B14a04 - Pathology of the Ovaries

8/16/2019 B14a04 - Pathology of the Ovaries

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5c | Peradillo, Pescasiosa, Pineda

Block XIV | Pathology | Lesson 4

PATHOLOGY OF OVARIES Ansari P. Salpin, MD, DPSP

March 22, 2016

OUTLINEI. Non neoplastic lesions of the ovary

II. Polycystic Ovarian Disease

III. Ovarian Tumors

A.

Surface Epithelial Tumors

i. Serous Tumors

a. Serous cystadenoma

b.

Borderline Serous Tumor

c. Serous Adenocarcinoma

ii. Mucinous Tumors

a.

Mucinous cystadenoma

b. Mucinous borderline Tumor

c. Mucinous adenocarcinoma

iii. Endometrioid Adenocarcinoma

iv. Clear Cell Carcinoma

v.

Brenner Tumor

B. Sex Cord - Stromal Tumors

i. Fibroma

ii.

Thecoma

iii. Granulosa Cell Tumor

iv. Seroli – LeydigTumor

C.

Germ Cell Tumors

i.

Dysgerminoma

ii. Embryonal Carcinoma

iii. Choriocarcinoma

iv. Yolk sac Tumor

v. Mature Cyst Teratoma

vi.

Immature Teratoma

D. Metastatic Tumors in the Ovary

Ovarian Tumors can be classified according to:

Cell of origin:

1) surface epithelial (Müllerian epithelium);

2) sex cord (sex cord-stromal) tumors; and,

3)

germ cell tumors

NON-NEOPLASTIC LESIONS OF THE OVARY

Cystic Follicles and Follicular Cysts

Cysts usually arise from invaginated surface

epithelium and are the most common cause of

enlarged ovaries.

Cystic Follicles originate from unruptured

Graafian follicles or in follicles that have

ruptured and immediately sealed.

o May be multiple: especially cystic follicles

o Contain clear serous fluid

o

The cysts are lined internally by granulosa cells

and externally by theca interna cells.

o The theca cells are not yet luteinized (they’d

have a different name if they did)

Difference: Size

For uniformity sake, the cut off is 2 cm.

If the size the size of the cyst is >2 cm, we call it

follicular cyst. If it is


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PATHOLOGY OF OVARIES

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POLYCYSTIC OVARIAN DISEASE

Eponym: Stein-Leventhal Syndrome

o Affects 3 –6% (, 6 –10%) of reproductive women

[worldwide]

Reflects excess secretion of androgenic

hormones, persistent anovulation, and many

small subcapsular ovarian cysts.

Associated with obesity, type 2 diabetes, and

premature atherosclerosis

Pathogenesis:

Polycystic ovarian syndrome is brought about by

the increased production of luteinizing hormone

in the pituitary gland. This increase in LH would

promote production of androgens. These

androgens will be aromatized to the estrogen and

the adipose tissues. The estrogen will causepositive feedback to the LH and negative

feedback to the FSH. The Increase in LH will cause

degeneration of the graafian follicles. These

degeneration results to the formation of cystic

follicles.

The central feature of this disorder is the

dysregulation of the enzymes involved in

biosynthesis of androgens, particularly

17-α-

hydroxylase (the rate-limiting step in androgen

synthesis)

o Numerous cystic follicles associated with:

Oligomenorrhea

Persistent anovulation

Obesity (40%)

Hirsutism (50%)

Virilism (most common)

Increased levels of estrone makes PCOS

patients at risk for endometrial hyperplasia

and carcinoma

Gross: multiple cortical cystic follicles lined by

granulosa and theca cells

If we examine the ovary, you have numerous

cystic or follicular cysts. These are simply

degeneration of the follicles.

Polycystic ovarian disease. (A) The ovarian cortex reveals numerous

clear cysts. (B) Sectioning of the cortex reveals several subcortica

cystic follicles

Microscopic:

o

Numerous follicles in early developmenta

stages

o

Follicular atresia

o

Increased stroma with occasional hyperthecosis

o Features of anovulation (thick, smooth capsule

and absence of corpus luteum)

Stromal hyperthecosis

o

Also called cortical stromal hyperplasia

o

Disorder of ovarian stroma seen in

postmenopausal women, but may overlap with

PCOS in younger women

o Uniform enlargement of the ovary (up to 7 cm)

o White to tan appearance on sectioning

o

Bilateral involvement

o Microscopic: hypercellular stroma and

luteinization of the stromal cells, which are

visible as discrete nests of cells with vacuolated

cytoplasm

o Clinical presentation: similar to those of PCOS

virilization may be more striking


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Theca lutein hyperplasia of pregnancy

o Physiologic condition in pregnancy

o Theca cells proliferate and the perifollicular

zone expands in response to pregnancy

hormones (gonadotropins).

o Concentric theca-lutein hyperplasia may appear

nodular as the follicles regress

o

Not to be confused with true luteomas of

pregnancy

OVARIAN TUMORS

80% are benign – mostly in young women between

ages 20 – 45 years

Borderline tumors occur at slightly older ages

Malignant tumors – common in older women,

between 45 – 65 years

Most tumors of the ovary arise ultimately from oneof three ovarian components:

o Surface/fallopian tube epithelium and

endometriosis (~60%)

o Germ cells, which migrate to the ovary from the

yolk sac and are pluripotent (~30%)

o

Stromal cells, including the sex cords, which are

forerunners of the endocrine apparatus of the

postnatal ovary (~8%)

Classification:

1.

SURFACE EPITHELIAL (MÜLLERIAN) TUMORS

Pathogenesis:

Previous theory : Arise from the mesothelia

layer of the ovary

Current theory: epithelial tumors do not come

from the ovary, they come from the fallopian

tubes from the endometrium

The fallopian tubes, however, arise from

the Müllerian ducts, which in turn is from

the mesothelium of the coelomic cavity in

which the ovaries arise from.

Studies conducted on the lining of the fallopian

tube: it contains p53 mutation

When they examined serous cell adenoma,

serous cell adenocarcinoma: they also have p53

mutations

So they propose that because of retrogrademenstruation, the endometrial cells were

implanted on the ovaries and undergo mutation

especially KRAS mutation

Another set of implicated genes are defects in

the repair genes BRCA1 and BRCA2, which is

also seen in breast cancers.

The invasion must be at least 1 cm. Some

authors, for serous tumors, consider a

malignant diagnosis if it is more than 0.5 mm

but for uniformity sake we will use 1 sq. mm. Classified according to the type of cells. In order of

decreasing frequency, the common epithelial

tumors are:

SEROUS: looks like tubal epithelium, looks

like fallopian tube (simple ciliated columna

epithelium)

MUCINOUS: looks like endocervical glands

or intestinal glands, easy to recognize with

basally located nuclei, clear cytoplasm

Intestinal type has poorer prognosis

compared to endocervical type

Differentiate by means of looking fo

goblet cells (intestinal type has goblet

cells)

ENDOMETRIOID: looks like endometria

cells

CLEAR CELL: has glycogen-rich cells like

endometrial glands in pregnancy


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TRANSITIONAL CELL (Brenner): resemble

the mucosa of the bladder

MIXED TUMORS

2. GERM CELL TUMORS

Arise from either the trophoblast or the primitive

germ cells.

Differentiae along several lines:

Dysgerminomas are composed of neoplasticgerm cells, similar to oogonia of fetal ovaries.

Teratomas differentiate toward somatic(embryonic or adult) tissues.

Yolk sac tumors form extraembryonicendodermal and mesenchymal tissue.

Choriocarcinomas feature cells similar to thosecovering the placental villi.

3.

SEX CORD-STROMAL TUMORS

4. METASTATIC TUMOR IN THE OVARY

Arise in the hilum, as it is rich in blood vessels

Epithelial Tumors further divided into:

a.

BENIGN:

o Single layer of cells without atypia, regardless of

lining (tubal/serous, endometrioid, or

mucinous)

o Cystadenoma, Cystadenofibroma, Adenofibrom

Benign epithelial tumors further classifi

according to predominant tissue:

Cystadenoma: if lined by simple cuboida

cells; mostly cystic.

Cystadenofibroma: if you have papillary

excrescences or solid masses lined by the

same cells; cystic and fibrous.

Adenofibroma: if you have solid tumor o

benign glands; mostly fibrous.

b. BORDERLINE

Previously called are atypical proliferative o

low malignant potential, but is no longer used.

Contains the word “borderline”, with tumor at

the end, not carcinoma (e.g.: borderline serous

tumor) Mild to moderate atypia which is not seen in

cystadenoma, cystadenofibroma and

adenofibroma

Nuclear or epithelial stratification in the form o

papillary structures or detached cell clusters.

Characterized by epithelial cell proliferation and

nuclear atypia, but not destructive stroma

invasion.

Microinvasion

Borderline tumors with stromal invasion Stromal invasion is not >10mm2

Grading based on Molecular Aberration

Common

Precursors

Most

Frequent

Mutations

Chromosomal

Instability

TYPE 1 TUMORS

LG serous CA APST, non-

invasive

MPSC

KRAS, BRAF Low

LG endometrioid CA Endometriosis CTNNB1,

PTEN

Low

Clear cell CA Endometriosis PIK3CA Low

Mucinous CA APMT KRAS Low

TYPE 2 TUMORS

HG serous CA - TP53 High

HG endometrioid CA - TP53 High

Undifferentiated CA - - -

Carcinosarcoma - TP53 -

LG- low grade; HG- high grade


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Clinicopathologic and molecular studies have

suggested that ovarian carcinomas may be broadly

categorized into two different types:

i. TYPE I (Low-grade tumors)

Heterogenous

a.

Type I tumors contain areas of mucinous

adenoma, borderline, and areas that are

malignant

b.

Get sample from solid areas; because solid

areas are most likely malignant

Low-grade serous carcinoma, low-grade

endometrioid carcinoma, mucinous carcinoma,

clear cell carcinoma (*placing clear cell

carcinoma in type I is a misclassification; they

are high grade carcinoma by nature)

Arise from a precursor lesion: it could come

from borderline then eventually became

microinvasive then frankly malignant

KRAS mutation (serous and mucinous), PTEN

mutation (endometrioid)

Type 1 tumors are low grade except clear cell

carcinoma

a.

Clear cell carcinoma is not graded

because in itself, it is grade 3.

b.

No need to mention the grade in the

report unlike in other tumors

c.

Clear cell CA is classified under type 1

because it has a precursor lesion (arises

from endometriosis)

3 neoplasms arise from endometriosis:

Endometrioid adenocarcinoma

Clear cell CA

Borderline mucinous tumor, endocervical type

ii. TYPE II

Type II tumors are most often high-grade serous

carcinomas that arise from serous

intraepithelial carcinoma

No precursor lesion – arise de novo,

malignant at the onset

High grade tumors, homogenous

Associated with p53 mutation

Includes high grade serous carcinoma, high

grade endometrioid carcinoma, malignant

mixed Müllerian tumor, undifferentiated

carcinoma

c. MALIGNANT: Cystadenocarcino

Adenocarcinoma, Carcinoma

SURFACE EPITHELIAL TUMORS

1.

SEROUS TUMORS

Most common bilateral tumor that is primary

to the ovary

Most are benign serous cystadenoma

May present as either a multicystic lesion:

o Papillary epithelium contained within a few

fibrous walled cysts (intracystic)

o

Papillae may rise from a fibrovascular core.o Mass projecting from the ovarian surface

Gross:

Benign tumors – smooth glistening cyst wal

with no epithelial thickening or with smal

papillary projections

Borderline tumors – increased number o

papillary projections

Malignant tumors – large areas of solid o

papillary tumor mass, tumor irregularity, and

fixation or nodularity of the capsule

(A) Serous borderline tumor

of the ovary. Note papillary

tumor growths.

(B) Serous carcinoma of the

ovary. Note irregular masses.

(C) Serous benign tumor of

the ovary. Note the glistening

surface.


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Bilaterality is common

o 20% of benign serous cystadenomas

o 30% of serous borderline tumors

o 66% of serous carcinomas

TYPES:

a.

Serous Cystadenoma – 60%

b.

Borderline Serous Tumor – 15%

c.

Serous Cystadenocarcinoma – 25%

A. Serous Cystadenoma

Benign ovarian tumor composed of tubal type

of epithelium and varying amount of stroma

If predominantly cystic – cystadenoma

Is prominent stromal component without

grossly visible cyst – adenofibroma Purely stromal component, no visible

cyst; tumor is solid, with scattered

glands, without atypia

If prominent stromal component with grossly

visible cyst – cystadenofibroma

Prominent stromal component, solid

cystic tumor

No necrosis unless complicated by torsion

(when there is torsion, you cannot classify

whether it is benign or malignant)

Incidence and Location:

Most common benign surface epithelial

tumor, arise in women 20 – 60 years old

Often bilateral and unilocular

Gross Findings

Simple, smooth-walled unilocular or

multilocular cyst with varying amount of

fibromatous stroma Papillary excrescences – does not mean that

its malignant

Solid areas may be present (fibromatous

component)

Necrosis absent, unless complicated by

torsion

Microscopic Findings

Simple architecture, non-branching papillae i

present with rare to absent finding

Single, orderly layer of nonstratified, cuboidal to

columnar epithelium, often ciliated

Nuclear atypia minimal or absent The nuclei are oriented perpendicular to the long

axis of the columnar epithelium.

Serous cystadenoma of the ovary. The cyst is lined by a single layerof ciliated tubal-type epithelium; no nuclear atypia

B.

Borderline Serous Tumor

Cellular stratification: papilla, tufting, cel

clusters

Lined by tubal type epithelium

Mild to moderate atypia

Psammoma bodies (Gr. “sand”) – concentric

lamillated calcified structures seen in papillary

tumors (below).

Extraovarian lymph node implants

Features are malignant but no stroma

invasion

Metastasis is not invasive – only implants

Noninvasive because there is no reaction in

the surrounding peritoneum (invasive =

fibroblastic proliferation around the tumor –

desmoplastic stroma)


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Incidence and Location

Bilateral – 30%

Advanced stage in 30 – 40%

Gross Findings

Large cystic or solid and cystic mass with

soft papillary projections and/or surfacepapillary excrescences


Numerous papilla, often broad and

edematous, with complex typically

hierarchal branching

This epithelial proliferation often grows in a

delicate, papillary pattern referred to as

“micropapillary carcinoma”, which is

thought to be the precursor to low-grade

serous carcinoma.

By definition, the presence of more than

focal microinvasion (i.e., discrete nests of

epithelial cells


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Gross Findings

Solid and cystic mass with necrosis and

hemorrhage

Surface excrescences and adhesions

When you have involvement of the surface

of the ovaries, you only have 2

considerations: serous adenocarcinoma and

metastasis

In endometrioid and mucinous CA, there

must be no surface involvement


Complex papillae and glands with slit-like

spaces, cellular stratification and

cytologically malignant cells

Destructive stromal invasion – mostimportant

Psamomma bodies may or may not be

present

Psammocarcinoma variant – >75%

Psamomma bodies

Psammomatous serous carcinoma

Better prognosis compared to the

usual serous CA

High-grade Serous Cystadenocarcinoma. There is a pronounced andcomplex papillary growth pattern compared with a borderline tumor.

Stromal invasion (bordered by the red line) is possible with high-

grade tumors.

When in doubt if it is low grade or high grade,

just diagnose as serous because the

management is similar.

2. MUCINOUS TUMORS

Surface of the ovary is rarely involved

Mostly unilateral

Tend to produce larger cystic masses (up to

more than 25 kg)

Multiloculated tumors filled with sticky

gelatinous fluid rich in glycoproteins

A. Mucinous Cystadenoma

Benign surface epithelium tumor composed

of endocervical type or intestinal type

mucinous epithelium

Basally oriented nuclei with clear cytoplasm

Most common mucinous ovarian tumo

(80%) Unilateral

When you see a bilateral mucinous tumor, then

it’s not primary ovarian, it’s a metastasis

Gross Findings

Unilocular or multilocular

Usually mulitloculated, and can present

with hundreds of small cysts

Contains gelatinous material

Often very large (>30cm)Size is not an indicator for malignancy

Largest tumor of the female reproductive

tract whether benign or malignant

Smooth capsule and cyst lining


Columnar pale staining mucinous

epithelium resembling endocervix o

intestine

Minimal or absent atypia

Minimal or absent stratification

If with atypia and stratification, the diagnosis

will be borderline. But atypia and stratification

must be ≥10% to qualify as borderli ne serous or

mucinous tumor.


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Mucinous Cystadenoma. (A) The tumor is characterized by

numerous cysts filled with thick, viscous fluid. (B) A single layer of

mucinous epithelial cells lines the cyst.

B. Mucinous Borderline Tumor

Surface epithelial tumor composed of

intestinal or endocervical type epithelium

with epithelial stratification and cytologic

atypia, BUT NO STROMAL INVASION

Almost always unilateral

Based on gross examination, you cannot

differentiate a cystadenoma from a

borderline tumor

Borderline mucinous tumor is managed like a

mucinous cystadenocardinoma (they do

complete staging, omental sampling, and they

remove the appendix)

Gross Findings

Large (>30 cm), reminantly cystic mass with

multiple loci

Borderline Diagnosis:

Borderline area must be 10%


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Gross Findings

Solid and cystic mass

Surface involvement typically absent, but

large tumor often exhibit rupture and/or

adhesions

Surface involvement is absent in contrast to

serous.

If you see surface involvement, consider

metastasis

Even with rupture, they do not produce

pseudomyxoma peritonei.

If you see pseudomyxoma peritonei, then the

primary is appendix not ovary.

May reach very large size (>30cm)

Microscopic Findings Cytoarchitectural features similar to, but

more severe than borderline mucinous

tumor with areas of invasion exceeding

5mm in linear extent or 10 mm2 in area

Two patterns of invasion

o Expansile – confluent glands

Back to back glands without

intervening stroma

Most common

Expansile Pattern of Mucinous Adenocarcinoma. The malignant

glands are arranged in a cribriform pattern and are composed ofmucin-producing columnar cells

o Destructive – individual cells

Shows obvious glandular stromal

invasion

Invasion is described as:

1.

Stromal reaction

2.

Confluent glands forming cribriform

pattern

3.

Back to back glands, without

intervening stroma

D.

Mucinous Tumor Associated with

Pseudomyxoma Peritonei

Marked by extensive mucinous ascites

cystic epithelial implants on peritonea

surfaces, adhesions and frequent

involvement of the ovaries.

Primary source is often the appendix.

Diffuse peritoneal adenomucinosis

Peritoneal carcinomatosis

3.

ENDOMETRIOID ADENOCARCINOMA

Present with solid and cystic areas of growth

Low-grade tumors that reveal glandula

patterns bearing a strong resemblance to those

of endometrial origin

May arise from endometriosis (40%)

Mostly malignant and bilateral

o Endometrioid: with endometrial CA

o

Serous: no involvement of the enometriumo Metastasis: surface and hilar involvement

Associated with synchronous low grade

endometroid adenocarcinoma of the

endometrium (15-20%)

If you have bilateral endometrioid

adenocarcinoma of the ovary and endometria

CA at the same time, there are criteria to

determine if the ovarian mass is a metastasis:

Grade of the tumor – high grade =

metastasis Depth of invasion –>50%

Presence of Lymph-Vascular Space Invasion

Ovarian tumor is nodular

Size of ovarian tumor >14cm

Ovary is always the metastasis (from

endometrium to ovary)

Ca-125 is ELEVATED


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Molecular study

Genetic alterations similar to endometrial

endometrioid carcinoma

o

Somatic mutations in b-catenin and PTEN

o

Microsatellite instability

o Germline mutation in DNA mismatch repair

associated with Lynch syndrome

Gross Findings

Cystic and solid with areas of hemorrhage and

necrosis

Bilaterality usually implies extension of the

neoplasm beyond the genital tract.


Round to elongated glands with or withoutsquamous differentiation infiltrating the ovarian

stroma

Serous vs endometrioid in grade 3 tumors:

difficult to differentiate because they are both

solid, unlike mucinous which is only grade 1 or

2; high grade tumors favour serous.

Differentiation vs serous tumor:

More likely to be serous if there is/are:

1.

Psamomma bodies

2.

Slit-like lumen More likely to be endometrioid if there is/are:

1.

Squamous differentiation

2.

Punched-out glands

3.

Adenofibromatous pattern

Endometrioid Adenocarcinoma. The endometrial glands are lined

with non-mucinous epithelium (compare with mucinous

adenocarcinoma). Foci of squamous metaplasia ( ) may be present.

4.

CLEAR CELL CARCINOMA

Malignant surface epithelial tumor composed o

cells with clear or eosinophilic cytoplasm and

large nuclei with hobnail cells

Hobnail cells can also be seen in serous

carcinoma

40% are bilateral

Associated with pelvic endometriosis in 50-70%

of cases

2/3 nulliparous

Associated with hypercalcemia

Classic architecture:

o Tubulocystic pattern composed of clea

and hobnail cells

o Papillary pattern – should have

hyalinized core (sclerotic stroma)o Serous and endometrioid –

fibrovascular core

Gross Findings

Thick walled unilocular cystic and solid mass

with fleshy nodules

Hemorrhage and necrosis on inner cyst wall and

adhesions over the capsule

May present as single fleshy nodule in an

endometriotic cyst (25%)

Micrscopic Findings

2 possible patterns:

o In solid neoplasms, the clear cells are

arranged in sheets or tubules

o

Cystic neoplasms have the cell line the

cystic spaces.

Tubulocystic, papillary and solid architecture

Polyhedral cells with abundant clear and

eosinophilic granular cytoplasm

Containing α1 antitrypsin (seen in yolk sac

tumor, rhabdomyosarcoma)


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Clear Cell Adenocarcinoma. The clear cells are polyhedral and have

eccentric, hyperchromatic nuclei without prominent nucleoli

Hobnail Cells. In its tubular form, malignant cells often display

bulbous nuclei that protrude into the lumen of the tubule (“hobnail

cell”).

4. BRENNER TUMOR

A form of cystadenofibroma

Benign surface epithelial tumor composed of

urothelium (in a fibromatous stroma)

Frequently asymptomatic

Gross Findings

Well circumscribed, solid with smooth external

surface from 2 –20cm

Sometimes with cystic component

Yellow or white tissue with small cyst and gritty

on cut section


Well circumscribed solid and cystic areas with

nests of uniform transitional epithelium

embedded in an abundant, fibromatous stroma

Not a sign of invasion because you do not

have dysmoplastic reaction.

Malignant equivalent: malignant Brenne

tumor, malignant transitional carcinoma

Dystrophic calcification (50%)

Ovoid cells with discernable grooves and smal

indistinct nucleoli (nuclear grooves – hallmark

but not exclusive)

Coffee bean like nuclei

Associated with mucinous and serous

cystadenoma and dermoid cyst (25%)Some of the nuclei can contain grooves

Brenner tumor. (Top) Brenner tumor (right) associated with a benign

cystic teratoma (left). (Bottom) Histologic detail of characteristic

epithelial nests ( ) within the ovarian stroma ( ).


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SEX CORD - STROMAL TUMORS

Derived from the ovarian stroma, which in turn is

derived from the sex cords of the embryonic gonad.

Undifferentiated gonadal mesenchyme eventually

produced structures of specific cell type in both

male (Sertoli and Leydig) and female (granulosa and

theca) gonads.

Tumors resembling all of these cell types can be

identified in the ovary.

TYPES

1.

Fibroma – benign

2.

Thecoma – benign

3.

Granulosa Cell Tumor

Microscopic appearance determinesbehavior (may be benign or malignant

labeled as borderline)

Treated as low malignant potential and

treated with radiotherapy

4.

Sertoli-Leydig Tumor

Always malignant

If just sertoli tumor or leydig tumor, they

are benign

1.

FIBROMA Account for 75% of all stromal tumors and 7%

of all ovarian tumors

Benign, fibromatous tumor of varying cellularity

composed of spindle, oval or round collagen

producing cells

Unilateral

Hormonally inactive

Presents as Pelvic mass, pain, ascites or urinary

frequency

Meig’s syndrome in 1% of patients (benign

tumor in ovary, ascites and hydrothorax)

Pseudomeig’s syndrome – if associated

with malignant tumor

Associated with Basal Cell nevus (Gorlin)

Syndrome

Increased incidence of basal cell carcinoma

medulloblastoma, ad rhabdomyosarcoma

attributed to heterozygous mutation in

Patched, a negatively acting component of the

Hedgehog receptor

Gross Description

Average of 6cm

Firm, white cut surface, may be lobulated

Soft, white to yellow cut surface if cellular

Yellow – because of thecoma component (10% = fibrothecoma)

Hemorrhage and necrosis when associated with

torsion (especially if pedunculated)

Bilaterally, multinodularity and calcification i

associated with Gorlin SyndromeLooks like leiomyoma, except it is white

Pedunculated and to polypoid growth in up to

1/5

Cystic change in 1/4

Microscopic description

Intersecting fascicles or storiform pattern o

spindle cells arranged in fascicles (whorled

pattern)

Variable degrees of collagen productionSame as leiomyoma

Difference with leiomyoma: Smooth muscle cel

nucleus=cigarette shape; fibroblast=tapered

2.

THECOMA

Solid, with yellow surface due to lipids

Stromal tumor composed of lipid containing

cells resembling theca cells with a variable

fibromatous component. Pure thecomas are

rare.

Unilateral

Pelvic mass or swelling in postmenopausa

women

Hormonally active, unlike the fibroma, and

hence may produce symptoms related to excess

androgen or estrogen production.


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Gross Findings

Composed of liquid-containing cells resembling

theca cells with variable fibromatous

component

fibromatous component should not be

>10%,lest it be identified as a fibrothecoma

5 –10 cm

Solid and yellow to gray white and sometimes

lobulated cut surface

Occasional cystic change and focal calcification

Extensive calcification in young women


Aggregates of oval to round cells alternating

with spindle cells

Theca cells – abundant pale to vacuolated

cytoplasm and round to oval nuclei Lutein cells – abundant eosinophilic cytoplasm

and large round nuclei

Minimal cytologic atypia and rare mitotic

activity

Thecoma-fibroma, gross. The thecoma component of the neoplasm

(*) gives the tumor a yellow hue. The redder, fibroma component is

seen adjacent.

Thecoma-fibroma, microscopic. A mix of elongated fibroblastic cells

weave between the thecoma component consisting of clusters of

cuboidal to polygonal cells (encircled)

3.

GRANULOSA CELL TUMOR

Granulosa cell should compose more >10% o

the entire tumor

Granulosa stromal cell tumor with a minimum

of 10% component of granulosa cells, often in a

fibrothecomatous background

If


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Proliferation of granulosa cells in a

fibrothecomatous background

Diffuse (sarcomatoid), trabecular (anastomotic

bands of cells), micro or macrofollicular, insular

(islands of cells) or gyriform patterns

Cells with scant cytoplasm and round to oval

nuclei with longitudinal groove

Minimal cytologic atypia and low mitotic activity

CALL-EXNER BODIES – hallmark, [rarely seen]

o Small, destructive, gland-like structures

filled with an acidophilic material

Remember only coffee bean nuclei similar in

your Brenner tumor and Call-Exner Bodies for

exam purposes.

Granulosa Cell Tumor. Granulosa cell tumors attempt to form

primitive follicles. The orientation of tumor cells about central spaces

results in the characteristic follicular pattern (Call-Exner bodies),

which may be filled with acidophilic material.

4.

SERTOLI-LEYDIG TUMOR

Aka ANDROBLASTOMA or ARRHENOBLASTOMA

It can be a Sertoli tumor or a Leydig tumor only.

Combination of both is usually malignant.

In Sertoli tumor you have to do special stains

and when if you do electron microscope you willsee Charcott-Butcher microfilaments. This is the

hallmark of Sertoli tumor.

In contrast to the Leydig tumor, you have to

stain with crystalloids or crystals to diagnose

Leydig tumor.

Tumor composed of Sertoli cells showing

varying degrees of differentiation admixed with

variable numbers of Leydig cells

Unilateral

Abdominal swelling and pain

Androgenic manifestation (1/3) Tumor cells secrete weak androgens (e.g

dehydroepiandrosterone)

Leydig cells produce testosterone

Sertoli cells form tubules

Occasional estrogenic manifestation

Gross Findings

Average size: 1.5cm

Solid, lobulated, tan to yellow cut surface

Purely Leydig: golden brown [benign course] Leydig produces Testosterone and occasionally

estrogen

Sertoli Cell Tumor, gross. Characteristic golden-yellow

appearance.


Sertoli-Leydig tumors are graded based on the

immature tubules

Well differentiated – tubules composed o

Sertoli cells or Leydig cells interspersed in a

fibroma-thecomatous stroma

Look for the Leydig component because they are

stromal cells, cuboidal or polygonal

Intermediate – outlines of immature tubules

and large eosinophilic Leydig cells

Poorly differentiated – sarcomatous pattern

with disorderly diposition of epithelial cords


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Leydig cells may be absent

Heterologous Elements – Bone, cartilage, glands

Looks like endometrioid adenocarcinoma

because they are arranged in hollow tubules

look for fibrothecomatous stroma with Leydig

cells

Leydig cells also look like thecoma, but if they

are in combination, then it easier to recognize

GERM CELL TUMOR

Most common is benign – mature cystic teratoma

For malignant tumors, the most common is

dysgerminoma followed by yolk sac tumor

Classification

1.

Dysgerminoma

2.

Yolk sac tumor

3.

Embryonal carcinoma

4.

Polyembryoma

5.

Choriocarcinoma

6.

Teratoma – mature, immature, monodermal

7.

Mixed germ cell tumorMost common combination: dysgerminoma

and yolk sac tumor

Testes: most common combination is yolk

sac and embryonal carcinoma

Testicular cancers do not have surface epithelial

tumor

Germ cell tumors can arise anywhere along midline

1.

DYSGERMINOMA

The ovarian counterpart of testicular seminoma

Least differentiated from all the other tumors

Has a good prognosis because it is chemo- and

radiosensitive compared to the other tumors

Malignant germ cell tumor resembling

primordial germ cells, morphologically identica

to seminoma and extragonadal germinoma

Most common malignant germ cell tumor

Most common in 2nd to 3rd decade

Rapidly growing mass

Elevated serum LDH and PLAP

LDH is non-specific. It is elevated on most

malignant neoplasms that are rapidly growing.

PLAP(placenta-like alkaline phosphatase) –

specific marker for germ cell tumors

PLAP is also not specific for dysgerminoma since

it is elevated on all germ cell tumors.

Rarely, elevated β-HCG [due to presence o

syncytiotrophoblast]

Normal AFP


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Gross Findings

Solid tumor of variable size (average 15cm)

Homogenously lobulated rubbery white to tan

cut surface

Calcifications may suggest an underlying

gonadoblastomaGonadoblastoma – germ cell tumor + sex

cord-stromal tumor (commonly

dysgerminoma + granulosa cell tumor)

One of the blastomas is commonly seen on

patients with abnormal sexual differentiation.

Most of the time they are phenotypically female

but the karyotyping is male.

Mostly unilateral; 10-15% are bilateral

Not exclusive to the ovary (1% - 2% of

ovarian neoplasm); can be a brain tumor-pineal gland

30-40 year olds

Dysgerminoma, gross. Solid, lobulated, with a white-tan color.

Microscopic

Arranged in nests and sheets

Separated by fibrovascular septa with

lymphoplasmocytic infiltrates or granulomas.

Although the lymphopalsmocytic infiltrates andgranulomas are not neoplastic, these are clues

to the diagnosis.

Composed of large, vesicular cells with clear

(glycogen-filled) cytoplasm, well-defined cell

boundaries, and irregularly flattened central

nuclei.

Brisk mitotic activity

Variable amount of stroma containing

inflammatory cells

Syncytiotrophoblasts cells in 23%

Responsible for the elevated beta hCG

IHC: CD 117 (C-KIT), PLAP

Without lymphoplasmacytic infiltrates, you candistinguish dysgerminoma from embryona

carcinoma with CD 117

CD 117 has both prognostic and predictive

significance which is also associated with

GastroIntestinal Stromal Tumors (GIST)

REMEMBER: sheets of malignant cells with

Lymphoplasmacytic infiltrates in the

fibrous stroma – hallmark

Clear cytoplasm All germ cell tumors, when you look at the

cytologic detail, they all look the same “angry

looking” (primitive looking, large nuclei, high

mitotic activity)

Immunohistochemistry is recommended

You usually request for β-HCG and AFP when

you have a young patient with solid tumor on

UTZ

Dysgerminoma. Polyhedral tumor cells with round nuclei and

adjacent inflammation

2.

EMBRYONAL CARCINOMAArise from the undifferentiated, totipotentia

germ cell

Often, young women who only present with

abdominal or pelvic mass

Primitive germ cell tumor morphologically

identical to its counterpart in the testis, capable

of somatic and extraembryonal differentiation

AFP normal to slightly elevated


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Tumor cells are highly pleomorphic with

overlapping nuclei –hallmark

Indistinct cytoplasmic border

Can form gland-like structures

β-HCG may also be elevated

REMEMBER: Both β-HCG and AFP slightly elevated:

EMBRYONAL CARCINOMA


Solid or nests

More differentiated tumor has gland-like spaces

and papillary structures

Very pleomorphic medium to large cells with

eosinophilic cytoplasm and centrally placed

hyperchromatic vesicular nuclei with prominentnucleoli

Indistinct cytoplasmic borders

Brisk mitotic activity with atypical mitoses

Syncitiotrophoblast cells may be present

Embryonal carcinoma.

3.

CHORIOCARCINOMA

Most aggressive

Maybe gestational (metastasis or associated

with pregnancy) or nongestational (no chorionic

villi)

Highly malignant germ cell tumor o

nongestational in origin (often placental

showing extraembryonic trophoblastic

differentiation

Only 1% of all germ cell tumors

Often seen inYoung females (


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Gross Findings

Unilateral, large, solid, gray to tan

Necrosis and hemorrhage may be extensive


Reticular (most common, microcyst,

pseudopapillary, solid, polyvesicular vitteline

patterns [usually mixed pattern]

Schiller-Duval bodies – pathognomonic,

present in 1/3 [25 –33% of cases]

A glomerulus-like structure composed of a

central blood vessel enveloped by tumor

cells within a space that is also lined by

tumor cells.

Primitive cells with clear to eosinophilic

cytoplasm Brisk mitotic activity

Vessels in the middle, with edematous stroma,

tumor cells; there is stroma in between the

vessels

Hyaline globules common

Only 2 ovarian tumors with hyaline globules:

clear cell carcinoma (seen in elderly) and yolk

sac tumor

Can also be found in the liver – hepatocellular

CAMost abundant chemical – α1-antitrypsin

A Schiller-Duval body. A blood vessel ( ) is surrounded by 2 layers

of tumor cells ( ) separated by a space.

5.

MATURE CYST TERATOMA

Aka Mature teratoma or Dermoid cyst

Called dermoid cysts as they are almost always

lined by skin-like structures.

Develop by parthenogenesis: Haploid

(postmeiotic) germ cells endoreduplicate to

give rise to diploid genetically female tumo

cells (46,XX).

Most common germ cell tumor

Benign germ cell tumor derived from any of the

germ cell layers that arise from pathenogenetic

differentiation of abnormal germ cells

Most common germ cell tumor

Typically less than 10cm

If more than 10cm with solid structures suspect

immature teratoma Mature cystic teratoma can turn malignant

Gross appearance

Cystic cut section with abundant hair and

sebaceous material

Solid mural nodule (Rokitansky protuberance

or tubercle of Rokitansky) associated with

teeth and bone.

10% bilateral

Mature tissue from all germ cell layersrecapitulating normal composition of different

organs

Components mostly from the ectoderm

stratified squamous epithelium, with underlying

skin adnexal structures, sebaceous, sweat

Sometimes mucinous tumor and mature

teratoma coexist

Sieve-like pattern resulting from

lipogranulomatous reaction

Malignant transformation

Squamous Cell CA – most common

Suspect malignant transformation if:

Large, >12 cm

Elderly patient

Papillary Thyroid CA - especially if tumor is

struma ovarii


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Vascular invasion must be present

Struma ovarii – mature cystic teratoma,

component: all thyroid follicle (100%)

Melanoma

Bilateral ovarian tumors: serous, metastasis,

endometrioid, dysgerminoma, cystic teratoma

Mature Cystic Teratoma of the Ovary. Photomicrograph of a mature

cystic teratoma shows epidermal and respiratory components. Tissue

resembling the skin exhibits an epidermis (E) with underlying

sebaceous glands (S). The respiratory tissue consists of mucous

glands (M), cartilage (C), and respiratory epithelium (R). BRONCHI

Monodermal or Specialized Teratomas

Often unilateral

Includes Struma ovarii (mostly thyroid tissue),

and ovarian carcinoid (from intestinal tissue)

Ovarian carcinoid can cause the carcinoid

syndrome if it produces enough 5-

hydroxytryptamine

Characterized by salt-and-pepper

appearance of nuclei

o

Differentiate from metastatic intestinal

carinoid (bilateral)

Combination of thyroid tissue and carcinoid is

strumal carcinoid

6.

IMMATURE TERATOMA

Heterogenous;, may also have mature

component; immature component are in the

solid areas

Differentiate between immature componen

and malignant component

Immature: chrondrocytes, enlarged nuclei

Germ cell tumor showing variable amounts of

immature tissues associated with mature

elements

More common in first two decades

Gross Findings

Large tumor with ruptured capsule in

approximately 50%

Solid, soft and fleshy cut section, often withcystic component

Solid – in contrast to mature cystic teratoma

which are cystic

Dermoid cyst identified in 1/4 of tumors and in

the opposite ovary in 10%

Microscopic findings

Tissues from the three germ cell layers with a

variable admixture of immature and mature

elements Amount of immature epithelium

[neuroectoderm or neuroepithelium] used in

grading

o

Grade 1 – 1 LPF in any one slide

o Grade 2 – 1-3 LPF in any one slide

o Grade 3 - >3 LPF in any one slide

The immature epithelium is responsible for the

behavior of the tumor; if numerous –

extraovarian sequence

Neuroepithelium may look like a gland

differentiate by looking at the background; i

fibrillary then it is neuroepithelium

The number or amount of neuroepithelium

is responsible for the prognosis of immature

teratoma.


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Immature teratoma illustrating primitive neuroepithelium.

METASTATIC TUMORS IN THE OVARY

Mullerian in origin Endometrium

Cervix

Extramullerian

Breast

GIT [more common] – stomach, colorectal,

pancreas, biliary tract

1. METASTATIC TUMOR

Bilateral involvement

Size less than 10cm

If greater than 10cm, probably bilateral

serous CA

If size less than 10 cm and looks like

endometrioid adenorcinoma, garland type

of necrosis, solid probably a metastasis

from the colon

Surface involvement – except in serous CA (also

has surface involvement)

Nodular growth pattern [on the surface]

Infiltrative growth pattern with stromal

dysmoplasia

Not a reliable criteria

Only when the pattern is mucinous in

morphology that it becomes a reliable

criteria for metastasis

Signet ring component (Krukenbergtumor) –

common in GI; most common origin: stomach

also breast

Hilar involvement(rich in lymphatics and blood

vessels)

Lympho Vascular Space Invasion(ovarian tumorarely invade lymphatic spaces)

Most common route of metastasis is

seeding

Krukenberg tumor. (A) The ovary is enlarged and the cut surface

appears solid, pale-yellow, and partially hemorrhagic. (B) A

microscopic section of A reveals mucinous (signet-ring) cells (clea

cells, arrows) infiltrating the ovarian stroma.

References:

The Doctor’s Lecture

Upperclass Notes

Robbin’s and Cotran Pathologic Basis of Disease

9th ed.

Rubin’s Pathology – Clinicopathologic

Foundations of Medicine, 7th ed.

Robbins and Cotran Atlas of Pathology, 3rd ed.

B14a04 - Pathology of the Ovaries

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