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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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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
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
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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
Microscopic Findings
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
Microscopic Findings
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.
Microscopic Findings
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
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 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
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.
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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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 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.
Microscopic Findings
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
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 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
Microscopic Findings
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.