. Bio Data of Patient a. Name b. Age c. Sex d. Residence e. Marital Status f. Education XYZ 55 years Female Chakwal Married Illiterate 8 yrs 18th March, 2011

g. Menopause h. Date of Admission

4. Presenting Complaints a. She presented as a known case of moderately differentiated Adenocarcinoma. b. Pain lower abdomen c. Dyspepsia d. Weakness 5. History of Presenting Illness. The patient had consistent pain lower abdomen for 3 months, which was dull in nature and associated with weakness, nausea and weight loss. There were no aggravating or relieving factors. No history of urinary or bowel complaints. Consulted a civil hospital. Laparotomy was done,
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bilateral ovarian cysts Histopathology report

were found. Cystectomy was revealed moderately

done.

differentiated

adenocarcinoma. After this procedure the patient reported to MH along with histopathology report for consultation. Her staging laparotomy was planned on 29th Mar 2011. 6. Past History. Not Significant

7. Obstetrical History a. Married for 30 yrs b. P7 - SVD c. Menopause for 8 yrs 8. Menstrual History a. Menarche - 13 yrs of age b. Menopause 50 yrs of age

9. Personal History. a. Huqqa Smoker b. HTN,DM, Asthma, IHD 10. Family History a. No H/O Ca Breast, Ca Ovary, Ca Endometrium b. Both parents were Hypertensive c. her sister having TB
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11. Socio Economic History. Belongs to a middle class family. 12. General Physical Examination. Well oriented lady, thin and lean looking pale and lethargic. a. BP b. Pulse c. Temp d. Pallor e. Lymph Nodes f. Thyroid 100/70mm of Hg 92 b/min 98.6 F Positive Not Palpable Not Enlarged Normal Bilaterally

g. Breasts h. Cyanosis i. j. Jaundice Edema

Absent

k. Weight

50 Kgs

13. Gynaecological Examination a. Speculum Examination (1) (2) (3) (4) Vulva Vagina distribution Hypoestrogenized, Scanty hair

Cervix normal looking No Vaginal discharge No local lesion

b. Bimanual Vaginal Examination (1) Uterus Normal in size (postmenopausal), Mobile

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(2) Fullness of all fornices c. Digital Rectum Examination - Normal

14. Systemic Examination a. Abdomen (1) Protuberant (2) Soft, non tender (3) Liver lower border Palpable (4) Spleen Not Palpable (5) BS - Positive (6) No mass Palpable (7) Ascites - Positive b. Respiratory System c. CVS d. CNS NAD

15. Investigation a. Blood CP (1) Hb (2) Plateletes (3) TLC b. CA-125 12.1 g/dl 370 x 10^9/L 9.4 x 10^9/L 24 U/ml 4.6 mmol/l WNL

c. BSR d. Urine for Biochemistry/Microscopy

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e. HBSAg/Anti HCV f. g. h. i. j. k. l. LFTs RFTs Urea/Creatinine/Na+/K+ Chest X-Ray ECG USG Abdomen/Pelvis CT Scan WNL Normal Bilateral Adnexal masses  Bilateral Adnexal masses  Pelvic ascites  Mild hepatomegaly

16. Diagnosis. Moderately Differentiated Adenocarcinoma 17. Management a. b. c. d. e. f. g. Counselling High risk consent taken Cross match sent 03 units RCC arranged Gut preparation done DJ Stenting done on 24th Mar 2011 Staging Laparotomy done on 29th Mar 2011 (1) (2) (3) (4) Uterus Atrophic, adherent to large gut & peritoneum on lt side Rt Adenexal friable mass (3 x 4 cm), bleed to touch & adherent to ureter Omentum Healthy looking Peritoneum Unhealthy looking
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(5) (6)

Ascitic fluid taken for cytology Omentum and Uterus sent for histopathology

Postoperative Management 18. Immediate Postoperative care a. Kept under high nursing care b. Given I/V antibiotics & I/V fluids c. Postoperative recovery was smooth 19. Histopathological Reports a. Omentum - no evidence of malignancy seen b. Ovaries Papillary Adenocarcinoma 20. Peritoneal washing cytology showed no malignant cells 21. Chemotherapy was started on 13th April 2011 22. Final Diagnosis. Papillary Adenocarcinoma

CLASSIFICATION & STAGING OF OVARIAN TUMORS 23. The World Health Organization classification (WHO) was introduced in 1973 based on four major types of tissues. Namely Surface germinal epithelium, Sex cords, Germ cells and Specialized ovarian stroma. All these can give rise to a variety of neoplasms. It relied primarily on the recognition of cell types and pattern of growth3.

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24. Modified WHO scheme of classification in 1995 a. Surface epithelial tumours (1) Serous tumours (a) Benign i. Cystadenoma and papillary cystadenoma ii. Surface pailloma iii. Adenofibroma and cystadenofibroma (b) Borderline malignancy (low malignant potential) i. Cystic tumor and papillary cystic tumor ii. Surface papillary tumor iii. Adenofibroma and cystadenofibroma (c) Malignant i. Adenocarcinoma, papillary adenocarcinom and papillary cystadenoma ii. Surface papillary adenocarcinoma iii. Adenocarcinofibroma and cystadenofibroma. (2) Mucinuous tumors (endocervical like and intestinal type) (a) Benign i. Cystadenoma ii. Adenofibroma and cystadenofibroma (b) Malignant i. Adenocarcinoma and cystadenocarcinoma ii Adenocarcinofibroma & cystadenocarcinofibroma (3) Endometrioid tumors (a) Benign i. Cystadenoma with squamous differentiation ii. Adenofibroma and cystadenofibroma iii. Adenofibroma and cystadenofibroma with squamous differentiation
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(b) Malignant i. Adenocarcinoma and cystadenocarcinoma ii. Adenofibroma and cystadenofibroma with squamous differentiation iii. Adenocarcinofibroma & cystadenocarcinofibroma iv. Adenocarcinofibroma & cystadenocarcinofibroma with squamous differentiation (c) Epithelial (endometrioid) stromal and (endometrioid) stroma i. Adenosarcoma, homologous and heterologous ii. Mesodermal (Mullerian) mixed tumor (carcinosarcoma) homologous and heterologous iii. Stroma sarcoma. (4) Clear cell tumour (a) Benign i. Cyst adenoma ii. Adenofibroma and cystadenofibroma (b) Malignant i. Adenocarcinoma ii. Adenocarcinofibroma and cystadenofibroma (5) Transitional cell tumours (a) (b) (c) (e) (6) (7) Brenner tumour Brenner tumor of borderline malignancy/ proliferating Malignant Brenner tumour Transitional cell carcinoma (non-Brenner type)

Squamous cell tumour Mixed epithelial tumour (specific types) (a) Benign (b) Of borderline malignancy/ or low malignant potential (c) Malignant

(8) (9) b.

Undifferentiated carcinoma Unclassified

Sex-cord Stromal Tumours

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(1)

Granulosa cell tumour (a) Juvenile (b) Adult

c.

Germ cell tumours (1) Dysgerminoma (a) Variant with syncytiotrophoblast cells (2) Yolk sac tumour (endodermal sinus tumor) (a) Variant Polyvesicular vitelline tumor (b) Hepatoid (c) Glandular (3) (4) (5) (6) Embryonal carcinoma Polyembryoma Choriocarcinoma Teratoma (a) Premature (b) Mature i. Solid ii. Cystic (dermoid cyst) iii. With secondary tumour formation (specify types) iv. Fetiform (Homunculus) (c) Monodermal and highly specialized i. Strauma ovary ii. Ariant with thyroid tumour (specify type) iii. Carcinoid iv. Insular v. Trabecular vi. Strauma carcinoid vii. Mucinous carcicoid viii. Neuroectodermal tumours ix. Sebaceous tumours x. Others

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(7)

Mixed (specify types) (a) Gonadoblastoma i. Variant with dysgerminoma or other germ cell tumor (b) Tumours of rete ovari i. Adenoma and cystadenoma ii. Carcinoma (c) Mesothelial tumours i. Adenomatoid tumour ii. Others (d) Tumours of uncertain origin i. Small cell carcinoma ii. Tumour of probable Wolffian origin iii. Hepatoid carcinoma iv. Oncocytoma (e) Gestational trophoblastic diseases (f) Soft tissue tumours specific to ovary (g) Malignant lymphomas (h) Unclassified tumours (i) Secondary (metastatic) tumours (j) Tumour like lesions i. Solitary follicle cyst ii. Multiple follicle cyst (polycystic disease) (sclero cystic ovaries)

d. Large solitary leuteivized follicle cysts of pregnancy and puerperium e. Hyper-rectio luteinalis (multiple leutinized follicle cysts) variant with corpora lutea. (1) Corpus luteum cyst (2) Pregnancy luteoma

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(3) Ectopic pregnancy (4) Hyperplasia of stroma (5) Stromal hyperthecosis (6) Massive edema (7) Fibromatosis (8) Fibromatosis (9) (10) f. Endometriosis Cyst, unclassified (simple cyst)

Inflammatory lesions (1) (2) (3) Xanthogranuloma Malakoplakia Other

25. Histologic Staging/Classification (FIGO, 1971) STAGE I - Tumour is confined to the ovary / ovaries Ia y Only one ovary is affected by the tumour, the ovary capsule is intact y No tumour is detected on the surface of the ovary y Malignant cells are not detected in ascites or peritoneal washings Ib
y

y y

Both ovaries are affected by the tumour, the ovary capsule is intact No tumour is detected on the surface of the ovaries Malignant cells are not detected in ascites or peritoneal

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washings Ic The tumour is limited to one or both ovaries, with any of the following:
y y y

The ovary capsule is ruptured The tumour is detected on the ovary surface Positive malignant cells are detected in the ascites or peritoneal washings

STAGE II Tumour involves one or both ovaries and has extended into the pelvis IIa y The tumour has extended and/or implanted into the uterus and/or the fallopian tubes. y Malignant cells are not detected in ascites or peritoneal washings IIb
y

The tumour has extended to another organ in the pelvis Malignant cells are not detected in ascites or peritoneal washingss Tumours are as defined in 2A/B, and malignant cells are detected in the ascites or peritoneal washings

IIc

STAGE III The tumour involves one or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis and/or regional lymph node metastasis. Includes liver capsule metastasis. IIIa y Microscopic peritoneal metastasis beyond the pelvis IIIb
y

Microscopic peritoneal metastasis beyond the pelvis 2 cm or less in greatest dimension Microscopic peritoneal metastasis beyond the pelvis
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more than 2 cm in greatest dimension and/or regional lymph nodes metastasis STAGE: IV Distant metastasis beyond the peritoneal cavity. And, liver parenchymal metastasis.

HIS TO GE NE SI S 26. Epithelial Tumours. Are derived from the surface epithelium of the ovary and are further classified as benign, borderline or malignant, according to cell type and behavior4. Epithelial tumours account for 60-65 % of all Ovarian tumours and approximately 90% of those that are malignant5. a. Serous Tumours: Serous tumours are the most common epithelial tumours (40-50%). Serous carcinoma is usually large and is often bilateral. It exhibits a mixture of cystic, papillary, and solid growth patterns. The carcinoma often invades through the ovarian capsule and grows on the surface of the ovary. Foci of necrosis and hemorrhage are common in serous carcinoma. Microscopically it has a papillary pattern and some times shows areas of calcification, which is called Psammoma bodies. b. Mucinous Tumours. Mucinous carcinoma is typically large, unilateral and composed of irregular cysts and glands lined by
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atypical mucinous cells, which often are stratified into four or more cell layers. They contain only endocervical-type cells, only intestinal-type mucinous cells, or a combination of the two, but are usually composed of cells that are not specifically suggestive of either endocervical- or intestinal-type mucinous cells. The main criterion of invasive mucinous carcinoma is the presence of obvious stromal invasion. Dissection of mucin into the stroma is especially common and extensive in cases of pseudomyoma peritonei and is designated pseudomyxoma ovarii2. c. Endometrioid Tumours. Endometrioid carcinomas histologically resemble the usual adenocarcinoma of the endometrium. These tumours are solid masses with a soft, firm, or fibrous consistency. They are often predominantly cystic and contain soft or firm solid nodular masses. These cysts are usually filled with chocolatecoloured fluid. 15 % cases of endometrioid carcinoma of ovary are associated with endometrial carcinoma. d. Clear Cell Tumours. These are commonly unilateral. The tumor is predominantly cystic which is unilocular and contains brown fluid. The inner surface has polypoidal projection. The

characteristic microscopic appearance is called Hob Nail

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appearance. Clear cell carcinoma frequently co exist with ovarian endometriosis and endometriod carcinoma of ovary , which suggests that it may be a variant of endometriod tumor. e. Transitional Cell Tumours (Brenner Tumours). Malignant transitional cell tumours (Brenner tumours) have both solid and cystic components. The cysts contain papillary or polypoid masses or solid nodules in their walls. The presence of soft masses or foci of necrosis may suggest malignancy. Malignant transitional cell tumors (Brenner tumors) resemble a high-grade transitional cell carcinoma of the bladder5. The tumor cells have pleomorphic, atypical nuclei, and the malignant transitional cells obviously infiltrate the stroma. f. Mixed epithelial tumors. Admixtures of the various subtypes of the surface epithelial- stromal category often occur. Almost all combinations of mixed epithelial tumors have been encountered. The WHO limits their identification to those neoplasms in which one or more components other than the predominant component account for at least 10% of the tumor on microscopic examination. g. Undifferentiated Tumour. Undifferentiated carcinoma is one that shows no differentiation or contains only rare, minor areas of

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differentiation according to the WHO. Marked cellular atypia, bizarre giant cells, and atypical mitoses are frequent.

Undifferentiated carcinoma grows rapidly, usually exhibits extra ovarian spread, and has the poorest prognosis of any epithelial carcinoma adenocarcinoma.

AETIOLOGY OF OVARIAN CANCER

27. The cause of Ovarian Cancer is unknown but some of the aetiological factors of ovarian cancer are a. Tubal ligation and hysterectomy (with ovarian conservation) is associated with a decrease risk of ovarian cancer [C] b. the use of combined oral contraceptive pills appears protective, with increasing duration of use increasing the level of

protection afforded [C] c. Women from families with hereditary ovarian cancer syndromes may reduce their risk of developing ovarian cancer by ever use of the combined oral contraceptive pills[C] d. Factors which reduce ovulation are associated with a reduced risk of ovarian cancer.

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e. Evidence of causal association between the use of ovulatory stimulants and the subsequent development of epithelial ovarian tumours is inconclusive. f. Hereditary ovarian cancers represent fewer than 10% of all ovarian cancers. g. Bilateral salpingo-oopherectomy is protective in BRCA mutation carriers [B] h. HNPCC has an association with cancers of the ovary and endometrium4 i. Infertility Treatment. Drugs used for ovulation induction

suggested being associated with subsequent increase risk of ovarian carcinoma. j. Pelvic Irradiation. Pelvic irradiation increases the risk of pelvic cancers including ovarian cancers. SYMPTOMS 28. Symptoms of ovarian cysts and tumours include a. Indigestion, gas or bloating b. difficulty urinating, or frequent need to urinate c. dull ache in the lower back d. pain during sexual intercourse

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e. painful menstruation and abnormal bleeding f. swelling and/or pain in the abdomen g. Pelvic pain radiating down the inner aspect of the leg is a common presenting symptom, and torsion classically presents as severe pain associated with vomiting h. Rupture of a large cyst may produce signs of peritonitis, particularly if the cyst contents are irritant (e.g. endometriotic cyst or dermoid cyst), and the patient may be shocked in cases of extensive rupture or continuing haemorrhage. DIAGNOSIS 29. Tests that look for ovarian cysts or tumours include a. Ultrasound. To determine the size and location of the cyst or tumour. b. Imaging tests. Computed tomography (CT), magnetic

resonance imaging (MRI), and positron emission tomography (PET) are highly detailed imaging scans to find ovarian tumours and see whether and how far they have spread. c. Laparoscopy. used for the treatment of ovarian cysts.

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d. CA-125. to look for a protein called CA-125, tend to be higher in some -- but not all -- women with ovarian cancer. This test is mainly used in women over age 35, who are at slightly higher risk for ovarian cancer. TREATMENT 30. In general, the course of treatment is determined by the stage of the cancer. Stages range from I to IV based on the cancer's specific characteristics, such as whether it has spread beyond the ovaries. Surgery is the main treatment for ovarian cancer. Following surgery, women with higher-stage tumours may receive chemotherapy. About 10 - 15% of epithelial ovarian tumours are referred to as "borderline because their appearance and behaviour under the microscope is between benign and malignant. These tumours are often referred to as carcinomas of low malignant potential because they rarely metastasize or cause death. Borderline ovarian tumours are most often seen in younger women with epithelial ovarian cancer. Surgery is usually recommended to remove these tumours. Chemotherapy may also be used to treat borderline tumours that appear to have more aggressive features (such as recurring after surgery).

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31. Treatment Options for Stage I and Stage II Ovarian Cancer. Treatment options for stage I and stage II ovarian cancer may include: a. Surgery. Removal of the uterus (total hysterectomy), removal of both ovaries and fallopian tubes (bilateral salpingooophorectomy), partial removal of the omentum, the fatty layer that covers and pads organs in the abdomen(omentectomy), and surgical staging of the lymph nodes and other tissues in the pelvis and abdomen. (Carefully selected premenopausal women in Stage I with the lowest-grade tumors in one ovary may sometimes be treated only with the removal of the diseased ovary and tube in order to preserve fertility.) b. Chemotherapy. Patients with stage IA or B disease, grade 1 (or sometimes grade 2), usually do not need further therapy after surgery. However, higher risk patients (stage IC, stage I/grade 3) are usually treated with platinum-based

chemotherapy to reduce their risk of subsequent relapse. 32. Treatment Options for Stage III and Stage IV Ovarian Cancer. Treatment options for stage III and stage IV ovarian cancer may include

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a. Surgery. Removal of the tumour (debulking), total abdominal hysterectomy, omentectomy b. Chemotherapy. Combination chemotherapy with a platinumbased drug and a taxane drug delivered intraperitoneally (through the abdominal cavity) 33. Treatment Options for Recurrent Ovarian Cancer. If ovarian cancer returns or persists after treatment, chemotherapy is the mainstay of treatment, although it is not generally curative in the setting of relapsed disease. Clinical trial options include additional surgical debulking, and biologic therapy combined with bilateral salpingo-oopherectomy, and

chemotherapy5. 34. Chemotherapy. Single chemotherapeutic agents active in epithelial ovarian cancer include6 a. Alkylaking agents (eg, cyclopthosphamide) b. Platinum Compounds (cisplatin and carboplatin) c. Anthracyclenes (eg, epirubicin) d. Taxanes (eg, paclitaxel and docetaxel) 35. Combination chemotherapy. The chemotherapeutic agents have been used in a number of combinations but the combinations

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containing cisplatin or carboplatin have shown higher response rate than others but without improving the survival rate. 36. Radiotherapy. It is not needed in stage Ia disease and is not

effective in patients with stage IV carcinoma of the ovary. It can be used as an alternative to chemotherapy in patients with stage Ib-IIIa. FOLLOW UP 37. CA-125. The patients receiving chemotherapy are followed with regular estimation of CA-125. A rapid fall in its level indicates chemosensitivity of the tumour. Persistent or rising levels of CA-125 indicate drug resistance or recurrence. PROGNOSIS 38. The prognosis of epithelial ovarian tumours is determined by the following factors a. Extent of disease at diagnosis b. Size of residual tumour bulk c. Positive retroperitoneal nodes d. Histological subtype and grading of tumour 39. The overall 5 year survival is approximately 35% in all epithelial ovarian tumours. The stage wise survival is as under

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Stage I II III IV

5 yrs survival 60-70% 43-51% 17.5% 4.7%

CLINICOPATHOLOGICAL REVIEW OF OVARIAN TUMOURS IN RAWALPINDI 40. Ovarian tumours pertaining to the cases diagnosed,

histopathologically at ______________ Laboratory, for the period from January 2010 to December 2010. During this period, total 264 cases of ovarian tumours were diagnosed. Out of these histopathologically about 67 cases were malignant and 197 were benign cases. The result pattern in relation to age and type diagnosed is summarized as under. a. Age Table-1: Age Distribution in 67 Malignant Cases Age (years) 11 20 21 30 No. of Cases 08 08 Percentage 11.91 11.91

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31 40 41 50 51 60 61 70 > 70 years Total

09 19 15 06 02 67

13.43 28.35 22.38 8.95 2.98 100.00

Table-2: Age Distribution in 197 Benign Cases Age (years) 11 20 21 30 31 40 41 50 51 60 61 70 > 70 years Total No. of Cases 13 78 73 25 04 04 197 Percentage 6.59 39.59 37.05 12.69 2.03 2.03 100.00

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b. Histological Diagnosis Table-3: Histological typing of 67 ovarian cancers Cancers Serous Cyst Adenocarcinoma Mucinous Adenocarcinoma Granulosa Cell Tumour Endometriod Adenocarcinoma Adenocarcinoma (moderately differentiated) Mucinous Borderline Tumour Yolk Sac Tumour Serous Borderline Tumour Clear Cell Carcinoma Immature Teratoma Poorly Differentiated Carcinoma Dysgerminoma Metastatic Signet Ring Cell Adenocarcinoma No of Cases Percentage

12 09 07 06 05

17.91 13.43 10.44 8.95 7.46

04 04 03 03 03 02 02 02

5.97 5.97 4.47 4.47 4.47 2.98 2.98 2.98

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Carcinoid Tumor Transitional Cell Carcinoma Mixed Sex Cord Stromal Tumour Diffused Large B-Cell Lymphoma Total

02 01 01 01
67

2.98 1.49 1.49 1.49

100

Table-4:Histological typing of 197 Benign Tumours Tumours Luteal cyst Follicular cyst Mucinous cyst adenoma Serous cyst adenoma Endometriod cyst Dermoid Cyst Total No of Cases Percentage

122 32 15 15 07 06
197

61.92 16.24 7.61 7.61 3.55 3.04

100

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c. Unilateral/Bilateral ovarian tumours Table-5: ovarian cancer Unilateral No of cases Percentage 57 85.07 Bilateral 10 14.93 Total 67 100

Table-6: Benign ovarian tumours Unilateral No of cases Percentage 162 82.23 Bilateral 35 17.77 Total 197 100

CONCLUSION 41. Ovarian tumours occurred in all age group. But majority of

malignant cases were in the age group of 41-50 and 51-60 years. In Benign tumours most of the tumours were in the age group of 21-30 and 31-40. Most of the tumours were unilateral. Amongst the

malignant tumours the highest number of cases seen were of Serous Cyst Adenocarcinoma (17.91%) followed by Mucinous Adenocarcinoma (13.43%).

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REFERANCES

Novak ER, Jones GS, Jones HW. Ovarian tumours. In: Gynaecological and Obstetrical Pathology. 6th Edition. Philadelphia; Saunders: 1997. P. 365-413.
2

Robert E Scully, Philips B Clement, Robert H Young. Ovarian surface epithelial-stromal tumours. In: Sternberg Diagnostic Surgical Pathology. 4th edn. Vol. 3. Philadelphia; Lippincott Williams & Wilkins: Mills SE, Cartes D, Greenson JK, Obserman HA, Reuter VE, Stoler MH Obstetrics & Gynecology by David M Luesely and Phillip N Baker, second edition, page 814.
4 3

Ibid

Harter P, du Bois A, Hahman M et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie 2006; 13: 1702-10

Silva EG, Robey-Cafferty SS, Smith TL, Gershenson DM (1999) Ovarian carcinomas with transitional cell carcinoma pattern. Am J Clin Pathol 93:457465

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