Ovary

Question 1

Follicular Cyst

Answer 1

• Benign cyst measuring at least 3 cm
• If < 3 cm, called cystic follicles
• Lined by an inner layer of granulosa cells
• Outer layer of theca cells
• Formed due to abnormal gonadotrophin stimulation
• Contain clear fluid

Question 2

Corpus luteum cyst

Answer 2

• Cyst over 3 cm in size
• Inner layer of luteinized granulosa cells
• Outer layer of theca cells
• Corpus luteum is a physiological postovulatory structure formed after the dominant follicle releases the ovum
• Its main purpose is to secrete estrogen and progesterone and it normally regresses at the end of the cycle
• Cystic dilation happens when corpus luteum fails to regress and becomes enlarged with fluid / blood

Question 3

Hyperreactio luteinalis

Answer 3

• Bilateral, ovarian enlargement due to multiple, luteinized follicle cysts
• Thin-walled cysts
• Rare
• Associated with hydatidiform mole, choriocarcinoma, fetal hydrops due to Rh sensitization and multiple gestations

Micro:
* Follicular cysts with luteinization of theca interna or granulosa cells, edema of theca layer and stroma

Question 4

Polycystic ovary disease

Answer 4

• Polycystic ovarian syndrome (PCOS) is a clinicopathologic syndrome comprising polycystic ovaries and characteristic clinical features

Clinical:
* Most common cause of anovulatory infertility
* Grossly enlarged, multicystic ovaries
* May not be enlarged in adolescent patients
* Associated with endometrial hyperplasia and endometrial neoplasia

Micro:
* Increased ovarian size, including thickness of cortical and subcortical stroma
* Thickened collagenized tunica
* Normal numbers of primordial follicles
* Twice the expected number of ripening and atretic follicles
* Multiple cystic follicles (1 - 2 mm) with luteinized theca layer (theca lutein hyperplasia)

Question 5

Endometriosis

Answer 5

• Presence of endometrial tissue outside of endometrium and myometrium, consisting of both endometrial glands and stroma
• Ectopically located endometrial tissue consisting of at least 2 of the following:
• endometrial type glands
• endometrial type stroma or
• evidence of chronic hemorrhage
• Endometriosis is associated with
• Ovarian clear cell carcinoma
• Endometrioid carcinoma

Molecular:
* ARID1A
* PIK3CA
* KRAS
* PPP2R1A

IHC:
* CD10 immunohistochemistry can be used to confirm the presence of endometrial stroma

Question 6

Neoplastic Lesions of Ovary

Answer 6

Epithelial (~95%)

Type 1
* Low Grade Serous –> KRAS, BRAF
* Endometroid –> KRAS, PIK3CA, PTEN, CTNNB1, ARID1A
* Mucinous –> KRAS, ERBB2, TP53
* Clear Cell –> KRAS, PIK3CA, PTEN, AKT2, ERBB2

Type 2
* High Grade Serous –> TP53, BRCA1/2
* Undifferentiated –> KRAS, HER2

Non-Epithelial (~5%)

• Germ Cell
• Ovarian Sarcoma
• Sex-Cord Stromal
• Small Cell Carcinoma

Pathogenesis:
* Type 1
Progress from benign tumours through borderline tumours
Give rise to low-grade carcinoma

• Type 2
  Arise from inclusion cysts/Fallopian tube epithelium
  Via intraepithelial precursors that are often not identified

Question 7

Type 1 vs Type 2 Serous Ovarian Cancers

Answer 7

Type 1
* Progress from Ovarian low malignant potential (LMP) tumors, also known as borderline epithelial ovarian tumors
* Usually low grade
* RAS pathway frequently mutated
* BRCA wild type
* Generally TP53 wild type
* p16 patchy
* Chromosomally stable
* Frequently platinum insensitive

Type 2
* De novo invasive tumours
* High grade
* RAS wild type
* BRCA dysfunction
* TP53 mutant
* P16 block-positive
* Wide spread DNA copy number change
* Usually platinum sensitive

Question 8

Spectrum of Tubal Epithelial Alterations

Answer 8

Serous tubal intraepithelial carcinoma (STIC)

• Lesion that is limited to the fallopian tube epithelium and a precursor to extrauterine (pelvic) high grade serous carcinoma

Micro:
* Confined to epithelium
* Significant atypia, architectural alterations
* High proliferative index
* Mutant pattern of p53 staining

• Important precursor lesion to recognize, as it is a criterion for assigning fallopian tube as primary site of high grade tubo-ovarian serous carcinoma irrespective of presence and size of ovarian and peritoneal disease

Terminology:
Various terms used to describe a spectrum of tubal epithelial alterations:

**Secretory cell outgrowths (SCOUTs): **
* Secretory cell expansion with variable ciliation
* Type 1 / tubal differentiation
* Type 2 / endometrioid differentiation
* Wild type p53 staining

p53 signature:
* Histologically normal epithelium (at least 12 cells)
* Mutant pattern p53 staining
* Low proliferation index (MIB1) (typically less than 10%)

**Serous tubal intraepithelial lesion (STIL): **
* Abnormal histology (high N/C but preserved polarity)
* Mutant p53
* Variable MIB1
* STIL is regarded as a lesion of uncertain significance and diagnostic features fall short of STIC

Question 9

Epithelial Ovarian Cancers

Answer 9

High Grade Serous Carcinoma
* 70% all carcinomas
* Precursor: STIC (Fallopian Tube Epithelium)
* Syndromes: BRCA1/2, Hereditary breast and ovarian cancer (HBOC)
* Mutations: TP53, BRCA1/2, HRD, Chromosomal instability, Aneuploidy
* Therapies: PARP inhibitors

Low Grade Serous Carcinoma
* < 5% all carcinomas
* Precursor: Serous borderline tumour (Fallopian Tube Epithelium)
* Syndromes: ??
* Mutations: KRAS, BRAF
* Therapies: MEK1/2 inhibitors

Clear Cell Carcinoma
* <10 % all carcinomas
* Precursor: Clear cell borderline tumour (Endometriosis)
* Syndromes: Lynch syndrome
* Mutations: ARID1A, PIK3CA, CTNNB1, PPP2R1A, MSI
* Therapies: Tyrosine Kinase inhibitors

Endometrioid Carcinoma
* <10 % all carcinomas
* Precursor: Endometrioid borderline tumour (Endometriosis)
* Syndromes: Lynch syndrome
* Mutations: PTEN, ARID1A, CTNNB1, PPP2R1A, MSI
* Therapies: mTOR inhibitors

Mucinous Carcinoma
* <5 % all carcinomas
* Precursor: Mucinous borderline tumour (unknown)
* Syndromes: ?
* Mutations: KRAS, HER2 amplification
* Therapies: Trastuzumab

Question 10

Serous Cystadenoma/ Adenofibroma

Answer 10

• Benign
• Partially or completely cystic lesion
• Measuring > 1 cm
• Composed of cells resembling fallopian tube epithelium or
• Cuboidal nonciliated epithelium resembling ovarian surface epithelium

Micro:
* Usually small, uni to multilocular cysts
* Lined by a single layer of tall, columnar, ciliated cells resembling normal tubal epithelium or
* Cuboidal nonciliated epithelium resembling ovarian surface epithelium
* Stroma contains spindle fibroblasts
* If papillae are present, they are simple

Adenofibromas and cystadenofibromas
* Composed predominantly of fibrous stroma
* Glands and cysts form a minor component
* If < 10% of the total tumor shows epithelial proliferation within the cysts that would qualify as serous borderline tumor –> designated as serous cystadenoma with focal epithelial proliferation

Question 11

Serous Borderline Tumour

Answer 11

• Low grade epithelial neoplasm
• Generally younger women with a favorable prognosis when diagnosed at an early stage
• Nonobligate precursor to low grade serous carcinoma (LGSC)
• Can give rise to extra-ovarian abdominoperitoneal or lymph node implants
• Frequently bilateral (up to 33%)
• If peritoneal implants –> risk of recurrence

Macro:
* Complex cystic lesion
* Some delicate papillary excrescences lining inner surface

Micro:
* Non-invasive
* Epithelial proliferation and atypia
* Floating epithelial tufts
* Arbourising papillae –> lined by pseudostratified, cilliated, fallopian tube type epithelium

Molecular:
* KRAS
* BRAF

Question 12

Implants

Answer 12

• Extraovarian spread is referred to as implants
• Two types:

1) Non-invasive –> Epithelial type, Desmoplastic type
2) Invasive –> LG serous Carcinoma

Question 13

BRCA

Answer 13

• BRCA 1 and 2 –> very high risk for HGSC
• Often get prophylactic salpingoophorectomy
• BRCA-related cancers have ‘SET’ –> Solid, pseudo-Endometrioid, and Transitional morphology
• Lots of tumour-infiltrating lymphocytes
• Most originate in fallopian tube –> tubal origin until proven otherwise
• Normal tube –> p53 mutation –> STIC –> invasive HGSC –> spreads to ovary
• Rx –> cytotoxic chemotherapy and debulking staging surgery

Question 14

Mucinous cystadenoma and adenofibroma

Answer 14

• Benign
• Mucinous neoplasm
• Cysts and glands lined by gastrointestinal or Müllerian type mucinous epithelium
• Lacks architectural complexity or cytologic atypia
• May arise from mature teratoma or Brenner tumour

Macro:
* Usually unilateral (95%)
* Smooth or bosselated surface

Cystadenoma:
* Uni or multilocular cyst with variably sized smooth walled locules
* Filled with dense, viscous, sticky, gelatinous material
* No solid areas or papillary excrescences
* Mean size 10 cm, rarely > 30 cm

Adenofibroma:
* Usually smaller
* Predominantly white and solid with variable amounts of small cysts

Molecular:
* KRAS mutations in 68% of cases

Question 15

Mucinous borderline tumor

Answer 15

• Noninvasive
• Mucinous neoplasm with complex architecture and gastrointestinal type differentiation

Macro:
* > 90% of the tumors are unilateral
* Mean size: 22 cm; some tumors can measure as large as 50 cm
* Cysts are multiloculated with mucinous contents
* Smooth external surface
* Solid areas and necrosis may be present

Micro:
* Complex architecture with tufting and villus formation
* Epithelium resembles low grade dysplasia of the intestine
* Goblet cells, neuroendocrine cells and occasional Paneth cells present
* Neoplastic cells have hyperchromasia, crowding, stratification and mitotic activity
* Glands with luminal mucin

IHC:
CK7
CK20 (variable)
CDX2 (variable) [the extent of expression of CK7 is greater than that of CK20 or CDX2] (Am J Surg Pathol 2006;30:1130)
PAX8 (focal)
SATB2 is positive in a small subset of cases

Question 16

Mucinous carcinoma

Answer 16

• Unilateral
• Large, complex solid and cystic masses without surface involvement
• 77% of ovarian mucinous carcinomas are metastases
• 23% are ovarian primaries
• Of the ovarian primaries, most arise in a benign or borderline tumor

Two types of invasion -
* Expansile
* Infiltrative –> destructive

• Expansile tumors are usually stage I and behave “benign”
• Infiltrative tumors may demonstrate malignant behavior and cause death even if stage I

Grading:
Not standardized and does not predict prognosis independent of stage.

• Grade 1-no solid areas
• Grade 2-up to 50% solid foci
• Grade 3-more than 50% solid foci
• Severe nuclear atypia can increase raise grade I or II carcinomas by one grade

Molecular:
* KRAS mutations frequent

IHC:
CEA
CK7
CK20
CA125 (weak)

Question 17

Ovarian mucinous tumours - Primary vs Mets

Answer 17

Primary
* Unilateral&raquo_space;> Bilateral
* Often >10cm
* Usually expansile growth pattern
* No LVI
* No surface involvement
* No hilar involvement
* May have associated teratomas, Brenner tumours, mural nodules
* Rarely associated with pseudomyxoma peritoneii
* SATB usually negative, SMADA4 retained

Metastasis
* Bilateral > Unilateral
* Rarely >10cm
* Usually infiltrative growth pattern
* Often LVI
* Often surface involvement + acellular mucin
* Hilar involvement often present
* Associated ovarian pathology usually absent
* SATB2 usually positive in GI mets, SMADA4 may be lost

Common sites of involvement
* Appendix
* Pancreas
* Colon
* Gallbladder
* Stomach
* Cervix

Question 18

Mural Nodules

Answer 18

• Grossly circumscribed nodules
• Most associated with primary ovarian mucinous neoplasms (less frequently other ovarian tumor types)
• May be microscopically invasive but still separate / distinct from the associated mucinous tumor
• Associated mucinous tumor may be benign, borderline or malignant
• Reactive and malignant can be hard to tell apart

Types:
* Reactive (sarcoma-like)
* Benign neoplastic (leiomyomatous)
* Malignant (anaplastic carcinoma, sarcoma, carcinosarcoma)

Question 19

Endometrioid carcinoma of the Ovary

Answer 19

• Ovarian carcinoma resembling endometrioid adenocarcinoma of the endometrium
• Usually low grade and diagnosed at early stages
• May be associated with endometriosis and adenofibroma
• Stage is the most important prognostic factor

Macro:
* Usually unilateral; only 5% bilateral
* Cystic with solid component and areas of hemorrhage

Micro:
* Most common –> confluent (back to back) glands
* Stromal invasion usually by expansion
* Rarely, destructive stromal invasion can be observed
* Squamous metaplasia (morules or keratin pearls) can be seen

Histologic grading:
* Same as for endometrial endometrioid adenocarcinoma

• FIGO grade 1: less than 5% solid component
• FIGO grade 2: 6 - 50% solid component
• FIGO grade 3: more than 50% solid component

IHC:
* Keratin cocktails
* EMA
* CK7
* PAX8 (15% negative)
* ER and PR
* p53: wild / normal type expression (most tumors), high grade endometrioid cancers might demonstrate mutational pattern
* Mismatch repair protein deficiency has been reported in up to 23% of tumors

Question 20

Clear cell carcinoma of the Ovary

Answer 20

• Malignant epithelial tumor
• Usually unilateral
• Solid to cystic
• May be associated with endometriosis or Lynch syndrome
• Stage is the most important prognostic factor

Micro:
* Clear, eosinophilic or hobnail cells
* 3 classic growth patterns, frequently admixed but 1 pattern may predominate

Papillary:
* Most frequent (70%)
* Usually small, round, simple, nonbranching papillae with fibrous / hyalinized, edematous / myxoid or empty (open tumor rings) stromal cores
* Lined by 1 - 2 layers of cuboidal, flattened or hobnail cells
* Micropapillary tufts may be seen

Tubulocystic:
* Frequent (65%)
* Variably sized tubules and cysts, with or without intraluminal dense eosinophilic secretions and outpouchings
* Lined by a single layer of hobnail, cuboidal or flattened cells
* Often associated with an adenofibromatous background

Solid:
* Least common (62%)
* Diffuse sheets or nested clusters of polyhedral cells separated by delicate septa exhibiting clear to eosinophilic cytoplasm

Molecular:
* ARID1A
* PIK3CA

IHC:
* CK7 +
* HNF-1B +
* Napsin A +
* PAS + –> glycogen rich cytoplasm
* ER/PR -
* WT1-

Question 21

Brenner tumors

Answer 21

• Tumor composed of transitional / urothelial-like epithelium, typically embedded in fibromatous stroma
• Benign, borderline and malignant variants are recognized, based on the growth pattern and cytological features of the epithelial cells
• Cell of origin of Brenner tumors is controversial; they may arise from Walthard rests
• No atypia
• No increased mitotic activity

Micro:

Benign Brenner tumor:
* Nests of bland transitional epithelium present within fibromatous stroma

Borderline Brenner tumor:
* Papillary architecture with papillae covered by multilayered transitional epithelium
* There is variable but usually low grade cytological atypia

Malignant Brenner tumor:
* Stromal invasion by carcinoma with transitional cell features
* Associated with a benign or borderline Brenner tumor

IHC:
* p63
* GATA3
* CK7
* Uroplakin
* Thrombomodulin
* EMA
* CEA

Question 22

Walthard cell nests

Answer 22

• Nests, plaques or cysts (with eosinophilic luminal material)
• Metaplastic transitional epithelium involving the serosal surface of fallopian tube, mesosalpinx and mesovarium
• Benign common incidental finding
• Bland transitional type epithelium forming small nests / cysts

Micro:
* Small solid nests or cysts of transitional type epithelium
* Relatively uniform nuclei with irregular borders and nuclear grooves, located beneath the serosa of tubal / paratubal / paraovarian tissue
* Cystic lesions may have eosinophilic luminal secretions
* Rare or no mitotic figures

IHC:
* p63
* GATA3
* CK7

Negative:
* PAX8
* CK20
* Uroplakin
* SALL4

Pathogenesis:

Early events:
* Activating PIK3CA mutations (27%)
* CDKN2A loss (55%)

Two different pathways, Late events:
* FGFR3 alterations (45%)
* MDM2/TP53 alterations (46%)

Question 23

Ovarian Cancer Genetics

Answer 23

Sporadic:
* 85-90%

Hereditary:
* 10-15%
* 80-90% –> BRCA1 and 2, RAD51c and RAD51D –> Hereditary Breast and Ovarian Cancer Syndrome
* Further syndromes –> Lynch, Li-Fraumeni, Cowden, Gorlin, Peutz-Jeghers

Hereditary Breast and Ovarian Cancer Syndrome:
* BRCA1
* BRCA2
* Breast, Ovary, Melanoma, Prostate, Pancreatic Ca

Hereditary Breast and Ovarian Cancer Syndrome:
* RAD51C
* RAD51D
* BRIP1
* Ovary Ca

Lynch Syndrome:
* MLH1
* MSH2
* MSH6
* PMS2
* EPCAM
* Uterine, Colon, Ovary, Pancreatic, Gastric, Small Bowel, CNS, Renal, Sebaceous

Cowden Syndrome:
* PTEN
* Breast, Uterine, Thyroid, Colon, Renal, Sebaceous

Li-Fraumeni:
* p53
* Sarcomas, Breast, Adrenal, Brain, Lung, Endometrial

Peutz-Jegers:
* STK11
* GI, Breast, Ovarian, Sex cord stromal, Uterine, Cervical

Gorlin-Goltz Syndrome:
* Autosomal dominant
* PTCH1 –> Chromosome 9
* Dental/Ossesum anomalies
* Cutaneous anomalies –> BCC, dermal cysts
* Opthalmic –> Hypertelorism strabismus
* Neurological –> retardationm, calcification of falx cerebri
* Sexual anomalies –> Hypogonadism, Ovarian tumour

Question 24

Ovarian Sex Cord Stromal Tumours

Answer 24

Pure Stromal Tumours:
* Fibroma
* Thecoma
* Steroid Cell
* Leydig Cell
* Sclerosing Stromal

Pure Sex Cord Tumours:
* Adult Granulosa Cell
* Juvenile Granulosa Cell
* Sex Cord Tumour with Annular Tubules

Mixed Sex Cord-Stromal Tumours:
* Sertoli-Leydig Cell

Hormone Producing Ovarian Tumours:

Oestrogen Producing:
* Granulosa Cell
* Thecoma

Androgen Producing:
* Steroid Cell
* Sertoli-Leydig Cell
* Leydig Cell

IHC:
* Either +ve or -ve for CK
* Almost always EMA -ve
* +ve EMA suggests epithelial mimic
* Inhibin –> Relatively specific marker
* Calretinin –> More sensitive, less specific
* CD56 –> cytoplasmic and membranous
* WT1 –> Nuclear
* SF-1

Question 25

Fibroma

Answer 25

• Benign stromal tumor
• Fibroblastic cells
• Variably collagenous stroma

Macro:
* Well circumscribed mass with smooth, lobulated surface
* Firm, chalky, solid, white to yellow-white to tan-yellow cut surface that may be whorled
* Frequent oedema resulting in softer consistency
* Mean size 6 cm
* Usually unilateral (< 10% bilateral)
* Cystic degeneration in ~25% of cases
* Calcifications in ~10% of cases

Micro:

• Spindled or ovoid cells
• Abundant collagen
• Bland nuclear features

Variants:
* Cellular Fibroma –> Cellular with scant collagen, mild atypia, increased mitoses
* Mitotically Active Cellular Fibroma
* Minor Sex Cord Elements

IHC:
WT1
SF1
FOXL2 (no mutation)
Inhibin: 50% of cases, often focal or weak
Vimentin
CD56
ER/PR
SMA
Reticulin: differentiates fibroma (individual pericellular reticulin staining pattern) from diffuse type of adult granulosa cell tumor (nested reticulin staining pattern)

Syndromes:
* Gorlin Syndrome –> if young and bilateral
* Meig’s Syndrome –> Fibroma + Ascites + Pleural Effusion (resolve after removal of ovarian tumour)

Question 26

Thecoma

Answer 26

• Ovarian stromal neoplasm
• Almost always benign
• Usually occurs in postmenopausal women who present with uterine bleeding

Macro:
* Usually unilateral
* Most are < 5 cm
* Solid, yellow and lobulated or white with focal yellow areas
* Occasional cystic change and hemorrhage
* Necrosis is rare

Micro:
* Sheets of uniform cells
* Pale greyish-pink cytoplasm
* Cytologically bland
* Reticulin surrounds individual cells

IHC:
Inhibin
Calretinin
Reticulin stain shows a pericellular pattern
SF1
FOXL2
WT1
CD56
Vimentin
Oil red O in lipid rich cells

Question 27

Steroid cell tumor

Answer 27

• Ovarian stromal tumor composed of steroid cells with malignant potential
• Mostly unilateral
• Half of cases have androgenic manifestations –> hirsuitism

Macro:
* Wide size range
* Unilateral (95%)
* Solid, well circumscribed, occasionally lobulated
* Sections from yellow-orange (lipid rich) to red-brown (lipid poor) to dark brown-black (abundant lipochrome pigment)
* Occasionally with necrosis, hemorrhage and cystic degeneration

Micro:
* Architectural pattern: diffuse (most common) but occasionally in nests, cords, pseudoglandular and follicle-like arrangements
* Stroma: usually sparse (85%) but may be fibrotic or hyalinized, rarely edematous or myxoid
* Polygonal to rounded tumor cells with distinct cell borders, central nuclei and moderate to abundant cytoplasm
* Tumor cell cytoplasm: eosinophilic and granular (lipid poor) to vacuolated and spongy (lipid rich);
* Lipochrome pigment present (40%)

IHC:
Inhibin
Calretinin
SF1
MelanA
Androgen receptor (64%)
Vimentin (75%)
CD99

Question 28

Leydig cell tumor of the Ovary

Answer 28

• Benign steroid cell tumor composed of polygonal cells with abundant eosinophilic cytoplasm and Reinke crystals
• Postmenopausal occurrence
• Predominantly located in the ovarian hilus, close to nerve fibers
• Often lobulated or nodular growth
• Reinke cytoplasmic crystals present
• Secretes androgens –> masculisation

Micro:
* Unencapsulated neoplasms
* Smooth or irregular borders located in the hilus, next to nonmedullary nerve fibers
* Round to polygonal cells with abundant eosinophilic or vacuolated cytoplasm and round nuclei with small nucleoli
* Reinke crystals: eosinophilic, cytoplasmic rod, rectangular or hexagonal crystals
* Lipochrome pigment is common
* May have cytoplasmic pseudoinclusions or bizarre nuclear atypia

IHC:
Inhibin
Calretinin
MelanA
MITF
SF1
CD99

Question 29

Adult granulosa cell tumor

Answer 29

• Low grade indolent malignant neoplasm originating from granulosa cells of the ovarian follicles
• 20-30% chance of local recurrence, 5-20 years after diagnosis
• Secretes Oestrogen –> Menorrhagia, PMB, Amenorrhea

Micro:
* Scant, pale architecture
* Grooved nuclei
* Varied architecture –> Sheet-like, trabecular, ribbon-like, microfollicullar
* Call-Exner bodies filled with pink secretions
* Frequent mitoses

Molecular:
FOXL2 point mutations

IHC:
* FOXL2 immunostain is a sensitive (80%) and specific (99%) marker for sex cord stromal tumors (SCST)
* SF1: most sensitive marker for this as well as most common sex cord stromal tumors
* Inhibin A: more specific marker
* Calretinin
* **Reticulin: shows lack of pericellular staining and highlights nests or large groups of granulosa cells and vessels, helps differentiate diffuse pattern from fibroma / thecoma **
* Low molecular weight cytokeratin (CAM5.2, AE1 / AE3): 30 - 60%, usually dot-like or globoid perinuclear pattern
* S100: 50%
* CD99: 70%
* Vimentin, WT1, CD56 and SMA

Question 30

Juvenile granulosa cell tumor

Answer 30

• Sex cord stromal tumor composed of primitive appearing granulosa cells with follicular and solid growth patterns
• Sex cord stromal tumor with primitive granulosa cell differentiation
• Solid and follicular growth
• Almost always occurs in patients younger than 30 years
• Lacks the FOXL2 somatic mutation seen in adult granulosa cell tumor
• Usually stage IA and associated with a favorable prognosis

Macro:
* Usually unilateral with a smooth surface
* Mean size 12.5 cm
* Multiloculated, cystic and solid tumor with yellow-white solid areas
* May have hemorrhage and necrosis

Micro:
* Cells are round, abundant oesinophilic cytoplasm
* NO GROOVES
* Macrofollicular
* Basophillic secretions
* Frequent mitoses

Molecular:
NO FOXL2 mutations

IHC:
Inhibin
Calretinin
SF1
WT1
FOXL2
BRG1 (SMARCA4) (retained)

Question 31

Sex cord tumor with annular tubules

Answer 31

• Distinctive variant of sex cord stromal tumor
• Characterized by sharply circumscribed nests composed of ring-like tubules that encircle basement membrane-like material
• 2 types: sporadic and syndromic, the latter is associated with Peutz-Jeghers syndrome

Macro:
Nonsyndromic tumors:
* Unilateral masses ranging in size from several millimeters to 3 cm
* Solid, tan to yellow
* Cysts may be seen and occasionally may predominate

Syndromic tumors:
* Bilateral and multifocal lesions
* Often microscopic; may not be grossly visible
* Gritty texture may be noted if there is a mass

Micro:
* Syndromic and nonsyndromic tumors have similar morphology
* Variably size round nests of sharply delineated simple and complex tubules
* Tubules contain basement membrane-like material, which may also be present around the tubules
* Cells are columnar with clear cytoplasm
* Antipodal nuclei.

Tumors associated with Peutz-Jeghers syndrome:
* Calcifications within the tubules may be seen
* May be associated with endocervical gastric type adenocarcinoma (adenoma malignum)

Nonsyndromic / sporadic tumors:
* May focally transition to granulosa or Sertoli cell morphology
* Cytologic atypia and mitotic activity may rarely be seen
* May be hyalinized

IHC:
Calretinin
WT1
Inhibin
SF1
FOXL2
CD56

Question 32

Sertoli-Leydig cell tumor

Answer 32

• Accounts for < 0.5% of all ovarian neoplasms
• Common in young patients –> mean age of 25
• Composed of sex cord (Sertoli cells) and stromal (Leydig cells) elements
• May occur sporadically or in patients with DICER1 syndrome

3 molecular subtypes:

DICER1 mutant:
* Younger age
* Moderately / poorly differentiated
* Retiform or heterologous elements

FOXL2 c.402C>G (p.Cys134Trp) mutant:
* Postmenopausal patients
* Moderately / poorly differentiated
* No retiform or heterologous elements

DICER1 / FOXL2 wildtype:
* Intermediate age
* No retiform or heterologous elements
* Including all well differentiated tumors

Micro:
* Well differentiated
* Moderately differentiated
* Poorly differentiated

• Histologic grade and subtype correlates with clinical behaviour
• Sertoli-Leydig cell tumour with heterologous elements (Rhabdomyoblasts)
• Sertoli-Leydig cell tumour with retiform variant
• Intestinal metaplasia may be seen.

IHC:
* General sex cord proteins, such as inhibin, calretinin, SF1, FOXL2, CD56, WT1 and CD99
* Vimentin and pancytokeratin
* MelanA / MART1 in Leydig cells
* CK20 and CDX2 in heterologous intestinal type mucinous epithelium
* AFP, arginase and HepPar1 in hepatoid elements
* Reticulin histochemical staining may be helpful in differentiating Sertoli-Leydig cell tumor (completely absent or nested pattern) from fibromas and thecomas (individual pericellular reticulin network)
* Absence of reticulin staining is not specific for Sertoli-Leydig cell tumors, as adult granulosa cell tumors and epithelial ovarian tumors also show the same staining pattern

Question 33

DICER1 Syndrome

Answer 33

• Varients of protein encoded by DICER1 gene on chromosome 14
• DICER1 syndrome is a rare, inherited genetic disorder that increases the risk of developing tumors
• Autosomal dominant

Tumors

• Pleuropulmonary blastoma: A cystic lung tumor that may transform into an invasive tumor if not diagnosed and treated early.
• Multinodular goiter (MNG): A non-cancerous thyroid condition in which there are multiple nodules throughout the thyroid.
• Cystic nephroma: A non-cancerous kidney tumor.
• **Sertoli-Leydig cell tumor: **An ovarian tumor that is more common in females with a faulty DICER1 gene.

Other conditions

• Goiter (an enlarged thyroid)
• Polyps in the colon may also occur.
  Inheritance

Question 34

Sclerosing stromal tumor

Answer 34

• Benign stromal tumor
• Pseudolobular appearance resulting from alternating cellular and hypocellular areas

Macro:
* Typically unilateral
* Well circumscribed
* White-yellow variegated solid mass
* Often edema and cysts
* Hemorrhage, calcifications and rarely necrosis may be seen

Micro:
* Moderately cellular pseudo-lobuiles with numerous thin-walled vessels.
* Cellular areas –> fibroblasts and lip-laden vaculolated cells
* Separated by oedematous connmective tissue or dense collagenous stroma
* Sclerosis is present within the nodules
* Rare mitoses

Molecular:
GLI2 rearrangements in 81%
FHL2 is the most common gene partner

IHC:
Inhibin
calretinin
FOXL2
CD10
smooth muscle actin
Diffuse TFE3 expression in a subset of tumors

Question 35

Small cell carcinoma of the Ovary

Answer 35

1. Pulmonary Type
2. Hypercalcaemic Type –> More common

Hypercalcaemic Type
* Young women
* Unilateral
* Associated with paraneoplastic hypercalcaemia
* Undifferentiated tumour
* Diffuse growth of small, monotonous cells with scant cytoplasm
* Often focal macro follicle-like spaces
* Often a component of larger cells with more cytoplasm
* Very aggressive

IHC:
Diffuse WT1
Focal CK and EMA
Loss of nuclear SMARCA4 / BRG1 expression

Pulmonary Type
* Must exclude a metastasis
* Older women
* Often bilateral with extra-ovarian spread
* Diffuse growth of smnall cells with scant cytoplasm
* Salt and Pepper chromatin, and moulding
* Losts of mitoses and apoptotic bodies
* Poor prognosis

Question 36

Germ Cell Tumours

Answer 36

• Dysgerminoma
• Yoke Sac Tumours
• Embryonal Carcinoma
• Choriocarcinoma
• Teratoma
• Struma Ovarii

Question 37

Dysgerminoma

Answer 37

• Malignant primitive germ cell tumor with no specific type of differentiation
• Most common germ cell tumour (Female seminoma)
• Most common in children and young women
• Usually unilateral
• Elevated serum LDH
• Rarely elevated hCG
• Excellent prognosis with chemotherapy

Micro:
* Sheets or nests of uniform cells with clear or eosinophilic cytoplasm and distinct cell membranes
* Nuclei are rounded, often with angulated edges
* Tumor often separated by fibrous septae containing cytotoxic T cells and epithelioid histiocytes that can extend into tumor

Molecular:
Majority have isochrome 12p
ckit mutations

IHC:
SALL4
OCT3/4 –> nuclear positivity
D2-40
CD117
PLAP

Question 38

Yolk sac tumor

Answer 38

• Most common before the age of 30
• Usually unilateral ovarian mass with predilection for right ovary
• Usually occurs as a pure form or rarely as a component of a mixed germ cell tumor
• Numerous morphologic patterns, with the hallmark Schiller-Duval bodies
• Elevated serum alpha fetoprotein (AFP)
• Usually favorable clinical outcomes due to chemosensitivity
• Pure hepatoid and glandular intestinal types associated with poorer prognosis

Molecular:
Chromosome 12 abnormalities, usually isochromosome 12p

Micro:
* Multiple patterns
* Most common –> reticular/microcystic
* Schiller-Duval bodies –> A central blood vessel surrounded by layers of tumor cells, contained in a cystic space

IHC:
SALL4: marker of primitive germ cell differentiation
AFP: highly specific but 60% sensitive, often patchy / focal and weak
Glypican 3: less specific but stronger expression
PLAP
HNF1β
Pancytokeratin
GATA3: positive in reticular / microcystic, papillary and polyvesicular vitelline patterns but not in the glandular pattern
HepPar1: positive in glandular and hepatoid patterns
CEA, albumin: positive in hepatoid pattern
TTF1: positive in foregut / respiratory pattern
CDX2: positive in glandular intestinal type pattern
Villin: positive in reticular / microcystic and glandular intestinal type patterns

Question 39

Embryonal Carcinoma

Answer 39

• Primitive appearing ovarian tumor that is histologically similar to embryonal carcinoma of the testis
• Often a component in a malignant mixed germ cell tumor of the ovary; the pure form is exceedingly rare
• May show serum elevation of AFP or βhCG with positive pregnancy test
• Aggressive but respond to chemotherapy

Micro:
* Similar to embryonal carcinoma of the testis
* Often mixed with other malignant germ cell tumor components
* Sheets and nests of large, primitive pleomorphic cells with abundant cytoplasm
* Round nuclei with coarse membranes, at least 1 prominent nucleolus and brisk mitotic activity
* Occasional papillae and gland morphology
* Syncytiotrophoblast-like tumor cells are seen (hCG+) around sheets of tumor cells or within stroma
* Hyaline globules, similar to yolk sac tumor, may also be present
* Glandular pattern may mimic endometrial carcinoma or glandular morphology of a yolk sac tumor

Molecular:
Isochrome 12p

IHC:
SALL4, OCT 3/4 and SOX2 nuclear positivity
CD30 membranous positivity
OCT 3/4 more sensitive than CD30 but can also be expressed in dysgerminoma
AE1 / AE3
βhCG positive in syncytiotrophoblastic cells
AFP may be expressed in both tumor cells and hyaline globules
CD30 expression might decrease after chemotherapy

Question 40

Choriocarcinoma

Answer 40

• Rare primary ovarian tumor; < 1% of primitive ovarian germ cell tumors
• May develop from:
• Ovarian pregnancy (gestational choriocarcinoma),
• Germ cell tumor (pure or mixed, non-gestational choriocarcinoma) or
• Surface epithelial tumor with choriocarcinomatous differentiation
• Markedly elevated bHCG –> monitoring helps predict reecurrence and response to therapy
• Non-gestational choriocarcinomas are difficult to treat –> unresponsive to chemotherapy
• Mets to lungs, liver, bone, and viscera are common at diagnosis

Micro:
* Composed of cytotrophoblast, intermediate trophopblast and multinucleated syncytiotrophoblast around periphery of blood channels

IHC:
Cytokeratin, CD10, human placental lactogen, EMA
Syncytiotrophoblasts are hCG+

Question 41

Teratoma

Answer 41

• Composed of tissues form 2-3 germs layers
• Often and cystic and unilateral
• Common elements –> skin with adnexal structures, cartilage, GI, Brain

Types:
* Mature (benign)
* Immature (malignant)
* Teratoma with malignant transformations
* Monodermal teratomas –> struma ovarii –> mostly/all thyroid
* Carcinoid –> resemble well-differentiated NET tumours of GI tract

Mature Teratoma
* Mature tissue representing at least 2 embryonic layers
* If malignant transformation (rare), prognosis is related to the type of malignancy
* Most common ovarian tumor (20% of all ovarian tumors, 95% of all ovarian germ cell tumors)
* Reproductive age
* 10% bilateral

Immature Teratoma
* Malignant germ cell tumor of the ovary composed of cells from the 3 germ layers and containing variable amounts of mature and immature tissue
* Affects mostly young females < 20 years old
* Grossly solid ovarian tumor mass with necrosis and hemorrhage on cut sections
* Grading is based on the amount of immature neuroepithelium
* Can have associated nodal or peritoneal gliomatosis (presence of mature neural tissue), which increases risk of recurrence
* Grading and stage are the most important factors for prognosis and prognosis is greatly improved after chemotherapy

Struma Ovarii
* Ovarian teratoma either composed predominantly or exclusively of benign thyroid tissue or with any amount of malignant thyroid tissue
* Most common thyroid malignancy to occur in struma ovarii is papillary thyroid carcinoma, followed by follicular carcinoma

Macro:
* Typically unilateral
* <10cm
* Smooth surfaced
* Solid, brown or green-brown
* Fibrous septa
* Fluid-filled cysts containing brown-green gelatinous fluid

Micro:
* Mature thyroid tissue or adenoma with small and large follicles lined by a layer of columnar, cuboidal, or flattened epithelium
* May show changes similar to thyroid gland –> hyperplasia or thyroiditis

IHC:
* PAS higfhlights colloid
* Thyroglobulin highlights thyroglobulin in the struma component

Monodermal teratomas: carcinoid tumour:
* Primary carcinoid rumours of the ovary are associated with other teratomatous elements in 85-90% cases
* Most commonly insular carcinoid
* 30 to 80 years
* Carcinoid syndrome –> flushing, diarrhoea, abdo cramping, cardiac involvement
* Elevated urinary 5-hydroxyindole acetic acid

Micro:
* Insular carcinoid resembles midgut carcinoid –> discrete groups of small uniform cells separated by fibrous stroma.
* Nuclei with coarse chromatin
* Rare mitoses
* Associated with other teratomatous components

IHC:
* Chromogranin
* Synaptophysin
* NSE positive

Question 42

Germ Cell Tumour Markers

Answer 42

PLAP
* All

SALL4
* All

LIN28
* All

OCT3/4
* Dysgerminoma
* Embyronal Carcinoma

SOX2
* Embryonal Carcinoma
* Immature Teratoma

D2-40
* Dysgerminoma
* Choriocarcinoma

CD30
* Embyronal Carcinoma

AFP
* Yolk Sac
* Immature Teratoma

Glypican-3
* Yolk Sac
* Immature Teratoma
* Choriocarcinoma

B-hCG
* Choriocarcinoma