Ovarian tumours

Gross photo of a malignant ovarian tumour. (WC/Doc James)

The article examines ovarian tumours including ovarian cancer.

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

What was labeled "ovarian cancer" in the past may really arise from fallopian tube. The label tubo-ovarian cancer has been advocated to address this change. These tumours are dealt with in this article.

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.

Definition

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

Elements

Elements & points (RMI 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.

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 carcinoma.
   • High-grade serous carcinoma. †
   • Low-grade serous carcinoma.
2. Endometrioid carcinoma.
3. Mucinous carcinoma.
4. Clear cell carcinoma.
5. Brenner tumour.

Note:

• † Transitional cell tumours are now grouped with high-grade serous 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:

• 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.

Predictive power of Silverberg grading

Good correlation with five year survival (rounded values):

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

Peritoneal implants

General

Applies only to:

• Serous borderline tumour.
• Seromucinous borderline tumour.

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.

Staging of ovarian cancer

• The CAP protocol talks of in the pelvis and outside the pelvis - pT2 versus pT3.
• Omental involvement is considered outside the pelvis; it is pT3.

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:

Features	Serous	Endometrioid	Mucinous
Histology	low grade: cilia, columnar cells, psammoma bodies, papillary arch.; high grade: marked nuclear pleomorphism, prominent red nucleoli, psammoma bodies	gland forming - esp. cribriforming, endometrium-like	mucinous glands, colon-like
Differentiators	cilia, psammoma bodies	squamous metaplasia	mucin, often 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 - overview

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 carcinoma of the ovary

• AKA ovarian serous carcinoma.

Main article: Serous carcinoma of the ovary

Serous cystadenoma of the ovary

• AKA ovarian serous cystadenoma.
• Related to adenofibroma and serous cystadenofibroma.

Main article: Serous cystadenoma of the ovary

Ovarian serous borderline tumour

• AKA serous borderline tumour of the ovary.
• AKA serous tumour of low malignant potential of the ovary, abbreviated SLMP.
• AKA serous ovarian tumour of low malignant potential.

General

• Usually benign.
• Require long term follow-up.

Microscopic

Features:

• Cuboidal to columnar epithelium with mild to moderate atypia.
• No invasive.
• "Sparse" mitoses.
• +/-Psammoma bodies.
• +/-Micropapillary architecture - often described as a medusa head pattern.

DDx:

• Serous carcinoma of the ovary - focus a with stromal invasion >5mm (linear measurement) or > 10 mm² (area).
  • Invasive cells are "pink", i.e. have abundant eosinophilic cytoplasm,; also, cells usu. large (~2-3x size of non-invasive component), and typically have an enlarged nucleus (~2x non-invasive component).
• Clear cell carcinoma of the ovary - classically associated with endometriosis, have simpler, smaller papillae without branching.

Images:

• Serous ovarian LMP tumour (radiographics.rsna.org).

Subclassification

Typical subdivided into:

• Micropapillary serous borderline tumour.
• Typical serous borderline tumour (SBOT).

General

• Common.
• 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.

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 (duke.edu).
• Normal gastric mucosa: gastric mucosa (WC).

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.

Seromucinous borderline tumour of the ovary

• AKA endocervical-type mucinous and mixed cell-type tumour.

General

• Rare.
• Associated with endometriosis.

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 cystadenoma of the ovary

• AKA ovarian mucinous cystadenoma.

Main article: Mucinous cystadenoma of the ovary

Mucinous borderline tumour of the ovary

• AKA ovarian mucinous borderline tumour.
• AKA ovarian mucinous tumour of low malignant potential.

General

• Requires extensive sampling - to avoid missing an adenocarcinoma.

Note:

• The WHO prefers borderline over low malignant potential as the descriptor for these tumours.

Classification

Subdivided into:

1. Intestinal type mucinous borderline tumour of the ovary ~ 90% of cases.
2. Endocervical type mucinous borderline tumour of the ovary ~ 10% of cases.

Gross

Intestinal type mucinous borderline tumour of the ovary and endocervical type mucinous borderline tumour of the ovary:

• Complex multiloculated mass with mucin.
• Often large - may > 30 cm.

Microscopic

Intestinal type mucinous borderline tumour of the ovary

Features:

• Mucinous differentiation:
  • Tall columnar cells with apical mucin - usu. resembles gastric foveolar epithelium.
• Layering of epithelial cells (stratification).
  • Must be <= 3 cells.
• +/-Papillary infoldings.
  • Projections into the cystic space.
• +/-Mild nuclear atypia.
• +/-Mitoses (focally).

Notes:

1. Resembles a villous adenoma of the colon.
2. Borderline component must be >= 10% of the tumour.
   • Lesions with <10% borderline component are known as mucinous cystadenoma of the ovary with focal proliferation or mucinous cystadenoma of the ovary with focal atypia.

DDx:

• Mucinous adenocarcinoma of the ovary.
• Mucinous cystadenoma of the ovary.
• Mucinous cystadenoma of the ovary with focal proliferation.

Images:

• Ovarian MBT (webpathology.com).
• Ovarian mucinous borderline tumour and benign mucinous tumour (webpathology.com).

Endocervical type mucinous borderline tumour of the ovary

Features:

1. Cells with mucinous differentiation resembling endocervical epithelium:
   • Tall columnar cells with grey apical mucin.
2. Cells with eosinophilic cytoplasm - known as "pink cells".
3. Ciliated cells.

• Neutrophils associated with the epithelium/mucin - common.

Images:

• Endocervical type mucinous borderline tumour - low mag. (webpathology.com).
• Endocervical type mucinous borderline tumour - high mag. (webpathology.com).

Comparing intestinal versus endocervical

Feature	Intestinal	Endocervical
Primary mucin producing cell	clear - well-diff. component, eosinophilic (pink)	eosinophilic (pink), grey or clear
Size	tall columnar (height:width >3:1) "champagne flute"	stubby columnar (height:width <3:1)
Accompanying epithelial cells	+/-goblet cells	pink cells, ciliated cells
Other cells	none	neutrophils (intraepithelial) - common
Images	high mag. (webpathology.com)	low mag. (webpathology.com), high mag. (webpathology.com)

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OVARY AND CYST, LEFT, OOPHORECTOMY:
- MUCINOUS BORDERLINE TUMOUR, INTESTINAL TYPE, ARISING FROM A MUCINOUS CYSTADENOMA (INTESTINAL TYPE).
- OVARIAN PARENCHYMA.

Mucinous adenocarcinoma of the ovary

• AKA ovarian mucinous adenocarcinoma.
• AKA ovarian mucinous carcinoma.

General

• Malignant.
• May arise in endometriosis.
• Poor response to chemotherapy vis-à-vis serous carcinoma.

Gross

Features:

• Multiloculated.
• Sticky, gelatinous fluid (glycoprotein).
• +/-Necrosis.
• Typically unilateral.

Microscopic

Features:

• Mucinous differentiation.
  • Tall columnar cells in glands with apical mucin.
    • May have an endocervical-like or intestinal-like appearance - see subtypes.
• Invasive morphology - one of the following:
  1. Back-to-back glands/confluent growth pattern.
  2. Desmoplastic stromal response.
  3. Cribriforming of glands.
• Malignant characteristics:
  • +/-Nuclear atypia.
  • +/-Necrosis.
  • No cilia.

DDx:

• Mucinous borderline tumour of the ovary.
• Metastatic mucinous carcinoma.

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: [2]

Comparison of mucosa:

• Normal endocervical mucosa: endocervical mucosa (duke.edu).
• Normal colonic mucosa: colonic type mucosa (WC).

IHC

• CK7 +ve.
• CK20 +ve.

Endometrioid carcinoma of the ovary

• AKA endometrioid ovarian carcinoma.
• AKA endometrioid adenocarcinoma of the ovary.
• AKA ovarian endometrioid adenocarcinoma.

General

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

Gross

• Usually solid and cystic.

Image:

• Endometrioid carcinoma of the ovary (uchc.edu).

Microscopic

Features:

• 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.

DDx:

• Sertoli-Leydig cell tumour - also has tubules.
• Serous carcinoma of the ovary.

Clear cell carcinoma of the ovary

• AKA ovarian clear cell adenocarcinoma, abbreviated OCCC.
• AKA ovarian clear cell carcinoma.
• AKA clear cell adenocarcinoma of the ovary.

Main article: Clear cell carcinoma of the ovary

Transitional cell carcinoma of the ovary

Main article: Transitional cell carcinoma of the ovary

Brenner tumour

Main article: Brenner tumour

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.

Image:

• Ovarian metastasis - low mag. (WC/Nephron).

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.

Main article: Sex cord tumour with annular tubules

Juvenile granulosa cell tumour

Main article: Juvenile granulosa cell tumour

Adult granulosa cell tumour

• AKA granulosa cell tumour.
  • Should not be confused with granular cell tumour.
  • Ideally, it should be called adult granulosa cell tumour to avoid confusion with juvenile granulosa cell tumour.

Main article: Adult granulosa cell tumour

Gross

• Classically solid.

IHC

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

Molecular

Currently not used for diagnosis.

• FOXL2 point mutation seen in 86 of 89 tumours.

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 fibroma-thecoma group fibroma unless there are lipid-laden cells and more than minimal alpha-inhibin positivity.

Ovarian fibroma

Main article: Ovarian fibroma

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.

Gross

Features:

• Solid yellow mass, usu. well-circumscribed.

DDx:

• Ovarian fibroma - white solid mass.
• Fibroma-thecoma (fibrothecoma).

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).

DDx:

• Endometrioid carcinoma of the ovary.
• Luteinized adult granulosa cell tumour - super rare, 50% of cell with eosinophilic cytoplasm, other findings of granulosa cell tumour, e.g. Call-Exner bodies.

Images

• 

  Sertoli-Leydig cell tumour - intermed. mag. (WC)

• 

  Sertoli-Leydig cell tumour - high mag. (WC)

• 

  Sertoli-Leydig cell tumour - very high mag. (WC)

www:

• Sex cord stromal tumour with Sertoli-Leydig component - several images (upmc.edu).

IHC

Features:

• WT-1 +ve.
• Melan A (MART-1) +ve - marks the Leydig component.
• Vimentin +ve.
• Calretinin +ve.
• CD99 +ve.

Others:

• CD34 -ve.
• Cytokeratin -ve (usually).

Hilus cell tumour

Main article: Leydig cell tumour

• AKA Leydig cell tumour.

General

• Rare.
• May cause virilization.
  • Development of male (sexual) characteristics in a female.
• Arise from hilus cells.

Microscopic

Features - see Leydig cell tumour:

• Moderate eosinophilic cytoplasm.
• +/-Reinke crystalloids (cytoplasmic inclusions).

DDx:

• Hilus hyperplasia.
• Sertoli-Leydig tumour.

Benign

• Benign mesothelial inclusion cyst - may mimic a tumour.

See also

• Ovary.
• Gynecologic pathology.