OVARIAN TUMOURS

Brief discussion

1. OVARIAN TUMOURS

2. Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H, Sion Hospital Joint Treasurer, FOGSI (2021-2024) Vice President, MOGS (2021-2022) Member Oncology Committee, SAFOG (2020-2021) (2021-2023) Dean AGOG & Chief Content Director, HIGHGRAD & FEMAS Courses Editor-in-Chief, FEMAS & JGOG Journal 50 publications in International and National Journals with 60 citations National Coordinator, FOGSI Medical Disorders in Pregnancy Committee (2019-2021) Chair & Convener, FOGSI Cell Violence Against Doctors (2015-16) Member, Oncology Committee AOFOG (2013-2015) Coordinator of 11 batches of MUHS recognized Certificate Course of B.I.M.I.E at L.T.M.G.H (2010-16) Member, Managing Committee IAGE (2013-17), (2018-20) Editorial Board, European Journal of Gynaec . Oncology (Italy) Course Coordinator of 3 batches of Advanced Minimal Access Gynaec Surgery (AMAS) at LTMGH (2018-19) DR. NIRANJAN CHAVAN MD, FCPS, DGO, MICOG, DICOG, FICOG, DFP, DIPLOMA IN ENDOSCOPY (USA)

3. NORMAL OVARIES Normal size 5 x 3 x 3cm Variation in dimensions can result from Endogenous hormonal production(varies with age and menstrual cycle) Exogenous substances , including OCs, GnRH agonists, or ovulation-inducing medication, may affect size.

4. Benign Ovarian Tumours Epidemiology Embryology Etiology Risk factors WHO classification Pathology of ovarian tumours Management (diagnosis & management) Surgery

5. Embryology of the ovary Primitive gonads appear around the 5 th week of IUL as the gonadal ridge from the coelomic epithelium on the medial aspect of the urogenital ridge. In the xx embryo , the cortex develop as the ovary and the medulla regress to a small area. The ovarian serosa is the direct descent of the coelomic epithelium and it gives rises to endocervical, endometrial, endosalphinx and the epithelium of the urogenital system. The undifferentiated serosal cells can undergo neoplastic changes and lead to tumours of the above tissues.

6. ► FOLLICULAR CYST ►CORPUS LUTEUM CYST ►THECA LUTEIN CYST ► TUBO OVARIAN ABSCESS ► BENIGN ►BORDERLINE ►MALIGNAN T ► ENDOMETRIOMA ►ENLARGED PCO ►PAROVARIAN CYST

7. (I) Functional (II) Inflammatory (III) Others (IV) Neoplastic (1) Germ cell (2) Epithelial (3)Sex cord stromal (a) Follicular cyst (b) Corpus Luteal cyst (c) Theca Luteal cyst Tubo -ovarian abscess (a) Endometrioma Ovary (a) Benign teratoma/ Dermoid Cyst (a) Serous cyst adenoma (b ) Mucinous cyst adenoma (c) Brenner tumour (d) Fibroma Thecoma (a) Granulosa cell , Sertoli - leydig cell CAUSES OF BENIGN OVARIAN CYSTS

8. Classification of ovarian mass 1. Simple cyst 2. Hemorrhagic cyst 3. Hyperstimulation in women who have undergone fertility treatment 4. Luteoma of Pregnancy 5. Endometrioma 6. Brenner's tumour 7. Epithelial tumours Serous, mucinous, endometroid and clear cell tumours. 8. Sex cord and Mesenchymal tumours Fibrothecomas, granulosa cell , sclerosing stromal and sertoli-leydig cell tumours. 9. Germ cell tumours Mature and immature teratomas, dysgerminomas, endodermal sinus tumours, embryonal carcinomas.

9. Functional ovarian cysts Follicular cysts Corpus luteum cysts Theca lutein cysts Luteomas of pregnancy By far the most common clinically detectable enlargements of the ovary in the reproductive years. All are benign and usually asymptomatic.

10. Follicular cysts Cystic follicle is defined as Follicular cyst of diameter > 3cm Most common functional cysts. Rarely larger than 8cm. Lined by granulosa cells Found incidentally on pelvic examination Usually resolve within 4 – 8 weeks with expectant management May rupture or torse occasionally causing pain and peritoneal symptoms.

11. Corpus luteal cyst Less common than follicular cyst. May rupture leading to hemoperitoneum and requiring surgical management( more in patients taking anti coagulants or with bleeding diathesis) Unruptured cysts may cause pain because of bleeding into enclosed ovarian cyst cavity.

12. Corpus luteal cyst

13. Theca lutein cysts Least common Usually bilateral Result from overstimulation of the ovary by β - hCG Do not commonly occur in normal pregnancy Often associated with hydatidiform moles, choriocarcinoma, multiple gestations, use of clomiphene and GnRH analogues. May be quite large (up to 30 cm) , multicystic, and regress spontaneously.

14. Theca lutein cysts

15. Management of functional cysts Expectant Watchful waiting for two or three cycles is appropriate. Combined oral contraceptives appear to be of no benefit. Should cysts persist, surgical management is often indicated. Oral contraceptives for functional ovarian cysts (Review) Cochrane Database of Systematic Reviews 2011

16. Asymptomatic simple cysts <5cms Likely physiological (do not require follow up ) 5-7 cms Yearly USG >7cm Require further imaging/surgical intervention. RCOG 2011

17. (a) Inflammatory ovarian cysts Tubo-ovarian abscess Are present in 14-38% of patients hospitalized with pelvic inflammatory disease (PID) . Commonly seen in patients with poor access to routine gynecologic care.

18. The traditional criteria for the diagnosis of PID include subjective bilateral abdominal pain as per patient report and positive physical examination findings for bilateral adnexal tenderness at palpation and cervical motion tenderness. A hydrosalpinx is generally anechoic, whereas a pyosalpinx may have increased echoes within the fluid.

19. (A) Endometrioma of ovary Most common site of involvement is the ovary. Endometriomas are pseudocysts formed by invagination of the ovarian cortex, sealed off by adhesions. They may completely replace normal ovarian tissue. Cyst walls are usually thick and fibrotic.

20. USG : anechoic cysts to cysts with diffuse low-level echoes to solid-appearing masses. Fluid–fluid or debris–fluid levels may also be seen. They may be unilocular or multilocular with thin or thick septations Malignant transformation: 0.3% to 0.8% Management: medical and/ or surgical

21. Chocolate cyst of Ovary on cut section Ovarian Endometrioma

22. Benign ovarian tumors Serous cystadenoma Mucinous cystadenoma Dermoid cyst Fibroma Thecoma Brenner’s tumor

23. (A) SEROUS CYSTADENOMA Generally benign Bilateral – 10% Risk of malignancy : 5 – 10 % borderline malignant, 20 -25% malignant GROSS : multilocular with papillary components. MICRO : low columnar epithelium with cilia Characteristic psammoma bodies (end products of degeneration of papillary implants)are found. Associated fibrosis may lead to “ cystadenofibroma ”

24. On USG Serous Cystadenoma Gross appearance Gross appearance Cut section appearance Cut section appearance

25. On MRI On USG Serous Cystadenoma

26. (B) MUCINOUS CYSTADENOMA Have tendency to become huge masses Gross : Round to ovoid masses with smooth capsules that are usually translucent or bluish to whitish gray. Interior divided by discrete septa into loculi containing clear, viscid fluid. Microscopy : Epithelium – tall, pale staining, secretary with basal nuclei and goblet cells 5 – 10% are malignant

27. Epithelium – tall, pale staining, secretary with basal nuclei and goblet cells

28. Mucinous cystadenoma on MRI

29. DERMOID CYST/ Benign cystic teratoma Often bilateral (15 -25%) GROSS : thick, opaque , whitish wall. CONTENTS: hair, bone, cartilage, and a large amount of greasy sebaceous material. MICROSCOPICALLY : all the three germ layers (ectoderm, mesoderm and endoderm) Malignant change occurs in 1-3%. Usually of a squamous type. Risk of torsion is 15% An ovarian cystectomy is almost always possible, even if it appears that only a small amount of ovarian tissue remains

30. Dermoid Cyst ( Benign Cystic Teratoma )

31. FIBROMA Most common benign, solid neoplasms of the ovary. Compose approx 5% of benign ovarian neoplasms and 20% of all solid tumors of the ovary. Frequently seen in middle-aged women. Characterized by their firmness and resemblance to myomas.

32. FIBROMA Misdiagnosed as exophytic fibroids or primary ovarian malignancy Not hormonally active Fibromas may be associated with ascites or hydrothorax as a result of increased capillary permeability thought to be a result of VEGF Mieg’s syndrome (ovarian fibromas, ascites and hydrothorax) is uncommon and usually resolves after surgical excision.

33. OVARIAN FIBROMA Microscopy .. Gross appearance

34. On MRI Ovarian Fibroma .

35. THECOMA Solid fibromatous lesions that show varying degrees of yellow or orange discoloration. Almost always confined to one ovary. Usually >40 years, 65% after menopause. May be hormonally active and hence associated with estrogenic or occasionally androgenic effects. Luetinised thecoma – younger, sclerosing peritonitis and ascites Leydeig cell thecoma – associated with Reinke crystals Rarely malignant

36. BRENNER TUMOR It is named for Fritz Brenner, who characterized it in 1907. The term "Brenner tumor " was first used by Robert Meyer, in 1932. Uncommon tumor grossly identical to fibroma . Arise from Walthard cell rests , also from surface epithelium, rete ovarii and ovarian stroma. Brenner tumors are usually found incidentally at pathologic evaluation, often in conjunction with a mucinous cystadenoma or dermoid cyst. They are relatively rare tumors and are most common in the fifth to sixth decades of life.

37. On microscopy – markedly hyperplastic fibromatous matrix interspersed with nests of epitheloid cells showing coffee bean pattern Considered uniformly benign. But scattered reports of malignant Brenner’s available. Endocrinologically inert, but could be associated with virilization and endometrial hyperplasia. Cut section Microscopy

38. Ovarian Gonadal Sex Cord Stromal Tumours Granulose theca cell tumours Sertoli-Leydig cell tumours

39. Found in all age groups and associated with the pseudo precocious puberty. Early breast development , menstrual disorders, postmenopausal vaginal bleeding make up the characteristic symptom. Granulosa Stromal Sex cord tumours

40. Granulosa Stromal Sex cord tumours Laboratories studies demonstrate an increase in the number of mature epithelial cells in the vaginal cytologic specimen, elevated urinary and serum estrogen levels and varirant degree of endometrial proliferation. Microscopy : The characteristic cell is the round or slightly ovoid granulosa cell with its dark nucleus. Mitosis are common and the ovum like “ Call Exner bodies “ are classic .

41. SERTOLI LEYDIG CELL TUMOURS Also called as Androblastoma . Often affect females beneath the ages of 40yrs. Usually be luteinised, simulating the classic pattern of the testes and producing steroids. Generally benign, may produce the masculinisation.

42. CLINICAL PRESENTATION Asymptomatic – accidentally discovered on USG Chronic pattern of pain , increasing abdominal girth over months or weeks. Associated with secondary symptoms of anorexia, nausea, vomiting, urinary frequency. Could be associated with primary or secondary amenorrhea, menstrual irregularities, virilization, precocious puberty Become acutely symptomatic if undergoes torsion, rupture or haemorrhage. Benign ovarian neoplasms are indistinguishable clinically from malignant counterparts

43. COMPLICATIONS Of Benign ovarian tumours Torsion : Commonly seen in Dermoid cyst, serous cystadenoma . Intracystic hemorrhage : serous Cystadenoma , venous congestion. Infection : Following torsion. Rupture : Big and tense type,following trauma. Pseudomyxoma peritonei : Seen in Mucinous Cystadenoma Intestinal Obstruction Malignancy : Rare .

44. MALIGNANT OVARIAN TUMORS 6% of all cancers among women 15-20% of all gynaecological cancers 4 th most common cause of cancer death exceeded only by Breast, Colon and lung Highest incidence in industrialised countries, Sweden having highest (14.9/100000) and Japan having lowest incidence rate (2.7) Incidence in India-4.6/100000

45. Risk factors Most important risk factor- Nulligravida Incessant Ovulation Theory -suggest more the ovulatory traumas, more are chances of epithelial cell cancers Early Menarche, Late Menopause, delayed first pregnancy (more than 30 years) Ovulation inducing Drugs Talcum powder and Asbestos Hormone Replacement Therapy more than 10 years History of Breast Cancer Hereditary Breast Ovarian Cancer- Associated with BRCA1 and BRCA2 mutation Hereditary Non Polyposis colorectal Cancer- Associated with endometrial and ovarian cancer. Associated with three DNA mismatch repair.MLH1,MSH2,MSH6

46. Pathological classification

47. Primary epithelial tumors All types can be benign, malignant and borderline. Benign -Gross-Cystic Microcopic -fine papilla, no stromal invasion, no nuclear atypia Borderline - Gross-Cystic with solid foci Microscopic-complex papilla, nuclear atypia, no stromal invasion Malignant - Gross-Mostly solid with foci of hemorrhages and necrosis Microscopic-Papillary complexity, Stratification, nuclear atypia, Stromal invasion .

48. Germ cell tumour- dysgerminoma Most common age-1 st 2 decades Rapidly growing. May present as palpable abdominal mass Dysgerminoma- Commonest germ cell tumour 10-30 years of age Tumor markers - HCG,LDH,AFP Treatment is surgery followed by radiation after 30 years. Fertility loss is a concern. So in younger patients conservative treatment with Preservation of fertility is mainstay of treatment.

49. dysgerminoma

50. Yolk Sac Tumour/ Endodermal Sinus Tumour Mean age-16-18 years 100% unilateral Highly malignant with rapid growth Gross- soft, greyish brown areas Micro- Schiller Duval bodies

51. Embryonal Carcinoma Most malignant . Present as abdominal mass. Present at very young age-mean - 14 years . Tumor markers - HCG, AFP.

52. Metastatic Tumours Krukenberg Tumours : Smooth surface Bilateral Primary from-Mainly stomach, large Bowel, Breast Signet ring cells are hallmark on microscopic picture

53. Spread Transcelomic - ’exfoliated cells’ Lymphatic Direct Haematogenous

54. Symptoms And Signs Symptoms - Non specific like abdominal distension, dyspepsia ,dull aching abdominal pain, sudden weight loss Signs- Anemia, Supraclavicular and inguinal lymphadenopathy Edema of leg, Ascites, Abdominal lump, On P/V- Nodules palpated in posterior fornix separate from uterus Pleural Effusion

55. OVARIAN TUMOUR SCREENING MULTI MODEL Ca 125 and Ultrasound scanning Ca 125 >30 u\ml is abnormal Ca 125 is an antigen found in the foetal amniotic and coelomic epithelium in adults. I t is found in mesothelial cells of pleura, pericardium and tubal, endometrial, endocervical and the ovary. The surface epithelium of normal foetal and adult ovaries does not express the antigen except in inclusion cysts, papillae or metaplasia An elevated level is found in 50% of stage 1 and >90% in women with advanced disease. Sensitivity is 97% Specificity is 96% False positive in : C a endometrium ,Ca colon, endometriosis, fibroid, PID, pregnancy and menstruation

56. Risk of Malignancy Index(RMI) RMI- U*M*CA125 U-Ultrasound score.1 point each for multilocularity, metastasis, bilaterality , solid areas M-Menopausal State-1-Premenopausal 3- Postmenopausal Low Risk---<25 Moderate ---25-250 High--->250

57. Tumour Markers CA-125 Most widely used but non specific. Extremely useful for follow up after the Treatment HE4 Most specific and sensitive tumour marker Ova-1 --Transthyretin, ApolipoproteinA1, Transferrin,Beta2 macroglobulin, CA-125. FDA Approved Other Markers - HCG, LDH, Human epididymis protein 4,Mesothelin, B7H4, Decoy receptor3

58. Risk of Ovarian Cancer Algorithm ROCA Based on slope of CA-125 measurements at regular intervals . Proposed to increase performance of single threshold measurement of CA-25 Being evaluated with TVS as a two stage screening process

59. simple ultrasound-based rules for the diagnosis of ovarian cancer. ultrasound obstetgynecol2008 RCOG 2011

60. FIGO STAGING

61. MANAGEMENT Preop Evaluation Surgical management Chemotherapy NACT Follow-up

62. Pre-op Evaluation Blood investigations - CBC, LFT, RFT, FBS, PLBS, TSH ECG Urine routine microscopy Imaging- TAS/TVS/CECT,MRI/PET scan Tumour markers Mammography GI endoscopies

63. FNAC Poor sensitivity More over spillage of tumor cells Only for those patients who cant undergo surgical intervention and need neo adjuvant chemotherapy(NACT)

64. MANAGEMENT SPECTRUM Primary Surgery 1. Early Stage Ovarian Cancer 2. Advanced stage ovarian Cancer Neoadjuvant chemotherapy and interval cytoreductive surgery Laparoscopic Surgery

65. Surgery Sequential Systematic exploration of organs

66. TAH+BSO Suspicious areas biopsied Infracolic omentectomy /omental wedge biopsy Retroperitoneal lymph node sampling

67. Surgical Treatment BORDERLINE TUMOUR- Unilateral oophorectomy, No subsequent chemo required Stage1 epithelial - TAHBSO +lymph node sampling Stage2 epithelial-TAHBSO+ PALTINUM BASED CHEMOTHERAPY Advance Cancers-Neoadjuvant Chemotherapy with cytoreductive surgery

68. Chemotherapy No of cycles- 6-8 - Advanced stage cancers 3-6 - Earlier stage cancers Platinum based chemotherapy is required Currently CARBOPLATIN+PACLITAXEL is found to have better survival rate.

69. OTHER IMAGING MODALITIES CT, MRI, PET not recommended in the initial evaluation CT scan: evaluating LN involvement, Omental mets, peritoneal deposits, hepatic mets, obstructive uropathy or a probable alternate primary site when cancer is suspected based upon TVS MRI : differentiating non adnexal pelvic masses (like leiomyomata), expensive and inconvenient. ACOG GUIDELINES 2007

70. Benign Ovarian tumour Malignant Ovarian tumour Common in middle age group Painless unless complicated No oedema No varicosities Generally unilateral Unilocular Thin walled Thin septae if present No papillae or solid contents Normal or decreased vascularity on doppler No metastasis Slow growing Smooth, cystic Freely mobile No ascites or if present clear fluid on paracentesis Seen at extremes of ages May be painful Oedema maybe present Varicosities may be present May be bilateral Multilocular Thick walled Thick septae Mixed echogenicity High vascularity, low pulsatility index and low resistance index Metastasis in advanced disease Rapidly growing Solid, nodular, irregularly shaped Fixed Ascites present and on paracentesis the fluid may be blood stained.

71. Treatment

72. INDICATIONS FOR SURGERY Any solid ovarian lesion Any ovarian lesion with papillary vegetation on the cyst wall Any adnexal mass >10cm in diameter Palpable adnexal mass in a premenarchal or postmenopausal women Torsion or rupture suspected

73. Ovarian mass in reproductive age group <5 cms . >/= 5 cms USG USG cystic observation Complex, solid, suspicious Persistence or progression surgery

74. CYST ASPIRATION Diagnostic cytology has poor sensitivity to detect malignancy, ranging from 25% to 82% Not therapeutic, even when a benign mass is aspirated Approx. 25% of cysts will recur within 1 year Aspiration of a malignant mass may induce spillage and seeding of cancer cells into the peritoneal cavity.

75. OPERATIVE MODALITIES Laparoscopy vs laparotomy – decision based on suspicion of malignancy and technical expertise No RCTs comparing recurrence rates following laparoscopy or laparotomy. The objective is to try cystectomy if possible. Laparoscopic surgery for benign ovarian tumours is associated with less pain, shorter hospital stay, and fewer adverse events than with laparotomy. Cochrane Database of Systematic Reviews 2009

76. SURGERY Young women : Ovarian cystectomy Oophorectomy ( salpingo oophorectomy) Parous women : Total Abdominal Hysterectomy with Bilateral oophorectomy Others : Individualisation

77. The standards for laparoscopy in benign tumours Careful examination of the external surface of the tumour and sampling of the peritoneal cavity A voidance of any tumoral rupture P rotection of the ovarian tumour with an endoscopic bag before removal

78. ROLE OF FROZEN SECTION The diagnostic accuracy of frozen section analysis is high for malignant and benign ovarian tumours, but accuracy is poor in the case of borderline ovarian tumors. Medeiros 2005

79. Conclusion Ovarian masses are very commonly seen in general population. Most of the times these are simple functional tumours which resolve spontaneously within six to eight weeks. However an in-depth understanding of the ovarian masses is needed as the grave consequences may follow, if there is a wrong diagnosis. Imaging studies especially ultrasound is a prime tool in diagnosing ovarian tumours. Careful consideration to woman’s need should be addressed before selecting any method of treatment .