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High grade serous carcinoma

Authors: Erna Forgó, M.D., Teri A. Longacre, M.D.

Editorial Board Member: Jennifer A. Bennett, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Last author update: 23 July 2020

Last staff update: 3 June 2024

Copyright: 2003-2025, PathologyOutlines.com, Inc.

PubMed Search: High grade serous carcinoma ovary

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Table of Contents

Cite this page: Forgó E, Longacre TA. High grade serous carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovarytumorserouscarcinomahg.html. Accessed April 1st, 2025.

Definition / general

Epithelial carcinoma of serous cell lineage with papillary, glandular and solid growth patterns and high grade cytologic atypia

Essential features

Often bilateral, solid and cystic ovarian masses
Solid, pseudoendometrioid, transitional cell carcinoma-like (SET) appearance more common in BRCA1 mutations; need to refer to genetic testing
3 patterns of aberrant p53 expression correlate with TP53 mutation
Most important prognostic factor is stage, ~40% overall 5 year survival

Terminology

High grade serous adenocarcinoma

ICD coding

ICD-O: 8461/3 - malignant epithelial serous tumors, high grade serous carcinoma

Epidemiology

Accounts for majority of ovarian carcinoma diagnoses and related deaths
Affects women disproportionately in western nations
Increased risk in Caucasian as compared with African American women
Decreased risk with several menstrual and reproductive factors:
- Parity
- Later age at menarche
- Earlier age of menopause
- Oral contraceptive use
Increased risk with estrogen only hormonal therapy, combined estrogen and progestin regimens

Sites

Tubo-ovarian, peritoneum

Pathophysiology

Hereditary predisposition in 15 - 20% of cases involving BRCA genes (Am J Surg Pathol 2016;40:404):
- BRCA1 germline mutations cause 50% lifetime risk of ovarian cancer at average age of ~50 years
- BRCA2 germline mutations causes lower lifetime risk (10 - 35%) at a later age (average ~55 years)
Associated with homologous recombination defects
Hereditary predisposition in 6% of women with Fanconi anemia
A significant proportion arise in the fallopian tube and spread to the ovaries and peritoneum

Clinical features

Mean age: 63 years
Abdominal distension / bloating / pain
Nausea
Anorexia / early satiety
Back pain
Urinary incontinence
Advanced disease at presentation in ~80% of cases

Diagnosis

CT with contrast is the preferred imaging modality
Diagnosis is by surgical resection and histologic examination of resected tissue - may be associated with serous intraepithelial carcinoma (STIC) in fallopian tube (Histopathology 2014;65:149, Int J Gynecol Pathol 2017;36:230)

Laboratory

Elevated serum CA-125 level

Radiology description

Unilocular or multilocular, often bilateral, cystic and solid ovarian masses
Papillary projections identifiable
Peritoneal implantations and lymphadenopathy visible

Radiology images

Images hosted on other servers:

Cystic mass with papillary projections

Prognostic factors

Most important: stage, ~40% overall 5 year survival
In advanced stage disease, the amount of residual tumor present after staging and debulking is the most important factor
Low Ki67 proliferation index associated with platinum resistance and decreased survival
CD3+ or CD8+ tumor infiltrating lymphocytes confer favorable prognosis

Case reports

13 year old girl and 69 year old woman with normal sized ovarian carcinoma syndrome (Horm Mol Biol Clin Investig 2018;35:1)
22, 35 and 47 year old women with low grade serous neoplasms of the ovary with transformation to high grade carcinomas (Int J Gynecol Pathol 2012;31:423)
51 year old woman with high grade serous ovarian cancer 3 years after bilateral salpingectomy (Mol Clin Oncol 2017;6:201)
58 year old woman presented with an adnexal mass (Case of the month #538)
73 year old woman with serous carcinoma of the ovary that metastasized to the tail of the pancreas (Mol Clin Oncol 2016;5:41)

Treatment

Bilateral salpingo-oophorectomy with hysterectomy, debulking and staging biopsies
Chemotherapy (neoadjuvant and adjuvant)
Poly (ADP-ribose) polymerase (PARP) inhibitors with best response in patients with BRCA1 / BRCA2 mutations or other homologous recombination deficiency and platinum sensitivity (Cancer Chemother Pharmacol 2018;81:647, Invest New Drugs 2018;36:828)

Gross description

Often bilateral
Variable in size; often large, ~30% of cases with grossly normal ovary or surface nodules < 1 cm
Exophytic with solid or papillary growth
Solid areas tan to white with necrosis and hemorrhage
Serous / bloody fluid filled cysts
Fallopian tube can be grossly involved at fimbriated end

Gross images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Cystic mass with papillary tumor growth

Frozen section description

Nuclear pleomorphism (> 3x variation in size)
Moderate to severe nuclear atypia
Can have large bizarre forms
Increased mitotic figures, can be atypical

Frozen section images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

SET pattern

Necrosis, nuclear pleomorphism

Nuclear atypia and pleomorphism

Microscopic (histologic) description

Solid masses of columnar to cuboidal cells with eosinophilic cytoplasm and slit-like spaces (fusion of papillae)
Solid, pseudoendometrioid, transitional cell carcinoma-like (SET) appearance (more common in BRCA1 mutations) (Mod Pathol 2012 Apr;25(4):625)
Hierarchical papillary branching, glandular and cribriform patterns common
Significant nuclear atypia
Significant nuclear pleomorphism (> 3x variation in size) with large, bizarre and multinucleated forms (Hum Pathol 2005;36:1049)
Prominent nucleolus, often large and eosinophilic
High mitotic index: ≥ 12 mitotic figures per 10 high power fields, often atypical
Necrosis is frequent
Can have increased CD3+ or CD8+ tumor infiltrating lymphocytes (more common in BRCA1 mutation)
Psammoma bodies are variable
Serous tubal intraepithelial carcinoma (STIC) (90% fimbria, 10% ampulla / isthmus) exhibits similar histologic features; may be bilateral (10 - 20%) and multifocal
Findings after neoadjuvant chemotherapy: single cells in a background of histiocytic reaction and fibrosis, clear cell change, decrease in mitotic figures, increased psammoma bodies

Microscopic (histologic) images

Contributed by Erna Forgó, M.D., Teri A. Longacre, M.D., Jijgee Munkhdelger, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D. and Stephanie L. Skala, M.D. (Case #538)

Significant nuclear atypia and pleomorphism

Micropapillary growth pattern

SET pattern

PAX8 positive

ER positive

Variable PR (negative in this case)

WT1 positive

CK7 positive

CK20 negative

p53 overexpression

p53 null phenotype

Serous tubal intraepithelial carcinoma (STIC)

p53 overexpression in STIC

Ovarian serous carcinoma immunoprofile

High grade serous carcinoma with SET features

High grade serous carcinoma with SET features

Aberrant p53 expression

Virtual slides

Contributed by Andrey Bychkov, M.D., Ph.D.

High grade serous carcinoma

Cytology description

3 dimensional clusters or single cells with scant cytoplasm
Significant nuclear pleomorphism (> 3x variation in size)
Prominent nucleoli

Cytology images

Contributed by Erna Forgó, M.D. and Teri A. Longacre, M.D.

Malignant glandular cells in 3D clusters and singly

Positive stains

PAX8, WT1, p16 (~60%), ER (80%), PR (30%), CK7, D2-40 (variable), calretinin (variable, may be focal)
Aberrant p53 expression that correlates with TP53 mutation, 3 patterns (J Pathol Clin Res 2016;2:247, Int J Gynecol Pathol 2019;38 Suppl 1:S123):
- Overexpression: strong, diffuse nuclear staining in > 80% of cells (missense mutation)
- Null phenotype: complete absence of staining (loss of function mutation)
- Cytoplasmic expression: Cytoplasmic p53 expression with intensity similar to that of internal nuclear controls (loss of function mutation disrupting nuclear localization domain)
High Ki67 proliferation index (> 75%) (Oncotarget 2016;8:107877)

Negative stains

CK20, Napsin A

Molecular / cytogenetics description

TP53 alterations in nearly all cases
Germline, somatic or promoter hypermethylation (inactivation) of BRCA1 and BRCA2 in ~50% of cases (Am J Surg Pathol 2016;40:404)
Prominent DNA copy number changes, including CCN1, MYC, NOTCH3, PIK3CA, AKT oncogenes

Sample pathology report

Ovary and fallopian tube, right, salpingo-oophorectomy:
- Ovary
  - High grade serous carcinoma (see comment and synoptic report)
- Fallopian tube
  - Intravascular involvement by high grade serous carcinoma
Ovary and fallopian tube, left, salpingo-oophorectomy:
- Ovary
  - High grade serous carcinoma
- Fallopian tube
  - Intravascular involvement by high grade serous carcinoma
  - Paratubal cysts
Comment: We reviewed the frozen sections and confirm the diagnosis rendered. Histologic sections of the right and left adnexa show a high grade neoplasm growing in a solid trabecular pattern that involves both ovaries without capsular disruption. Abundant tumor associated lymphocytes are present. The tumor cells are positive for CK7 and PAX8 with abnormal (overexpression) of p53 but negative for CK20. Estrogen receptor and progesterone receptor expression is negative. These features are best characterized as high grade serous carcinoma which displays a SET (solid, pseudoendometrioid or transitional) pattern. Ovarian carcinomas which show a SET pattern of high grade serous carcinoma may be associated with BRCA gene mutations (somatic or germline).

Differential diagnosis

Low grade serous carcinoma:
- Minimal nuclear pleomorphism (< 3x variation in size) (Hum Pathol 2005;36:1049)
- Low mitotic index (< 12 mitotic figures per 10 high power fields)
- p53 wild type expression
- p16 negative or patchy positive
Clear cell carcinoma:
- Associated with endometriosis
- Often lower stage at presentation
- Distinctive architecture with variable admixture of tubulocystic, papillary and solid growths
- Composed of clear, eosinophilic, cuboidal or hobnail cells
- WT1, ER negative
- HNF-1B, Napsin A positive
Undifferentiated carcinoma:
- Discohesive, often monomorphic cells
- Often decreased expression of keratins and EMA
- PAX8 often negative or weak
- Association with mismatch repair protein or SWI/SNF protein deficiency
Metastatic endometrioid serous carcinoma:
- Tumor mass, with or without endometrial intraepithelial carcinoma (precursor lesion) in the endometrium
- Usually WT1 negative or patchy
Endometrioid adenocarcinoma:
- Often lower stage at presentation
- Associated with endometriosis
- ER, PR diffusely positive
- WT1 variable, p16 patchy positive, p53 wild type expression
Malignant mesothelioma:
- Simple papillae lined by 1 cell layer without tufting
- Less severe nuclear atypia
- Low mitotic activity
- D2-40, calretinin positive
- ER negative

Board review style question #1

An ovarian tumor is shown. This particular pattern, called SET (solid, pseudoendometrioid, transitional cell carcinoma-like), is most commonly associated with which genetic mutation?

BRCA1
KRAS
P53
PIK3CA

Board review style answer #1

A. BRCA1. SET (solid, pseudoendometrioid or transitional) pattern has a strong correlation between the presence of BRCA1 mutation and ovarian high grade serous carcinoma phenotype. These tumors also tend to have a higher mitotic index, increased tumor infiltrating lymphocytes and necrosis that can be comedonecrosis or geographic necrosis, when compared with unassociated cases. Recognition of this architectural growth pattern allows for the initiation of appropriate genetic testing and referral into necessary screening programs.

Comment Here

Reference: High grade serous carcinoma

Board review style question #2

Which is the most important prognostic factor for overall survival of ovarian high grade serous carcinoma?

Grade
Histologic subtype
Mitotic index
Stage

Board review style answer #2

D. Stage. Stage is the most important prognostic factor in ovarian high grade serous carcinoma, with a ~40% overall survival at 5 years. In advanced stage disease, the amount of residual tumor present after staging and debulking is the most important factor for survival. Ovarian, tubal and peritoneal high grade serous carcinomas are staged the same. It has been proposed that ovarian disease in absence of serous intraepithelial carcinoma (STIC) be classified as ovarian in origin, ovarian disease in the presence of STIC be classified as tubal in origin and peritoneal disease in absence of ovarian or tubal involvement be classified as peritoneal in origin.

Comment Here

Reference: High grade serous carcinoma

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