B14a04 - Pathology of the Ovaries

Block XIV | Pathology | Lesson 4

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

OUTLINE I. II. III.

Difference: Size

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

 For uniformity sake, the cut off is 2 cm.

>2 cm, we call it follicular cyst. If it is 10mm 2

Grading based on Molecular Aberration

4. METASTATIC TUMOR IN THE OVARY

Common Precursors

Most Frequent Mutations

Chromosomal Instability

APST, non-

KRAS, BRAF

Low

CTNNB1,

Low

TYPE 1 TUMORS

LG serous CA

invasive MPSC

LG endometrioid CA

PTEN

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

Clear cell CA

Endometriosis

PIK3CA

Low

Mucinous CA

APMT

KRAS

Low

HG serous CA

-

TP53

High

Single layer of cells without atypia, regardless of

HG endometrioid CA

-

TP53

High

lining

Undifferentiated CA

-

-

-

Carcinosarcoma

-

TP53

-

Epithelial Tumors further divided into: a. BENIGN: o

Endometriosis

(tubal/serous,

mucinous)

endometrioid,

TYPE 2 TUMORS

or

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)

Includes high grade serous carcinoma, high grade endometrioid carcinoma, malignant mixed Müllerian tumor, undifferentiated carcinoma

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,

c. MALIGNANT: Cystadenocarcinoma, Adenocarcinoma, Carcinoma SURFACE EPITHELIAL TUMORS 1. SEROUS TUMORS Most common bilateral tumor that is primary

low-grade

to the ovary

endometrioid carcinoma, mucinous carcinoma, clear

cell

carcinoma

(*placing

clear

cell

carcinoma in type I is a misclassification; they

Most are benign serous cystadenoma  May present as either a multicystic le sion: o

are high grade carcinoma by nature)

fibrous walled cysts (intracystic)

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

Papillary epithelium contained within a few



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

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

(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.

Page 5 of 21

Block XIV | Pathology | Lesson 4

PATHOLOGY OF OVARIES Microscopic Findings

 Bilaterality is common o

20% of benign serous cystadenomas

o

30% of serous borderline tumors

o

66% of serous carcinomas



Simple architecture, non-branching papillae if present with rare to absent finding



Single, orderly layer of nonstratified, cuboidal to columnar epithelium, often ciliated

TYPES:

a.



Serous Cystadenoma – 60%

 The nuclei are oriented perpendicular to the long

b. Borderline Serous Tumor – 15% c.

Nuclear atypia minimal or absent axis of the columnar epithelium.

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

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

cyst; tumor is solid, with scattered B. Borderline Serous Tumor

glands, without atypia If prominent stromal component with grossly





Cellular stratification: papilla, tufting, cell clusters

visible cyst – cystadenofibroma Prominent stromal component, solid



Lined by tubal type epithelium

cystic tumor



Mild to moderate atypia



Psammoma bodies (Gr. “sand”) –  concentric,

No necrosis unless complicated by torsion (when there is torsion, you cannot classify

lamillated calcified structures seen in papillary

whether it is benign or malignant)

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 







Extraovarian lymph node implants

Papillary excrescences – does not mean that

Features are malignant but no stromal

its malignant

invasion

Solid areas may be present (fibromatous

Metastasis is not invasive  – only implants

component)

Noninvasive because there is no reaction in

Necrosis absent, unless complicated by

the surrounding peritoneum (invasive =

torsion

fibroblastic proliferation around the tumor  –

desmoplastic stroma) Page 6 of 21

Block XIV | Pathology | Lesson 4

PATHOLOGY OF OVARIES Incidence and Location

C. Serous Cystadenocarcinoma - with stromal



Bilateral – 30%

invasion



Advanced stage in 30 – 40%



Gross Findings 

Malignant

epithelial

ovarian

tumor

composed of tubal-type epithelium

Large cystic or solid and cystic mass with soft papillary projections and/or surface papillary excrescences

Incidence and Location 

Most

common

histologic

subtype

of

surface epithelial ovarian carcinoma

Microscopic Findings 

Numerous



papilla,

edematous,

with

often

broad

complex

and

Bilateral in 60% Most common bilateral malignant tumor

typically

of the ovary

hierarchal branching

Differentials for bilateral ovarian mass:

 This epithelial proliferation often grows in a

serous CA, metastatic CA from colon,

delicate, papillary pattern referred to as

endometrioid CA [mucinous CA are always

“micropapillary

is

unilateral  –  if bilateral, it is a metastatic

thought to be the precursor to low-grade

mucinous CA, not primary mucinous CA

serous carcinoma.

from the ovary]

carcinoma”,

which

 By definition, the presence of more than



focal microinvasion (i.e., discrete nests of epithelial cells 75%

Gross Findings

Psamomma bodies Psammomatous serous carcinoma



Unilocular or multilocular  Usually mulitloculated, and can present

Better prognosis compared to the

with hundreds of small cysts

usual serous CA

 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

epithelium

resembling

mucinous

endocervix

or

intestine 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

management is similar.

serous 

because

the



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.

Page 8 of 21

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

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

Borderline mucinous tumor is managed like a mucinous

cystadenocardinoma

(they

do

complete staging, omental sampling, and they remove the appendix)

with stromal invasion 

Uncommon surface epithelial carcinoma



Unilateral With stromal invasion of more than 10 mm2 If less than 10 mm 2, label it as borderline

Gross Findings 

Large (>30 cm), reminantly cystic mass with multiple loci

undifferentiated.  A poorly differentiated adenoCA may be a

Borderline area must be 10% 30cm)

Microscopic Findings 

adhesions

involvement of the ovaries.

 primary is appendix not ovary. 

with



Diffuse peritoneal adenomucinosis



Peritoneal carcinomatosis

Cytoarchitectural features similar to, but more severe than borderline mucinous tumor with areas of invasion exceeding 2

5mm in linear extent or 10 mm  in area

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

Two patterns of invasion o

Expansile – confluent glands Back

to

back

glands



May arise from endometriosis (40%) Mostly malignant and bilateral

without

intervening stroma

o

Endometrioid: with endometrial CA

Most common

o

Serous: no involvement of the enometrium

o

Metastasis: surface and hilar involvement



Associated

with

endometroid

synchronous

adenocarcinoma

low of

grade 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 met astasis: 

Expansile Pattern of Mucinous Adenocarcinoma. The malignant glands are arranged in a cribriform pattern and are composed of mucin-producing columnar cells o

Grade of the tumor  –  high grade = metastasis

Destructive – individual cells Shows obvious glandular stromal invasion



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 Page 10 of 21

Block XIV | Pathology | Lesson 4

PATHOLOGY OF OVARIES 

Molecular study  Genetic alterations similar to endometrial

4. CLEAR CELL CARCINOMA 

endometrioid carcinoma

cells with clear or eosinophilic cytoplasm and

o

Somatic mutations in b-catenin and PTEN

large nuclei with hobnail cells

o

Microsatellite instability

Hobnail cells can also be seen in serous

o

Germline mutation in DNA mismatch repair

carcinoma

associated with Lynch syndrome

 40% are bilateral 

Gross Findings 

Malignant surface epithelial tumor composed of

Cystic and solid with areas of hemorrhage and

Associated with pelvic endometriosis in 50-70% of cases



2/3 nulliparous

necrosis

Associated with hypercalcemia

 Bilaterality usually implies extension of the

Classic architecture:

neoplasm beyond the genital tract.

o

Tubulocystic pattern composed of clear and hobnail cells

Microscopic Findings 

o

Round to elongated glands with or without

Papillary

pattern

 – 

should

have

hyalinized core (sclerotic stroma)

squamous differentiation infiltrating the ovarian

o

stroma

Serous

and

endometrioid

 –

fibrovascular core

Serous vs endometrioid in grade 3 tumors: difficult to differentiate because they are both

Gross Findings

solid, unlike mucinous which is only grade 1 or



2; high grade tumors favour serous. Differentiation vs serous tumor: 

with fleshy nodules 

More likely to be serous if there is/are: 1. Psamomma bodies

Hemorrhage and necrosis on inner cyst wall and adhesions over the capsule



2. Slit-like lumen 

Thick walled unilocular cystic and solid mass

May present as single fleshy nodule in an endometriotic cyst (25%)

More likely to be endometrioid if there is/are: 1. Squamous differentiation

Micrscopic Findings

2. Punched-out glands

 2 possible patterns:

3. Adenofibromatous pattern

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)

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 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

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

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 2 –20cm 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 Increased incidence of basal cell carcinoma,

SEX CORD - STROMAL TUMORS 



medulloblastoma, to

ad

rhabdomyosarcoma;

Derived from the ovarian stroma, which in turn is

attributed

heterozygous

mutation

in

derived from the sex cords of the embryonic gonad.

Patched, a negatively acting component of the

Undifferentiated gonadal mesenchyme eventually

Hedgehog receptor

produced structures of specific cell type in both male (Sertoli and Leydig) and female (granulosa and 

Gross Description

theca) gonads.



Average of 6cm

Tumors resembling all of these cell types can be



Firm, white cut surface, may be lobulated

identified in the ovary.



Soft, white to yellow cut surface if cellular Yellow  – because of thecoma component (10% = fibrothecoma)

1. Fibroma – benign

Hemorrhage and necrosis when associated with

2. Thecoma – benign

torsion (especially if pedunculated)

3. Granulosa Cell Tumor

Bilaterally, multinodularity and calcification if

Microscopic

appearance

determines

associated with Gorlin Syndrome

behavior (may be benign or malignant  labeled as borderline)

Looks like leiomyoma, except it is white 

Treated as low malignant potential and treated with radiotherapy

Pedunculated and to polypoid growth in up to 1/5



Cystic change in 1/4

4. Sertoli-Leydig Tumor Always malignant

Microscopic description

If just sertoli tumor or leydig tumor, they



are benign

Intersecting fascicles or storiform pattern of spindle cells arranged in fascicles (whorled pattern)

1. FIBROMA



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



Variable degrees of collagen production Same as leiomyoma

of all ovarian tumors

Difference with leiomyoma: Smooth muscle cell

Benign, fibromatous tumor of varying cellularity

nucleus=cigarette shape; fibroblast=tapered

composed of spindle, oval or round collagen producing cells 

Unilateral

 Hormonally inactive 



 Solid, with yellow surface due t o lipids 

Stromal tumor composed of lipid containing

Presents as Pelvic mass, pain, ascites or urinary

cells resembling theca cells with a variable

frequency

fibromatous component. Pure thecomas are

Meig’s syndrome  in 1% of patients (benign

rare.

tumor in ovary, ascites and hydrothorax) Pseudomeig’s syndrome – if associated

with malignant tumor 

2. THECOMA

Associated with Basal Cell nevus (Gorlin)

Syndrome



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.

Page 13 of 21

Block XIV | Pathology | Lesson 4

PATHOLOGY OF OVARIES Gross Findings

3. GRANULOSA CELL TUMOR

Composed of liquid-containing cells resembling

Granulosa cell should compose more >10% of

theca

the entire tumor

cells

with

variable

fibromatous

component fibromatous



component

should

not

be

Granulosa stromal cell tumor with a minimum of 10% component of granulosa cells, often in a

>10%,lest it be identified as a fibrothecoma

fibrothecomatous background



5 –10 cm

 If 3 LPF in any one slide



if



it

produces

enough

5-

hydroxytryptamine  Characterized

o

by

salt-and-pepper

The immature epithelium is responsible for the

appearance of nuclei 

behavior

of

the

tumor;

Differentiate from metastatic intestinal

extraovarian sequence

carinoid (bilateral)

Neuroepithelium

may

look

if

numerous  – like

a

gland,

differentiate by looking at the background; if  Combination of thyroid tissue and carcinoid is

strumal carcinoid

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

Not a reliable criteria Only when the pattern is mucinous in that it becomes a reliable

criteria for metastasis

References: 

dysmoplasia

morphology

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.

The Doctor’s Lecture

Upperclass Notes  Robbin’s and Cotran Pathologic Basis of Disease, 9th ed.  Rubin’s Clinicopathologic Pathology –  th Foundations of Medicine, 7  ed.  Robbins and Cotran Atlas of Pathology, 3 rd ed.

Page 21 of 21