Ovarian pathology

Dysgerminoma

*Malignant* germ cell tumor of ovary - Most common in *adolescents* - Equivalent to *male seminoma but rarer* (seminoma is a malignant, painless, homogeneous testicular enlargement that does not occur in infancy; presents with large cells in lobules with watery cytoplasm and "fried egg" appearance) - 1% of all ovarian tumors; 30% of germ cell tumors - *Sheets of uniform "fried egg" cells* resembling oocytes - *hCG, LDH* = tumor markers - Associated with *gonadal dysgenesis* Prognosis: - Exquisitely radiosensitive; cure possible with radiotherapy - 90% five year survival (so it's very important to recognize this tumor!)

Immature teratoma

*Malignant*, aggressive germ cell tumor - Young ages exclusively (average 18 years) - Can contain all 3 germ layers - Originates from totipotent germ cells - Characterised by the presence of immature or embryonic tissue, as well as the mature tissue elements seen in a mature teratoma - The proportion of immature neuroepithelium present correlates with the tumour grade (and hence prognosis) - Main component usually neuroepithelial (neuroectoderm) - Typically represented by immature/embryonic-like neural tissue Prognosis: - 50-60% 5 year survival - Requires triple agent chemo

General concepts based on presentation: - Age - Hormonal manifestations - Gross appearance of tumor

- Child → think about germ cell tumor - Older adult → worry about malignant epithelial cell tumor - Cystic → usually benign - Solid/necrotic → usually malignant - Hormone production → think sex cord/stromal tumor

Ovary during reproductive life - normal gross

- Larger in relation to uterus - Holes/hemorrhages in surface where ovulation occurred

Ovary at birth - normal gross

- Ovaries are long and flat - Large compared to uterus

Why may prophylactic salpingectomy may be beneficial for prevention of high grade serous ovarian cancer?

- Precursor lesion to high grade serous may be dysplasia or in-situ carcinoma of fallopian tube - Close proximity of fallopian tubes and ovaries results in ovarian tumor - Individuals with genetic predisposition may benefit (p53 & BRCA mutations) - *Any alteration in the structure* of the fallopian tube and ovary due to disease will result in *alteration of function* (Fallopian tube purpose is to scoop up ovum and propel it to meet with sperm)

Gross appearance of endometriosis

- Red-brown nodules on serosal surfaces - Large blood-filled cysts within ovary (endometrioma) - Fibrous adhesions between organs, ligaments - Can affect bowel, urinary bladder, etc

Tumor metastatic to ovary

- Small percentage of all ovarian tumors (1 - 3%) - From breast, other genital tract tumors (endometrial and cervical cancer) and colon/appendix/other GI primary tumors - Now thought that many mucinous tumors of the ovary may be primary from appendix metastasizing to ovary (causing pseudomyxoma peritonea)

Ovary after menopause - normal gross

- Smaller, more wrinkled, fibrotic, scarred - Should not be able to be palpated upon physical exam

Types of pathology of the ovary

1. Infections 2. Endometriosis 3. Non-neoplastic cysts 4. Neoplasms

How do malignant epithelial ovarian tumors spread?

1. Initial spread within pelvis *along surfaces of uterus, both ovaries and fallopian tubes* 2. Higher stages spread *everywhere within abdomen* - Omentum may become completely replaced by carcinoma

Function of ovaries

1. Reproduction - Produce eggs (half of zygote) 2. Hormone production - Aids in reproduction - Maintain health (bones, sexual organs, psychologic health)

Types of non-neoplastic cysts

1. Surface inclusion cysts (nonfunctional) 2. Follicular cysts (functional) 3. Theca-lutein cysts (functional) 4. Polycystic ovaries

Ways to differentiate between non-neoplastic cysts

1. The normal epithelium that the cyst/tumor lining most resembles 3. Functional vs non-functional cyst

Choriocarcinoma

A malignant, trophoblastic cancer, usually of the placenta - Also classified as a germ cell tumor and may arise in the testis or ovary - Characterized by early hematogenous spread to the lungs (most carcinomas spread via lymphatics except HCC, RCC, follicular thyroid carcinoma, and choriocarcinoma) - *↑beta hCG* - Disordered syncytiotrophoblastic and cytotrophoblastic elements - *Hematogenous metastases to lungs and brain* - May produce *gynecomastia, symptoms of hyperthyroidism* (hCG is structurally similar to LH, FSH, TSH) - Belongs to the malignant end of the spectrum in gestational trophoblastic disease (GTD)

Palpable post-menopausal ovary syndrome

A postmenopausal ovary normally cannot be felt - If it can be, it's ABNORMAL

Theca-Lutein cyst

A type of *bilateral functional ovarian cyst* filled with clear, straw-colored fluid - Often *bilateral/multiple* - Exact etiology is unknown, but usually associated with *markedly elevated levels of beta-human chorionic gonadotropin (beta-hCG)* - Associated with choriocarcinoma and hydatidiform moles (produce hCG) - *Should resolve* several weeks after offending cause

General physiology of ovarian cyst formation

After ovulation, corpus luteum can be sustained by hCG from fetus, degenerate into corpus albicans, or sometimes become a cyst

Surface inclusion cyst

Aka non-functioning ovarian cyst - Does not produce hormones - Comes from surface epithelium (may be "pinched off") Pathophysiology: - May form from pinching off of epithelium during closure of ovulation hole

Other germ cell tumors

All highly *malignant* and *rare* - May be found mixed together 1. Yolk sac tumor (endodermal sinus tumor) 2. Choriocarcinoma - Tumor of placental tissue - Beta-hCG production 3. Embryonal carcinoma

Brenner tumor

An uncommon surface epithelial tumour of the ovary - Histological similarity to the urothelium (bladder epithelium) - Solid tumor that is pale yellow-tan and appears encapsulated - "Coffee bean" nuclei on H&E stain. - Majority are benign

Classification categories of ovarian neoplasms

Based on cell of origin - Newly discovered genetic mutations are being used for sub-classification 1. Epithelial 2. Germ cell 3. Sex cord/stromal 4. Metastatic to ovaries

Fibroma (ovarian)

Benign ovarian neoplasm of sex cord/stromal origin - Unilateral - *Meigs syndrome*: triad of ovarian fibroma, ascites, hydrothorax - "Pulling" sensation in groin Micro: - Bundles of spindle-shaped fibroblasts

Thecoma

Benign ovarian neoplasm of sex cord/stromal origin - Unilateral - Like granulosa cell tumors, may produce estrogen - Usually presents as abnormal uterine bleeding in a postmenopausal woman Micro: - Luteinized cells (lipid/sterol containing cells)

Granulosa cell tumor gross

Can have endometrial hyperplasia from production of sex steroids

Mature cystic teratoma (dermoid cyst)

Comprises 95% of germ cell tumors, 10% of all ovarian tumors (common) - *Benign* (may undergo malignant degeneration in 1% of cases) - Found at any age (most common ovarian tumor in reproductive years, i.e. females 10-30 years old) - Originates from totipotent germ cells in ovary (46XX) - Cystic mass containing elements from all 3 germ layers (eg teeth, hair, sebum) - May be bilateral Main problems: - Can present with pain secondary to ovarian enlargement (mass effect) or torsion of ovary with infarct and rupture - Infection, infertility - *Struma ovarii:* A monodermal form of mature cystic teratoma with thyroid tissue that uncommonly presents in hyperthyroidism

Endometriosis

Endometrial glands that arise outside of endometrium that respond cyclically to normal hormones produced by the ovary (proliferate, secrete, and bleed) - Prevalent disease (affects 10% of women of reproductive age) - Endometrial tissue may be different from normal endometrium because it has increased survival - Several theories of development Symptoms: - Characterized by cyclic pelvic pain, bleeding, dysmenorrhea, dyspareunia, dyschezia (pain with defecation), infertility; normal-sized uterus Theories of development: 1. Regurgitation through fallopian tube into peritoneal cavity 2. Extrapelvic dissemination through pelvic veins 3. Lymphatic dissemination 4. Metaplastic differentiation of coelomic epithelium 5. Extrauterine stem/progenitor cell theory: Progenitor cells from bone marrow differentiate into endometrial tissue Complications: - Continual stimulation of glands and bleeding leads to fibrosis and adhesions - Blood may accumulate in cystic spaces ("chocolate cysts") - Association between endometriosis and ovarian cancer Treatment: - Control of bleeding - Goal = relieve pain and prevent/correct infertility - NSAIDs, OCPs, progestins, GnRH agonists, danazol, laparoscopic removal. (danazol = Synthetic androgen that acts as partial agonist at androgen receptors, decreasing hormone production from ovaries)

Microscopic appearance of endometriosis

Endometrial tissue, blood remnants, and/or scarring - Endometrial glands, stroma, and hemosiderin pigment (a consequence of bleeding) - Fibrosis (scarring): consequence of continued bleeding

How can endometriosis tissue remain viable outside of the endometrium?

Endometriotic tissue may be different from normal endometrium - Perhaps some type of stimulation by growth factors/cytokines that enables survival of tissue

Epithelial ovarian tumors

Epidemiology: - 80% of ovarian cancers Types/naming: - Can be benign, malignant, or borderline malignant 1. *Cell types:* serous, mucinous, endometrioid (surface epithelium is altered through metaplasia) 2. *Solid vs cystic* 3. *All epithelial* vs *with fibrosis component* - Papillary structures common (papilla are fibrovascular cores covered by epithelium) Gross: - Can be solid or cystic or combined - Generally, more solid = more malignant; more cystic = more benign Symptoms: - Cause mass effect: pain, abdominal distension, GI (bowel obstruction), GU complaints (vague) - May have palpable post-menopausal ovary (abnormal) - Endocrine manifestations Treatment: - Malignant lesions require extensive surgery, with adjuvant chemotherapy/radiotherapy Staging: - Reflects spreading of disease

Follicular cysts

Functional cyst that comes from a follicle vs the surface epithelium - Very common - Distention of unruptured graafian follicle - Usually occurs during ovulation - May produce hormones (i.e. estrogen) - Simple (unilocular) cysts - Lined by granulosa cells - May be associated with hyperestrogenism, endometrial hyperplasia - May regress after menstrual cycle Epidemiology: - Occurs in newborns due to stimulation from maternal hormones (hCG from placenta) - Most common ovarian mass in young women

Polycystic ovaries

Functional ovarian cysts seen in some with a specific syndrome - Part of *Stein-Leventhal syndrome*: polycystic ovarian disease (PCOD) which can have many manifestations Presentation: - Young women - Enlarged, bilateral cystic ovaries - Amenorrhea/oligomenorrhea - Hirsutism - Acne - Decreased fertility - Virilism - Obesity - Insulin resistance Associations: - Increased risk of endometrial cancer secondary to unopposed estrogen from repeated anovulatory cycles Pathophysiology: - Hyperinsulenima and/or insulin resistance hypothesized to alter hypothalamic hormonal feedback response → chronically elevated LH (no spike to induce ovulation), excessive androgens (eg testosterone) from theca interna cells → ↓rate of follicular maturation → enraptured follicles (cysts) and anovulation Treatment: - Weight reduction - OCPs - Clomiphene citrate (Antagonist at estrogen receptors in hypothalamus to include GnRH pulses and ovulation) - Ketoconazole (Antiandrogen; Inhibits androgen synthesis inhibits 17,20-desmolase) - Spironolactone (Antiandrogen; inhibits steroid binding)

Polycystic ovaries gross & microscopic

Gross: - Numerous follicle cysts, but *no corpora luteal* or corpora hemorrhagic or corpora albicantia (i.e. *no signs of ovulation*) Microscopic: - Cysts lined with granulosa cells

What are borderline ovarian tumors (tumors of low malignant potential)? Why are these tumors important to recognize?

Have morphologic *features* and *prognosis* INTERMEDIATE between benign and malignant tumors - Most confined to one ovary (stage 1) - Important criterion: *lack of invasion of stroma* Important to recognize because: - May use conservative surgery - Survival rates are *high* - Course may be *indolent* - May be precursors to more invasive cancers Example: - Mucinous or serous tumors of borderline malignancy

Mucinous cystadenocarcinoma

Malignant ovarian epithelial tumor of mucinous cells - Associated with pseudomyxoma peritonea (like the benign mucinous cystadenoma)

Serous cystadenocarcinoma

Most common malignant ovarian tumor - Solid tumor of serous cells - Post-menopausal age - Most are bilateral - Psammoma bodies (concentric calcification of tumor necrosis) - Nuclear atypia

Serous cystadenoma

Most common ovarian neoplasm consisting of fallopian tube-like epithelium surrounding cysts, filled with watery fluid (vs mucinous cystadenomas which are filled with mucus-like fluid) - Benign - Often bilateral

Granulosa cell tumor

Most common type of sex cord/stroma tumor - *Malignant* - <5% of all ovarian tumors - Usually post menopausal women (women in 50s) (except for juvenile granulosa cell tumors) - Often produces estrogen and/or progesterone Presentation: (caused by increased estrogen production by tumor) - 75% have steroid production, sometimes with effect on endometrium - Postmenopausal bleeding - Sexual precocity (in pre-adolescents) - Breast tenderness Histology: - *Call-Exner bodies*: granulosa cells arranged haphazardly around collections of eosinophilic fluid, resembling primordial follicles Gross: - Solid - Unilateral - May be *yellow* (because of functioning, production of *steroids*) Prognosis: - 85% ten year survival overall, because most present with low-stage disease

Recent advances in theories about ovarian cancergenesis

Most epithelial ovarian cancers can be divided into high grade serous vs all others (low grade serous, borderline, endometrioid, mucinous, etc) in terms of *behavior* and *genetic mutations* - *High grade serous:* associated with *p53* and *BRCA mutations* - High grade serous are the worst acting and most difficult to treat/cure - Precursor lesion to HG serous may be dysplasia or in-situ carcinoma of *fallopian tube* - Prevention of HG serous may be via *prophylactic salpingectomy* with preservation of ovaries in genetically predisposed women - Endometrioid carcinomas may arise in setting of endometriosis

Age of onset of ovarian neoplasms

Most ovarian neoplasms are benign - Occur in young women Malignant neoplasms (cancers) occur in older women - Average age 60

Infections of the ovary

Occur as part of PID (along with Fallopian tube) Effects are similar to those from infection of fallopian tube: - Infertility - Adhesions - Sterility - Pelvic mass

Epidemiology & risk factors of ovarian cancer

Ovarian cancer (malignant) is less common than endometrial and cervical cancer, but accounts for a *higher proportion of deaths* - Most women with ovarian cancer present with *advanced stage disease (stage III or IV)* - Few symptoms until tumor is large, and can often be ascribed to other organ processes (eg bladder or GI) Risk factors: - Nulliparity (never given birth) - Infertility - Dysgenetic gonads - Genetic factors: Family history, BRCA1/BRCA2, p53, Her2/neu Presentation: - Adnexal mass - Abdominal distension - Bowel obstruction - Pleural effusion Therapy: - Monitor response to therapy/relapse by measuring CA 125 levels (not good for screening)

Sertoli-Leydig cell tumors (Androblastomas)

Ovarian neoplasm of sex cord/stromal origin - Young women - Male counterpart of granulosa/thecal cell tumors - May be hormonally active (androgenic) with virilization in women; can have characteristic Reinke crystals

Endometrioma

Ovary becomes a cystic mass filled with blood - Enlarged ovary due to tissue replacement by endometriosis

Yolk sac (endodermal sinus) tumor

Rare ovarian germ cell tumor - Aggressive, in ovaries or testes and sacrococcygeal area in young children - Most common tumor in male infants (<3 years old) - Yellow, friable (hemorrhagic), solid mass - 50% have Schiller-Duval bodies (resemble primitive glomeruli) - AFP = highly characteristic tumor marker

Staging of ovary carcinoma

Stage 1: Growth limited to ovaries Stage 2: Growth involving one or both ovaries with pelvic extension Stage 3: Growth involving one or both ovaries with intraperitoneal *metastasis to the abdomen* (including omentum, small intestine etc) Stage 4: Growth involving one or both ovaries with *distant metastasis outside the peritoneal cavity*

What are tumors of germ cell origin?

Tumors arising from the primitive germ cell (totipotent cell) - Because germ cells migrate along the midline from the yolk sac during embryogenesis, germ cell tumors can be found *anywhere along their migratory route* (i.e. in midline, including retroperitoneum, mediastinum, but mostly gonads) - 15-20% of ovarian tumors - Account for most of the ovarian tumors in ages 0-20 years Types of tumors: 1. 95% of germ cell tumors are *benign cystic teratomas* found at any age 2. Remainder are *highly malignant, rare* and found exclusively in *very young females* (children to young adults) Classification: 1. Type of tissue present (what tissue the tumor most resembles) Spread of malignant germ cell tumors: - *Via lymphatics* vs surface spread (unlike epidermal ovarian neoplasms, which spread to the abdominal cavity via surface spread)

Tumors of sex cord/stroma origin

Tumors derived from granulosa cells and theca cells - Account for most of *functioning ovarian tumors* because these cells normally produce steroid hormones - ~10% of all ovarian tumors

Type I vs Type II tumors: genetics

Type 1: - Progress from benign tumors to borderline tumors - Include low grade tumors - Mucinous have KRAS mutations Type II: - Arise from inclusions/cysts - Demonstrate high grade qualities - Most commonly have serous histology - *p53 and BRCA1/2 mutations*

Mucinous cystadenoma

Usually benign ovarian tumor of epithelial cell origin consisting of cysts surrounded by mucinous (mucus-secreting) epithelium - 80% are benign - Associated with *pseudomyxoma peritonei*: intraperitoneal accumulation of mucinous material from ovarian or appendices tumor (from bursting of cyst) throughout the abdominal and peritoneal cavity, with adhesions, obstruction of bowel, etc. - Most mucinous tumors have *KRAS* proto-oncogene mutation Gross: - Complex cystic structures - Multioculated, large Microscopic: - Each cyst is lined by simple mucinous epithelium

Examples of composition of germ cell tumors

a) primitive germ cells (dysgerminomas/seminomas) b) teratomas made up of embryonal tissues and/or adult tissues c) structures resembling the placenta (choriocarcinoma) d) structures resembling early fetal tissue (yolk sac tumor) e) undifferentiated, primitive tissue (embryonal carcinoma)