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Block XIV | Pathology | Lesson 4

PATHOLOGY OF OVARIES
Ansari P. Salpin, MD, DPSP
March 22, 2016

OUTLINE
I.
II.
III.

Non neoplastic lesions of the ovary


Polycystic Ovarian Disease
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 (Mllerian 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 (theyd
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 <2 cm then we call it cystic
follicle.
Gross: Unilocular cyst with smooth external surface
So, when a patient presents with a unilocular
cyst with a clear serous fluid, the differential
diagnosis would always be a follicular cyst or a
serous cystadenoma. So you must perform
microscopic examination to differentiate
between the two.
Microscopic:
o Granulosa cells have uniform, round nuclei and
little cytoplasm
o Thecal cells are small and spindle shaped
Corpus Luteum cyst (corpora lutea)
o Bright yellow in color
o You can diagnose it just by gross examination of
the
ovary
even without microscopic
examination because it is a bright yellow color
with a central hemorrhagic area
o Lined by luteinized theca and granulosa cells on
microscopic examination
Luteinized:
abundant
eosinophilic
cytoplasm
o Clinical significance: when they enlarge and
they rupture, they cause hemoperitoneum
Follicular Cyst

Corpus Luteum Cyst

Corpus luteum cyst with areas of hemorrhage.


The color is bright yellow, typical of corpus
luteum.
When there is corpus luteum in the ovary, in
what menstrual phase is the endometrium? You
will be expecting secretory phase.
Page 1 of 21

5c | Peradillo, Pescasiosa, Pineda

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
POLYCYSTIC OVARIAN DISEASE
Eponym: Stein-Leventhal Syndrome
o Affects 36% (, 610%) 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 cause
positive 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-hydroxylase (the rate-limiting step in androgen
synthesis)

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 subcortical
cystic follicles

Microscopic:
o Numerous follicles in early developmental
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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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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 one
of 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 (MLLERIAN) TUMORS

Pathogenesis:
Previous theory : Arise from the mesothelial
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 Mllerian 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 retrograde
menstruation, 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 columnar
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 for
goblet cells (intestinal type has goblet
cells)
ENDOMETRIOID: looks like endometrial
cells
CLEAR CELL: has glycogen-rich cells like
endometrial glands in pregnancy
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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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 neoplastic
germ cells, similar to oogonia of fetal ovaries.
Teratomas differentiate toward somatic
(embryonic or adult) tissues.
Yolk sac tumors form extraembryonic
endodermal and mesenchymal tissue.
Choriocarcinomas feature cells similar to those
covering 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, Adenofibroma


Benign epithelial tumors further classified
according to predominant tissue:
Cystadenoma: if lined by simple cuboidal
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 or
benign glands; mostly fibrous.
b. BORDERLINE
Previously called are atypical proliferative or
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 of
papillary structures or detached cell clusters.
Characterized by epithelial cell proliferation and
nuclear atypia, but not destructive stromal
invasion.
Microinvasion
Borderline tumors with stromal invasion
Stromal invasion is not >10mm2
Grading based on Molecular Aberration
Common
Precursors

Most
Frequent
Mutations

Chromosomal
Instability

LG serous CA

APST, noninvasive
MPSC

KRAS, BRAF

Low

LG endometrioid CA

Endometriosis

CTNNB1,
PTEN

Low

Clear cell CA

Endometriosis

PIK3CA

Low

Mucinous CA

APMT

KRAS

Low

HG serous CA

TP53

High

HG endometrioid CA

TP53

High

Undifferentiated CA

Carcinosarcoma

TP53

TYPE 1 TUMORS

TYPE 2 TUMORS

LG- low grade; HG- high grade

Page 4 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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 Mllerian tumor, undifferentiated
carcinoma
c. MALIGNANT:
Cystadenocarcinoma,
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 wall
with no epithelial thickening or with small
papillary projections
Borderline tumors increased number of
papillary projections
Malignant tumors large areas of solid or
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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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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)

Microscopic Findings
Simple architecture, non-branching papillae if
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 layer


of ciliated tubal-type epithelium; no nuclear atypia

B. Borderline Serous Tumor


Cellular stratification: papilla, tufting, cell
clusters
Lined by tubal type epithelium
Mild to moderate atypia
Psammoma bodies (Gr. sand) concentric,
lamillated calcified structures seen in papillary
tumors (below).

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

Extraovarian lymph node implants


Features are malignant but no stromal
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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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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 surface
papillary excrescences
Microscopic Findings
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 <3 mm into the ovarian
stroma) identifies a tumor as low-grade
invasive serous carcinoma, rather than a
borderline tumor.
Cuboidal to columnar epithelium, often
ciliated with interspersed eosinophilic cells
with cellular stratification and tufting
Psammoma bodies, as well as extraovarian
and lymph node implants, may be present.
Borderline serous tumors may have
implants in the peritoneum and lymph
nodes but these are not metastases because
these are non-invasive implants.

Borderline serous tumor of the ovary. Papillations are seen, but with
no invasion of the stroma (blue line). Some papillations grow off of a
fibrovascular core (
), which can also be seen in other
cystadenomas.

C. Serous Cystadenocarcinoma - with stromal


invasion
Malignant
epithelial ovarian tumor
composed of tubal-type epithelium
Incidence and Location
Most common histologic subtype of
surface epithelial ovarian carcinoma
Bilateral in 60%
Most common bilateral malignant tumor
of the ovary
Differentials for bilateral ovarian mass:
serous CA, metastatic CA from colon,
endometrioid CA [mucinous CA are always
unilateral if bilateral, it is a metastatic
mucinous CA, not primary mucinous CA
from the ovary]
Low grade arise from borderline serous
tumors but the high grade directly arise de
novo.
Clinical features
Pelvic or abdominal enlargement
With or without weight loss
Vague pain
Urinary or GIT symptoms [in large tumors]
Elevated CA-125
Marker for ovarian CA; not that
elevated in mucinous CA of the ovary
(but
elevated
in
serous
and
endometrioid)
Molecular studies:
o KRAS and BRAF mutations in low-grade
tumors
o BRCA1, BRCA2, and p53 mutations in
high-grade tumors
Eventually
develop
tubal
malignancy and breast CA
Suspect malignancy in ovarian tumor if you
see a solid portion

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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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
Microscopic Findings
Complex papillae and glands with slit-like
spaces,
cellular
stratification
and
cytologically malignant cells
Destructive stromal invasion most
important
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 and


complex papillary growth pattern compared with a borderline tumor.
Stromal invasion (bordered by the red line) is possible with highgrade 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 tumor
(80%)
Unilateral
When you see a bilateral mucinous tumor, then
its not primary ovarian, its 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
Microscopic Findings
Columnar
pale
staining
mucinous
epithelium resembling endocervix or
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 borderline serous or
mucinous tumor.

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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES

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%
<10%: mucinous cystadenoma with focal
borderline proliferation
Once diagnosed as borderline, you must
indicate whether its intestinal type or
endocervical type (behaviour is different)
Intestinal type is more aggressive than
endocervical type
Microscopic Findings
Stratification of epithelium into 2-3 cell
layers
Mild to moderate atypia
Goblet cell present intestinal type

Mucinous borderline tumor. Note stratification of columnar cells


and nuclear atypia. Like its serous counterpart, papillary features
may be seen (although smaller). Also like its serous counterpart,
there is no invasion of the stroma.

C. Mucinous Adenocarcinoma
Surface epithelial tumor with cytologically
malignant mucinous epithelium associated
with stromal invasion
Uncommon surface epithelial carcinoma
Unilateral
With stromal invasion of more than 10 mm2
If less than 10 mm2, label it as borderline
tumor with microinvasion
Mucinous adenocarcinoma is almost always
well differentiated. We rarely see poorly
undifferentiated.
A poorly differentiated adenoCA may be a
metastasis rather than primary ovarian tumor.
Clinical features
Asymptomatic
Abdominal enlargement
Pain
Change in bowel or bladder function
CA-125 may not be markedly elevated
Molecular Studies
KRAS mutation
No association with BRCA1 or BRCA2
mutation
(compare
with
serous
cystadenocarcinoma)
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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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
intervening stroma
Most common

without

Expansile Pattern of Mucinous Adenocarcinoma. The malignant


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

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 peritoneal
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 glandular
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 enometrium
o 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 endometrial
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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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES

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.
Microscopic Findings
Round to elongated glands with or without
squamous 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

4. CLEAR CELL CARCINOMA


Malignant surface epithelial tumor composed of
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 clear
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 1 antitrypsin (seen in yolk sac
tumor, rhabdomyosarcoma)

Endometrioid Adenocarcinoma. The endometrial glands are lined


with non-mucinous epithelium (compare with mucinous
adenocarcinoma). Foci of squamous metaplasia ( ) may be present.

Page 11 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES

Clear Cell Adenocarcinoma. The clear cells are polyhedral and have
eccentric, hyperchromatic nuclei without prominent nucleoli

Microscopic Findings
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 Brenner
tumor, malignant transitional carcinoma
Dystrophic calcification (50%)
Ovoid cells with discernable grooves and small
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

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 220cm
Sometimes with cystic component
Yellow or white tissue with small cyst and gritty
on cut section

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


cystic teratoma (left). (Bottom) Histologic detail of characteristic
epithelial nests ( ) within the ovarian stroma ( ).

Page 12 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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
determines
behavior (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
Meigs syndrome in 1% of patients (benign
tumor in ovary, ascites and hydrothorax)
Pseudomeigs 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%
= fibroma; >10% = fibrothecoma)
Hemorrhage and necrosis when associated with
torsion (especially if pedunculated)
Bilaterally, multinodularity and calcification if
associated with Gorlin Syndrome
Looks 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 of
spindle cells arranged in fascicles (whorled
pattern)
Variable degrees of collagen production
Same as leiomyoma
Difference with leiomyoma: Smooth muscle cell
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 postmenopausal
women
Hormonally active, unlike the fibroma, and
hence may produce symptoms related to excess
androgen or estrogen production.
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Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
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
510 cm
Solid and yellow to gray white and sometimes
lobulated cut surface
Occasional cystic change and focal calcification
Extensive calcification in young women
Microscopic Findings
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.

3. GRANULOSA CELL TUMOR


Granulosa cell should compose more >10% of
the entire tumor
Granulosa stromal cell tumor with a minimum
of 10% component of granulosa cells, often in a
fibrothecomatous background
If <10%, it can only be a fibroma or thecoma
Potentially malignant (5-25%)
Unilateral, and presents with abdominal mass
or pain
Estrogenic manifestation 1/32/3 (produce
estrogen)
o Abnormal uterine bleeding in reproductive
or postmenopausal women. Endometrial
biopsy: hyperplasia/adenoCA
o Isosexual Pseudoprecocity in prepubertal
girls
Androgenic stimulation (10%)
Hemoperitoneum secondary to rupture in 10%
Elevated tissue and serum levels of inhibin are
associated with granulosa cell tumors. They also
express the neuronal protein calretinin.
Mutations in the FOXL2 gene are found in these
tumors.
2 Types of Granulosa Cell Tumor:
Juvenilealways benign
Adult potentially malignant
Adult type mostly seen in women. In juvenile
type we dont see Call-Exner bodies.
Gross Findings
Average of 12 cm
Predominantly solid or solid-cystic
Rarely uni- or multilocular cyst
Yellow white cut surface
Stromal tumors of the ovary secrete steroids,
cannot be distinguished because they are all
yellow in color
Frequent areas of hemorrhage

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


weave between the thecoma component consisting of clusters of
cuboidal to polygonal cells (encircled)

Page 14 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
Microscopic Findings
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 will
see 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.

Microscopic Findings
Sertoli-Leydig tumors are graded based on the
immature tubules
Well differentiated tubules composed of
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

Page 15 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES

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 tumor
Most 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 identical
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 -HCG [due to presence of
syncytiotrophoblast]
Normal AFP

Page 16 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
Gross Findings
Solid tumor of variable size (average 15cm)
Homogenously lobulated rubbery white to tan
cut surface
Calcifications may suggest an underlying
gonadoblastoma
Gonadoblastoma 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 tumorpineal gland
30-40 year olds

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 can
distinguish dysgerminoma from embryonal
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 -HCG and AFP when
you have a young patient with solid tumor on
UTZ

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 and
granulomas 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

Dysgerminoma. Polyhedral tumor cells with round nuclei and


adjacent inflammation

2. EMBRYONAL CARCINOMA
Arise from the undifferentiated, totipotential
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
Page 17 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
Tumor cells are highly pleomorphic with
overlapping nucleihallmark
Indistinct cytoplasmic border
Can form gland-like structures
-HCG may also be elevated
REMEMBER: Both -HCG and AFP slightly elevated:
EMBRYONAL CARCINOMA
Microscopic Findings
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 prominent
nucleoli
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 of


nongestational in origin (often placental)
showing
extraembryonic
trophoblastic
differentiation
Only 1% of all germ cell tumors
Often seen inYoung females (<20 years old),
presenting as a rapidly growing mass
Elevated -HCG
Hemoperitoneum secondary to extensive
hemorrhage
Pulmonary mass snowstorm [snowball
pattern on audio] pattern on chest X-ray
Associated with extensive necrosis and
hemorrhage

Gross Findings
Large hemorrhagic mass
Microscopic Findings
Syncytiotrophoblasts growing nests or sheets of
cytotrophoblasts in a plexiform pattern
Brisk mitotic activity in cytotrophoblasts
Extensive hemorrhage and necrosis
Vascular invasion common
Primary metastasis route: hematogenous
Chorionic villi absent
(+) chorionic villi= invasive
Worst prognosis among germ cell tumors
More common in the endometrium than in the
ovary
4. YOLK SAC TUMOR
Aka Endodermal sinus tumor
Most common malignant tumor in children
Malignant germ cell tumor showing extraembryonic differentiation, less commonly,
embryonic differentiation
Second most common malignant germ cell
tumor
Children and young females
Rapidly growing mass
Elevated AFP
Page 18 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES
Gross Findings
Unilateral, large, solid, gray to tan
Necrosis and hemorrhage may be extensive
Microscopic Findings
Reticular
(most
common,
microcyst,
pseudopapillary, solid, polyvesicular vitteline
patterns [usually mixed pattern]
Schiller-Duval bodies pathognomonic,
present in 1/3 [2533% 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
CA
Most abundant chemical 1-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 tumor
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 layers
recapitulating 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
Page 19 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES

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 5hydroxytryptamine
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 component
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 with
cystic 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; if
fibrillary then it is neuroepithelium
The number or amount of neuroepithelium
is responsible for the prognosis of immature
teratoma.

Page 20 of 21

Block XIV | Pathology | Lesson 4


PATHOLOGY OF OVARIES

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 tumor
rarely invade lymphatic spaces)
Most common route of metastasis is
seeding

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

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 (clear
cells, arrows) infiltrating the ovarian stroma.

References:

The Doctors Lecture


Upperclass Notes
Robbins and Cotran Pathologic Basis of Disease,
9th ed.
Rubins
Pathology

Clinicopathologic
th
Foundations of Medicine, 7 ed.
Robbins and Cotran Atlas of Pathology, 3rd ed.

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