Outline

Ovarian tumors

Epithelial (Mullerian) tumors

Serous tumors

Mucinous tumors

Endometrioid ovarian tumors

Clear cell carcinoma

Transitional cell tumors

Outline

Germ cell tumors

Teratoma

Dysgerminoma

Yolk sac tumor (endodermal sinus tumor)

Choriocarcinoma

Sex cord stromal tumors

Granulosa cell tumor

Fibroma, thecoma, fibrothecoma

Sertoli-Leydig cell tumor

Ovarian tumors

Benign = 80%; 20-45 y/o

Borderline/low malignant potential = slightly older

females

Malignant = more common in older females, 45-65 y/o

Ovarian cancer:

3% of all female cancers

5th cause of female cancer deaths

Diagnosed at advanced stage hence higher

mortality – most have spread beyond the ovary at

time of diagnosis

Ovarian tumors

WHO classification based on tissue of origin:

Surface/FT epithelium & endometriosis

Germ cells (pluripotent cells that migrate to the ovary

from the yolk sac)

Stromal cells & sex cords (endocrine apparatus of

ovary)

Metastatic tumors to the ovary

Symptoms: abdominal pain & distention, urinary & GI

tract obstruction 2° tumor invasion, vaginal bleeding

Epithelial tumors

Histologic types:

Serous

Mucinous

Endometrioid

Each histologic type classified as:

Benign

Borderline/low malignant potential (LMP)

Malignant

Pathogenesis of ovarian epithelial tumors

Fallopian tube origin of

high-grade serous carcinoma

Observed in BRCA1/BRCA2 germline mutation

carriers

Risk-reducing salpingo-oophorectomy

Serous Tumors Benign, borderline, and malignant types account for about 30% of

all ovarian tumors and ~50% of ovarian epithelial tumors

About 70% are benign or borderline, 30% are malignant

Benign and borderline tumors – younger patients 20-45 yrs

Malignant tumors – later in life unless genetically susceptible (BRCA 1 and 2)

Risk factors for malignant serous tumors:

BRCA1/2 mutation – estimated risk 20-60% by the age of 70 years (these mutations are present in about 5% of women younger than 70 with ovarian cancer)

Nulliparity/low parity

Family history

Reduced risk

OCP use

Tubal ligation

Ovarian serous carcinoma

Low-grade serous carcinoma

(LGSC)

Arise in serous

borderline tumors

Mutation: KRAS, BRAF,

ERBB2

Wild type: TP53

High-grade serous carcinoma

(HGSC)

Arise from STIC or

inclusion cysts

Mutation: TP53

Wild type: KRAS, BRAF

Amplification of

oncogenes, deletions of

tumor suppressor genes

Present in BRCA1/2 pts

BRCA1/2 mutation rare

in sporadic HGSC

Serous tumors

Biologic behavior depends on degree of differentiation and peritoneal

involvement (tumor present on ovarian surface vs spread to peritoneum)

SBT & LGSC – slow progression even with peritoneal involvement, patient

may survive for relatively long periods

HGSC – often widely metastatic, rapid clinical deterioration

Malignant tumors:

5 yr survival if confined to ovary – 70%

5 yr survival if involving peritoneum – 25%

Borderline tumors:

5 yr survival if confined to ovary – 100% - but may recur after many

years

5 yr survival if involving peritoneum – 90%

Serous borderline tumor

Increased complexity of the

stromal papillae

Stratification of the

epithelium

Mild nuclear atypia, but

invasion of the stroma is not

seen

Micropapillary pattern –

papillae are long and thin

(“medusa head”)

Thought to be the precursor

to low-grade serous

carcinoma

Serous borderline tumor (low malignantpotential)Low-grade Serous Carcinoma

Low-grade invasive serous carcinomas

frequently merge with areas

morphologically consistent with SBT

Nuclei are uniform, round, or oval with

evenly distributed chromatin with or

without a prominent nucleolus

Typically shows papillary or micropapillary

patterns combined with areas of invasion

into stroma

Should be p53 wild-type/patchy staining

High-grade Serous Carcinoma

More frequently seen than low-grade

Demonstrates a wide range of

morphologic patterns

A consistent feature is enlarged nuclei,

usually with prominent nucleoli and

many mitoses, which are often

abnormal

Nuclei may demonstrate bizarre

morphology

p53 staining will be either strongly and

diffusely positive or completely

negative

Mucinous tumors

Mucinous tumors account for 20-25% of all ovarian neoplasms

Occur in middle adult life

Majority are benign or borderline tumors, most are unilateral

KRAS proto-oncogene mutation found in benign, borderline, &

malignant mucinous tumors

Pseudomyxoma peritonei:

Characterized by extensive mucinous ascites, cystic epithelial

implants on peritoneal surfaces, adhesions, and bilateral ovarian

involvement

Most cases are due to an appendiceal mucinous neoplasm (not

primary ovarian mucinous tumor), which is involving the bilateral

ovaries

Mucinous Borderline Tumor

Demonstrate epithelial

stratification, tufting, and/or

papillary intraglandular growth

Mucinous Carcinoma

Characterized by expansile

(confluent) or infiltrative

types

Expansile growth – back to

back glands and cysts with

little intervening stroma which

appear to be invading into

stroma across a broad,

demarcated front

Infiltrative growth - glands,

sheets, or single epithelial

cells haphazardly invade the

stroma

Mucinous Tumors

Approximate 10-yr survival rate for stage I invasive malignant

mucinous tumors is approximately 90%

Mucinous tumors that have spread beyond the ovary – usually

fatal

Need to distinguish from metastatic tumor to ovary

Endometrioid Ovarian Tumors

Less common than serous or mucinous ovarian tumor, but 10-15% of all

ovarian cancers

15-20% coexist with endometriosis

15-30% coexist with endometrial endometrioid carcinoma → thought to

represent 2 separate tumors rather than metastasis

Molecular profile similar to endometrial endometrioid carcinoma

PI3K/AKT pathway increased signaling through mutations in PTEN, PIK3CA,

ARID1A, and KRAS

Mismatch repair genes mutations

CTNNB1 (beta catenin)

Endometrioid Carcinoma

Cystic and solid tumors

40% are bilateral

Appearance is similar to endometrioid

carcinoma of endometrium, but can have

multiple different histologic patterns

5-year survival rate for Stage I tumors is 75%

Clear cell carcinoma

Presently thought to be variant of endometrioid carcinoma (a/wendometriosis or ovarian endometrioid carcinoma)

Molecular profile similar to endometrial endometrioidcarcinoma (PIK3CA, ARID1A, KRAS, PTEN, and TP53 mutations)

5-yr survival: Confined to the ovaries (about 40% of tumors) –90%, Advanced stage – poor prognosis (~20%)

Rarely, they may give rise to paraneoplastic hypercalcemia

Transitional cell tumors (Brenner tumors)

Usually benign

Neoplastic epithelium

resembles urothelium

About 10% of epithelial tumors -

often incidental finding

Can rarely be malignant

Can be associated with other

tumors in the ovary (mucinous

cystadenoma)

Microscopic: fibrous stroma

resembling ovarian stroma with

demarcated nests of bland,

transitional type epithelium

Clinical course, detection, & prevention

of ovarian epithelial tumors

Most women with ovarian carcinoma present with high-stage disease

Signs/symptoms: lower abdominal pain, abdominal enlargement, GI complaints,

urinary frequency, pelvic pressure

Ovarian capsular rupture → peritoneal seeding; tumor nodules on serosal surfaces →

ascites

Metastasis: regional lymph nodes, liver, lungs, GI tract

High stage at clinical presentation → poor prognosis

Tumor biochemical tests for early diagnosis still n/a

CA-125 serum marker → used in patients with known dz for disease monitoring

Germ Cell Tumors

Includes:

Teratoma

Dysgerminoma

Yolk Sac Tumor

Choriocarcinoma

Others

Germ Cell Tumors

25% of all ovarian tumors

All occur in premenopausal age

95% of germ cell tumors are benign cystic teratomas

(dermoid cysts)

5% are exactly like testicular counterpart

Testicular seminoma = Ovarian dysgerminoma

AFP, HCG tumor markers

Ovarian Teratoma Common benign ovarian tumor in young adult female

Contain tissues from 3 germ layers: ectoderm (predominant), mesoderm, endoderm

Rare fetiform teratoma (Homunculus)

Mostly cystic, benign, ectoderm dominant

Rarely benign, solid → “monodermal” (e.g. carcinoid tumor; struma ovarii[benign thyroid tissue])

May rarely be malignant:

1% will undergo malignant transformation of a component – squamous cell carcinoma most common

Immature (fetal) teratoma (like testicular teratoma)

Mixed with other malignant germ cell components

Teratomas

Ovary

Mostly benign

Mature tissue

Mostly cystic

Mostly pure tumor

46,XX most common

karyotype

Testis

Mostly malignant

Immature fetal tissue

Mostly solid

Mixed with other germ

cell tumors

Aneuploid

Mature Cystic Teratoma

Mature Cystic Teratoma

Monodermal Teratoma

Most common:

Struma ovarii – teratoma composed

entirely of mature thyroid tissue

May be functional and cause

hyperthyroidism

Ovarian carcinoid – carcinoid tumor

supposedly arising from intestinal

tissue in teratoma

May be functional and can produce

5-hydroxytryptamine sufficient

enough to cause carcinoid syndrome

Only about 2% of ovarian carcinoids

metastasize

Immature Malignant Teratomas

Rare, contain tissues resembling embryonal and

immature fetal tissue - immature

neuroectodermal epithelium

Usually in young patients (~18 yrs)

Dysgerminoma

Ovarian counterpart to testicular seminoma

Represent 2% of ovarian cancers and 50% of

malignant ovarian tumors

75% occur within the second and third decades

80-90% are unilateral

Gross: Can present as a large, fleshy tumor with

solid yellow-white cut surface

Micro: Composed of large vesicular cells with

clear cytoplasm, well-defined cell boundaries,

and centrally-placed, regular nuclei

Tumors grow in sheets separated by fibrous

stroma with mature lymphocytes

Dysgerminoma

All dysgerminomas are malignant

Responsive to chemotherapy if spread

outside of the ovary

Unilateral tumor confined to the ovary has

up to 96% cure rate after salpingo-

oophorectomy

YOLK SAC TUMOR. WITH ALFA FETOPROTEIN (PINK BLOBS)

AFP (pink blob)Yolk sac tumor(Endodermal sinus tumor)

Schiller-Duval body

Second most common malignant germ cell tumor

Derived from malignant germ cells that are differentiating along the extraembryonic yolk sac lineage

Tumors produce α-fetoprotein

Schiller-Duval body – glomerulus-like structure composed of a central blood vessel enveloped by tumor cells within a space that is also surrounded by tumor cells

Demonstrate intracellular and extracellular material, some of which stain for α-fetoprotein by immunohistochemistry

Choriocarcinoma

Aggressive malignancy – usually presents

with metastasis to lungs, liver, and bone

and other sites at the time of diagnosis.

Most exist in combination with other

tumors

Resemble cytotrophoblast and

syncitiotrophoblast cells from placenta

Tumors produce high levels of chorionic

gonadotrophins, which may be helpful in

establishing the diagnosis or detecting

recurrences

Choriocarcinoma arising primarily from

the ovary (an not arising in a placenta) –

unresponsive to chemotherapy and often

fatal

Other Germ Cell Tumors Embryonal Carcinoma – highly malignant tumor of primitive

embryonal elements

Polyembryoma – embryonal tumor containing predominately

embryoid bodies

Mixed germ cell tumors – contain various combinations of

teratoma, yolk sac, and choriocarcinoma

Sex Cord Stromal Tumors

Tumors derived from ovarian stroma, which is derived from the embryonic gonad

Undifferentiated gonadal mesenchyme produces –Sertoli and Leydig cells in males and granulosaand theca cells in female

Tumors produced from these cells are often functional, and can produce masculinizing and feminizing effects in the patient due to androgen and estrogen production

Granulosa cell tumor (GCT)

Tumor cells resembele granulosa cells of a developing ovarian follicle

Classified as Adult GCT (95% of GCTs) or Juvenile GCT based on age of

patient and histologic characteristics of tumor

2/3rds in postmenopausal women

Clinical importance:

Estrogenic →

Young pts: precocious puberty

Adult pts: proliferative breast disease, endometrial

hyperplasia, endometrial carcinoma

Act as a low grade/indolent malignancy →

5-25% risk of malignancy

Malignancy carries risk of relapses 10-20 years after removal

Granulosa Cell Tumor

Tumors are associated with

increased serum levels of inhibin –

which is also seen associated with

other sex cord stromal tumors

Up to 97% of adult granulosa cell

tumors have been shown to

demonstrate FOXL2 gene

mutations

FOXL2 encodes a factor

important in granulosa cell

development

,

COMBINED LEYDIG (L) AND SERTOLI CELL(S) TUMOR,OVARY

L

S

CRYSTALLOID OF REINKE (ARROW) IN LEYDIG CELL TUMOR

Sertoli-Leydig

Cell Tumors

Generally functional tumors,

can produce masculinization

or defeminization, rarely

estrogenic effects

Demonstrate cells resembling

sertoli and leydig cells, can

show Crystals of Reinke in

leydg cells

50% of tumors demonstrate

mutations in DICER1 gene – a

gene responsible for proper

processing of micro-RNAs

MUCIN POSITIVE (PINK) SIGNET RING CELLS IN

KRUCKENBERG TUMOR (MICRO)

Metastatic tumorsto ovary:

• Breast, Lungs• GI (mucinous)• Endometrial• Leukemia• Lymphoma (eg.Burkitt’s)

“Krukenberg tumor”Bilateral, solid, mucinousSignet ring cellsPrimary: often from stomach

References