Ovarian tumours

The article examines ovarian tumours including ovarian cancer.

An introduction to the ovary is in the ovary article, which also deals benign cysts.

Clinical

Gynecologists use a scoring system to help decide which patients need surgery and estimate their pre-op risk of malignancy.

Risk of malignancy index

• Abbreviated RMI.
• There are two versions.

Elements & points (RIM 2):

1. Ultrasound features.
   • Significant findings: multilocular cyst, solid component, bilateral lesions, ascites, suspected intra-abdominal metastases (one finding=1 point, two or more findings=4 points).
2. Menopause/pre-menopause status (menopausal=4 points, pre-menopausal=1 point).
3. CA-125 (blood test) in U/ml.

$RMI\ score=ultrasound\ score\ x\ menopausal\ score\ x\ CA125\ level\ [U/ml].$

Interpretation:

• RMI > 200 -- predicts malignancy.

Classification

The Latta rule of fives

Can be divided as follows:

1. Surface epithelial tumours (most common).
2. Sex cord stromal tumours (SCSTs).
3. Germ cell tumours (GCTs).
4. Metastatic tumours.
5. Rare stuff that doesn't fit in any of the above (e.g. leiomyoma, angiosarcoma, ovarian small cell carcinoma of the hypercalcemic type).

Surface epithelial tumours:

1. Serous.
2. Endometrioid.
3. Mucinous.
4. Transitional cell tumours (Brenner tumour).
5. Clear cell carcinoma.

Sex cord stromal tumours:

1. Granulosa cell tumour (adult type, juvenile type).
2. Sertoli cell tumour.
3. Leydig cell tumour.
4. Fibroma.
5. Thecoma.

Germ cell tumours:

1. Dysgerminoma.
2. Endodermal sinus tumour (yolk sac tumour).
3. Embryonal carcinoma.
4. Choriocarcinoma.
5. Teratoma.

Common special tumours

Endometriosis-related tumours

Tumours associated with endometriosis:

1. Endometrioid.
2. Clear cell carcinoma.
3. Endocervical mucinous (AKA Seroumucinous type and Muellerian type).

Solid ovarian tumours

Simple version: basically anything sex cord stromal.

List:

• Brenner tumour.
• SCSTs:
  • Fibroma.
  • Thecoma.
  • Fibrothecoma.
  • Leydig tumour.
  • Sertoli cell tumour.
  • Sertoli-Leydig tumour.
  • Granulosa cell tumour.
  • Granulosa-theca cell tumour.

A morphologic approach

Where is the tumour arising?

• Central location -- think GCTs and SCST.
• Surface of ovary -- think surface epithelial tumour.
  • If no surface is apparent... possibly obliterated by tumour.

Spindle cell morphology?

• Consider sex cord stromal tumours.

Nests of cells?

• Consider Brenner tumour.

Gland-like structures?

• Endometrioid carcinoma.
• Granulosa cell tumour.

"Dirty necrosis":

• Definition: cellular debris within gland lumen.
• Characteristic of colorectal adenocarcinoma, may be absent in ovarian tumours -- limited value.

Grading of ovarian cancer

• Silverberg grading system, aka universal grading system.
• Based on pattern, cytologic atypia and mitotic rate.
• System somewhat similar to breast grading, which can be remembered as: TMN (tubular formation, mitotic rate, nuclear atypia).

Silverberg system

• Pattern:
  • Glandular = 1.
  • Papillary = 2.
  • Solid = 3.
• Cytologic atypia:
  • Slight = 1.
  • Moderate = 2.
  • Marked = 3.
• Mitoses (see note below):
  • 0-9/(0.345 x10 mm^2) = 1.
  • 10-24/(0.345 x10 mm^2) = 2.
  • >=25/(0.345 x10 mm^2) = 3.

Composite score (pattern score + cytologic score + mitotic score):

• Grade I = 3-5.
• Grade II = 6-7.
• Grade III = 8-9.

Note 1:

• Most resident microscopes have an eyepiece diameter of 22 mm. Thus, the approximate field diameter is 0.55 mm (22 mm/40 X = 0.55 mm), at highest magnification, and the field area is 0.23758 mm^2 (pi*(0.55/2)^2=0.23758 mm^2).
• The number of HPFs should be adjusted if the area per field is different than 0.345 mm^2.
  • If the field diameter is 0.55 mm and the sample area is 3.45 mm^2, this is equivalent to 14.52 HPFs (3.45 mm^2 / 0.23758 mm^2 = 14.52); thus, it would be appropriate to use 15 HPFs and the cut points above.

Note 2:

• A not-so-good alternative is to adjust the number of mitotic counts a keep the number of HPFs (10) constant.
  • If the mitotic rate per area is held constant, and the cut points are 9, 10 and 24, the equivalent mitoses per area are:
    • 0-4 mitoses/((HPF of 0.345 mm^2) x 10) = 1.
    • 5-11 mitoses/((HPF of 0.345 mm^2) x 10) = 2.
    • 12+ mitoses/((HPF of 0.345 mm^2) x 10) = 3.

Value of Silverberg...

Good correlation with five year survival (rounded values):

• Grade I = 90%.
• Grade II = 65%.
• Grade III = 40%.

Peritoneal implants

General

• In the setting of serous borderline tumours there is much ado about implants.

Classification

There are two types:

1. Non-invasive implants.
   • Subdivided into:
     1. Epithelial.
     2. Desmoplastic.
2. Invasive implants -- malignant cells within the stroma.

Notes:

• Invasive implants are significant clinically.
• Non-invasive implants have little clinical significance.

Microscopic

Non-invasive implant

Features (non-invasive implant epithelial-type):

• Papillary proliferation on surface.
• +/-Smooth contoured invagination into:
  • Submesothelium.
  • Omental fat lobules.
• No "stromal response":
  • Fibrosis.
• +/-Psammoma bodies.

Features (non-invasive implant desmoplastic-type):

• Stromal reaction restricted to the:
  • Serosal surface.
  • Fibrous septae.
• +/-Psammoma bodies.

Note:

• No "destructive invasion".
  • Irregular infiltration.

Invasive implant

Features (invasive implant):

• Irregular infiltration of tumour into the submesothelial tissue - key feature - characterized by:
  • +/-Solid nests.
  • +/-Small glands +/- irregular "bridging" connections between glands - common.
• Nuclear atypia - common.
• +/-Psammoma bodies.

Stains

• Elastin stain:
  • Non-invasive implants are sit superficial to the peritoneal elastic lamina (PEL).
  • Invasive implants are deep to the PEL.

Note:

• Elastin layer is not present in the omentum.

IHC

• Elastin stain.

Surface epithelial tumours

Most common subtypes - in short:

• Serous:
  • Columnar cells.
  • Cilia.
  • Psammoma bodies.
  • Papillae.
• Endometrioid:
  • Tubular glands.
  • Squamous differentiation (eosinophilic cytoplasm, well-defined cell borders, +/-keratin).
• Mucinous:
  • Tall columnar cells with mucin.
  • Glands with mucin.

Where to start when considering a malignant (epithelial) tumour of the ovary:

	Serous	Endometrioid	Mucinous
Characteristics	cilia, columnar cells psammoma bodies, papillary arch.	gland forming, endometrium-like	mucinous glands, colon-like
Differentiators	cilia, psammoma bodies	squamous metaplasia	mucin, lack of necrosis
Associations	atrophy	endometriosis, endometrial hyperplasia	(?)
Typical age	usually 60s+	40-60	varies (?)
Grade	typically high grade	typically low grade	often low
IHC	p53 +ve (diffuse), WT-1 +ve, CA-125 +ve, D2-40 +ve	WT-1 -ve	CK7 +ve, CK20 +ve (other tumours CK7 +ve, CK20 -ve)
Main DDx	poorly diff. endometrioid	serous	metastatic tumour (usually GI)

Serous tumours

General

• Most common malignant ovarian tumour.

Classification

Based on features predictive of behaviour:

• Benign.
• Borderline.
  • May have pseudostratification of epithelial cells.
  • "Usually, borderline if first impression is borderline."
• Malignant.
  • Cytologic atypia.
  • +/-Papillae.

Microscopic

Features:

• Tubal like epithelium:
  • Ciliated.
  • Columnar.
• Papillae.
• Psammoma bodies (concentric calcifications).

Note:

• In serous borderline tumours, micropapillae are thought to have significance -- assoc. with increased risk of distant recurrence - though is disputed.
• Psammoma bodies may be seen in endosalpingiosis.

Serous cystadenoma of the ovary

• AKA ovarian serous cystadenoma.

General

• Benign.
• Very common.

Gross

• Usually unilocular.

Microscopic

Features:

• Simple epithelium with cilia - key feature.
  • Cell morphology: columnar, cuboidal or flatted.

DDx:

• Serous cystadenoma fibroma.

Seromucinous borderline tumor of the ovary

General

• Rare.

Gross

• Mucin-filled cysts.

Image:

• Seromucinous borderline tumor of the ovary (unibas.ch).

Microscopic

Features:

1. Simple mucinous epithelium - endocervical type.
   • Tall columnar epithelium with apical pale cytoplasm.
2. Simple serous epithelium - with cilia.

Mucinous tumours

• May arise in endometriosis.

Gross

Features:

• Multiloculated.
• Sticky, gelatinous fluid (glycoprotein).

Microscopic

Features:

• Tall columnar cells in glands.
  • Apical mucin.
  • May vaguely resemble colorectal adenocarcinoma.
• Glands have mucin.
• +/-Nuclear atypia.
• NO cilia.

Subtypes

1. Endocervical type.
   • Less likely to be malignant.
   • More common than malignant type.
2. Intestinal type.
   • More likely to be malignant.
   • Goblet cells. (???)
     • One large clear apical vacuole.
   • If it doesn't look like intestine to you... it probably isn't.
   • May vaguely resemble colorectal adenocarcinoma (hyperchromatic, columnar nuclei, nuclear pleomorphism).
     • Image: [1]

Comparison of mucosa:

• Normal endocervical mucosa: endocervical mucosa.
• Normal colonic mucosa: colonic type mucosa.

Classification

• Benign. (Dx: mucinous cystadenoma or mucinous adenofibroma or mucinous cystadenofibroma)
  • Single layer of cells.
• Borderline. (Dx: mucinous tumour of uncertain malignant potential or borderline mucinous tumour)
  • Papillae.
• Malignant. (Dx: mucinous adenocarcinoma)
  • Usually intestinal subtype.

Note:

• Tumours may be heterogenous; benign appearing epithelium may be beside clearly malignant epithelium.
• Good sampling of mucinous tumours, i.e. many blocks, is important to lessen the chance of undercalling them.

Ovarian endometrioid carcinoma

General

• Associated with endometriosis, i.e. people with endometriosis are more likely to have 'em.

Microscopic

• Tubular glands.
  • Cribriform pattern common.
• May see mucinous secretion.
• May have squamous differentiation/squamous metaplasia (useful for differentiating from sex-cord stromal tumours and germ cell tumours). - very useful feature.

Clear cell carcinoma of the ovary

• AKA ovarian clear cell adenocarcinoma.
• AKA ovarian clear cell carcinoma.
• AKA clear cell adenocarcinoma of the ovary.

General

• Thought to be related to endometrioid carcinoma.
  • Increased risk of CC adenoca in people with endometriosis.
• Worse prognosis vs. other surface epithelial tumours

Microscopic

Features:

• Cystic/tubular architecture - important low power feature.
• Clear cells - cytoplasm is clear - key feature.
• Hobnail morphology - apical surface larger than basal surface.
  • "Nuclei bulge into the lumen".
• Hyaline droplets -- common, as in clear cell renal cell carcinoma.
  • Eosinophilic bodies within lumen.
• Nucleoli - prominent.

Note:

• Clear cell adenocarcinoma does not have to have clear cells. Yes, this is stupid; it is like papillary thyroid carcinoma -- which often isn't papillary -- see no truth in names.
  • The hobnail morphology is important if this is the case.

Images:

• WC:
  • Clear cell carcinoma - very high mag. - cropped (WC).
  • Clear cell carcinoma - intermed. mag. (WC).
  • Clear cell carcinoma - low mag. (WC).
• www:
  • Clear cell carcinoma of the ovary - several images (upmc.edu).

IHC

• HNF-1beta +ve.
  • Usu. -ve in serous carcinoma.
• WT-1 -ve.
  • Usu. +ve in serous carcinoma.

Panel for high grade serous vs. clear cell:

• ER, HNF-1beta, WT-1.

Transitional cell carcinoma of the ovary

General

• Rare.
• Fits into the transistional cell tumours category - in the surface epithelial group of ovarian tumours.

Microscopic

Features:

• Cystic spaces:
  • Small - punched-out border - very common.
  • Large.
• Papillae, usu. large, blunt.
  • Occasionally small and filiform.
• +/-Bizarre giant cells (35%)
• +/-Gland-like tubules.
• +/-Squamous differentiation.
• +/-Psammoma bodies.
• Cells:
  • Moderate basophilic cytoplasm and little intervening stroma.
  • Marked nuclear pleomorphism.
  • Mitoses - common.

Notes:

1. Resembles urothelial carcinoma.
2. No Brenner tumour component (benign or malignant) should be present.

Images:

• WC:
  • TCC - very low mag. (WC).
  • TCC - intermed. mag. (WC).
  • TCC - very high mag. (WC).

IHC

Features:

1. Vimentin +ve,
2. CA-125 +ve.
3. WT1 +ve.
4. CK20 -ve.
5. Thrombomodulin -ve.
6. Uroplakin III -ve.

Notes:

• 1-6 usu. opposite pattern in urothelial cell carcinoma.

Brenner tumour

General

• Fits into the transistional cell tumours category - in the surface epithelial group of ovarian tumours.

Epidemiology

• Mostly benign clinical course.
• Thought to arise from Walthard cell rest.
• Frequently an incidental finding, i.e. oophorectomy was done for another reason.

Gross

Features:

• Solid.

Microscopic

Features:

• Nests of transitional epithelium.
• "Coffee bean nucleus".
  • Elliptical shape (nucleus).
  • Nuclear grooves.
• Distinct nucleoli.

Notes:

• DDx of Coffee bean nucleus = granulosa cell tumour.

Images:

• "Coffee bean" nuclei (WC).
• Brenner tumour - intermed. magnifiction (WC).

Germ cell tumours

Main article: Germ cell tumours

These tumour are relatively uncommon, though are the most common grouping for young women.

Overview

• Dysgerminoma (most common).
  • Female version of seminoma.
• Yolk sac tumour (endodermal sinus tumour).
• Embryonal carcinoma.
• Choriocarcinoma.
• Teratoma.
• Mixed GCT - 60% of GCTs are mixed.
  • Common combinations:
    1. Teratoma + embryonal carcinoma + endodermal sinus tumour (yolk sac tumour) (TEE).
    2. Seminoma + embryonal (SE).
    3. Embryonal + teratoma (TE).

Mnemonic: SEE CT, S=Seminoma, Embryonal carcinoma, Endodermal Sinus Tumour, Choriocarcinoma, Teratoma.

Teratoma

Main article: Teratoma

• May be benign or malignant.
• Skin component only called "dermoid".

Dysgerminoma

General

• Female counterpart of seminoma -- look the same.

Epidemiology:

• Most common GCT in females.
• Prognosis usually good.

Microscopic

Features:

• Fried egg appearance (clear cytoplasm, central nucleus).
• Nuclear membrane has "corners", i.e. is "squared-off" - or "polygonal".
• +/- Lymphocytes - often prominent.
• +/- Granulomata.

Dysgerminoma vs lymphoma:

• Dysgerminoma has "squared-off" nuclei, i.e. the nuclei look are polygonal-shaped.

• Dysgerminoma - several cases (upmc.edu).

Gonadoblastoma

Main article: Gonadoblastoma

Details dealt with in the main article.

Microscopic

Features:

• Immature germ cells resembling Sertoli cells or granulosa cells.
  • Cells with moderate cytoplasm is a trabecular or tubular architecture.
• Primitive germ cells resemble those of a dysgerminoma.
  • Polygonal cells with a central nucleus, squared-off nuclear membrane and clear cytoplasm.
• +/-Calcification (very common).

Metastatic ovarian tumours

Main article: Metastases

Generally

• Mostly Muellerian origin (uterus, fallopian tube) or pelvic peritoneum.

Extramuellerian metastatic tumours

DDx:

• Breast.
• Gastrointestinal (GI) tract.
  • Pseudomyxoma peritonei, usu. appendiceal origin.
  • Krukenberg tumour = signet ring cell cancer with mucin production of GI origin.

Microscopic

Features:

• Predominantly surface involvement and nodular at low power.
• Signet ring cells (suggestive of GI or breast primary).
• Lymphovascular invasion.

Mucinous carcinoma - GI tract metastasis vs. primary ovarian

Gross

Features favouring metastatic disease:

• Bilaterality -- both ovaries involved.
• Small unilateral tumour size -- <10 cm = metastatic.
  • >13 cm = primary ovarian.

IHC

Ovarian tumours:

• Dipeptidase 1 (DPEP1) +ve.
• CK7 +ve.

Sex cord stromal tumours

General

• Most are unilateral.

IHC

• Most are positive for alpha-inhibin.
• Most are positive for calretinin -- considered more sensitive than alpha-inhibin.
• Melan A +ve.
• CD99 +ve.

Memory device MAC = melan A, alpha-inhibin, calretinin.

Sex cord tumour with annular tubules

• Abbreviated SCTAT.
• NOT sex cord tumour with angulated tubules.

General

• Associated with Peutz-Jeghers syndrome.
  • Large tumours more likely sporadic.
  • Small tumours more likely Peutz-Jeghers syndrome and incidental.

Microscopic

Features:

• Well-circumscribed nests of cells with nuclei at the periphery.
• Annular tubules (ring-shaped tubules) with dense hyaline material.

Notes:

• Annular = shape of a ring.

DDx:

• Sertoli-Leydig tumour - has double palisading with overlap of the layers.
• Granulosa cell tumour - have Call-Exner bodies, which don't have a well-defined/solid content.
• Brenner tumour - coffee-bean nuclei.

Images:

• SCTAT - image collection (gfmer.ch).
• Possible SCTAT (pathology.cn).

Juvenile granulosa cell tumour

General

• May secrete estrogen.
  • May present with endometrial pathology, e.g. endometrial hyperplasia or endometrioid endometrial carcinoma.
• May arise in males.

Gross

• Classically solid.

Microscopic

Features:

• Microcystic spaces.
• Moderate-to-marked nuclear atypia.
• Cuboidal-to-polygonal cell in sheets or stands or cords.
• Basophilic cytoplasm.

Notes:

• Juvenile variant of GCT has more nuclear pleomorphism.

Images:

• WC:
  • Juvenile granulosa cell tumour - intermed. mag. (WC).
  • Juvenile granulosa cell tumour - very high mag. (WC).

IHC

• Inhibin positive.
  • Inhibin negative in Brenner tumour.
• Calretinin +ve.

Adult granulosa cell tumour

• AKA granulosa cell tumour.
  • Should not be confused with juvenile granulosa cell tumour.

General

• May secrete estrogen.
  • May present with endometrial pathology, e.g. endometrial hyperplasia or endometrioid endometrial carcinoma.

Gross

• Classically solid.

Microscopic

Features:

• Classic appearance includes gland-like structures filled with acidophilic material (Call-Exner bodies).
• Small cuboidal to polygonal cell in sheets or stands or cords.
• Nuclear grooves.

Note:

• There is a "10% rule" -- if less than 10% of a SCST is granulosa cells... it isn't granulosa cell tumour.
• Juvenile variant of GCT has more nuclear pleomorphism.

DDx:

• Urothelial cell carcinoma (UCC).
  • UCC usually has extensive necrosis.
• Brenner tumour.
• Sertoli cell tumour.

IHC

• Inhibin positive.
  • Inhibin negative in Brenner tumour.
• Calretinin +ve.

Fibroma-thecoma group

• Some say fibromas and thecomas are related, while others believe they should be considered distinct entities.
• A combination of a fibroma and a thecoma is known as a fibrothecoma.

Note:

• Some discourage the use of the term fibrothecoma and sugguest calling tumours in the fibrom-thecoma group fibroma unless there are lipid-laden cells and more than minimal alpha-inhibin positivity.

Ovarian fibroma

General

• May be a part of:
  1. Meigs syndrome (mnemonic FAR: fibroma, ascites, right pleural effusion).
  2. Nevoid basal cell carcinoma syndrome (NBCCS), AKA Gorlin syndrome.
     • In NBCCS classically - calcified and bilateral.
• Very rarely transform to fibrosarcoma <1%.

Microscopic

Features:

• Spindle-shaped cells.
• Central nuclei.
• Stainable lipid - minimal or none.

Images:

• Ovarian fibroma - intermed mag. (WC).
• Ovarian fibroma - high mag. (WC).

IHC

• Inhibin -ve (~75%).

Thecoma

General

• Associated with compression & atrophy of ovarian cortex, thought to arise from medulla.
• Approx. 50% have symptoms related to estrogen secretion.
  • May also be viralizing.

Microscopic

Features:

• Nuclei with oval to spindle morphology.
• Abundant cytoplasm that is pale, vaculolated -- key feature.

Images:

• Thecoma - low mag. (WC).
• Thecoma - high mag. (WC).

IHC

• Alpha-inhibin +ve (90%+).

Sertoli-Leydig cell tumour

• AKA androblastoma.

General

• Sertoli and leydig cells are normal in the testis.
• Poorly differentiated tumours have sarcomatous features.

Microscopic

Features:

1. Sertoli or Leydig cells.
   • Leydig cells:
     • Abundant solid eosinophilic cytoplasm.
     • Round nuclei with fine chromatin and a small or indistinct nucleolus.
     • Often in small clusters ~ 5-25 cells/cluster.
   • Sertoli cells:
     • Pale/clear vacuolated cytoplasm.
     • Irregular nuclei with irregular/vacuolated-appearing chromatin.
     • Architecture: tubules, cords or sheets.
2. Stroma.
3. +/- Sarcomatous features (mucinous glands, bone, cartilage).

Images:

• WC:
  • Sertoli-Leydig cell tumour - intermed. mag. (WC).
  • Sertoli-Leydig cell tumour - very high mag. (WC).
• www:
  • Sex cord stromal tumour with Sertoli-Leydig component - several images (upmc.edu).

Pure Leydig cell tumour

General

• AKA Hilus cell tumour.

Microscopy

• Reinke crystalloids - in the cytoplasm of Leydig cells - testis article.

Benign

• Benign mesothelial inclusion cyst - may mimic a tumour.

See also

• Ovary.
• Gynecologic pathology.