High Grade Serous Ovarian Cancer

Shaukat Khanum Memorial Cancer Hospital and Research Centre
Iqra Yasin
High Grade Serous Ovarian Cancer
Fellow Gynecologic Oncology
SKMCH & RC, Lahore

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Outline
 Epidemiology
 Classification
 Genetics
 Origin
 Pathology
 Risk / Protective factors
 Clinical presentation
 Dissemination
 Screening
 Diagnosis
 Staging
 Treatment
 Follow up
 Prognosis
 Recurrent disease
 Summary
 References

Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries
CA: A Cancer Journal for Clinicians, Volume: 71, Issue: 3, Pages: 209-249, First published: 04 February 2021, DOI: (10.3322/caac.21660)

Epidemiology
 Ovarian cancer
 Worldwide
 8th most common female cancer (225,500
cases/year)
 8th leading cause of cancer-related mortality (140,200
cases/year)
 Most lethal gynecological malignancy
 USA (SEER)
 11.6 cases / 100,000 women per year (incidence)
 5 year survival: 47.4 %

Epidemiology
 Average lifetime risk: 1.3 %
 Risk of mortality: 1 %
 At time of diagnosis
 80 % advanced stage
 20 % early stage

Epidemiology

Classification

Classification (Epithelial Ovarian Cancer)
 Serous cancer
 Low grade (< 5 %)
 High grade (70 – 80 %) (HGSOC)
 Endometroid (15 %)
 Clear cell (5 %)
 Mucinous (3 %)
 Transitional
 Undifferentiated

Classification (clinicopathological and
genetics basis)

Genetics
 Universal p53 expression
 The Cancer Genomic Atlas (TCGA)
 BRCA 1  12.5 % (Germline 9 %, Somatic 3.5 %)
 BRCA 2  11.5 % (Germline 8 %, Somatic 3.5 %)
 Small number of somatic mutation involving
 CSMD3 (6 %) , NF1 (4 %), CDK12 (4 %)
 Gene copy number variation
 Amplification (CCNE1, MYC, MECOM)

Origin
 The precise cell and tissue of origin of HGSOC
 Controversial
 Theories
1. Unifying traditional theory of Ovarian Surface
Epithelium (OSE)
 Monolayered modified mesothelium with
uncommitted morphology and differentiation
 Fathalla theory of incessant ovulation
 No. of ovulatory cycles ∞
risk of acquiring HGSOC

Origin

Origin
 Theories
2. Tubal origin of serous cancer
 Piek et al proposed dysplastic lesion and occult HGSC
in fallopian tube in patient with BRCA 1/2 mutants
 Subsequent studies confirms presence of STIC (Serous
Tubal Intraepithelial Cancer) using SEEFIM (sectioning
and extensively examining the fimbriated end) protocol
 Molecular studies: confirms identical p53 mutation and
CCNE1 amplification in STIC (Precursor lesion) and
HGSC

Origin
 Theories
3. Early implantation of FTSEC (Fallopian Tube Secretory
Epithelial Cells) in OSE (= endosalpingiosis)
 Incorporation of FTSEC in Cortical inclusion cyst
(CIC)
 Metaplasia under influence of ovarian hormones
 Neoplasia due to pro inflammatory / pro-oxidative
environment of ovary

Pathology

Risk factor
 Geographical distribution
 High incidence (Northern and eastern Europe)
 Intermediate (West Europe, Australia, America)
 Low (Asia, Africa)
 Age
 Median age of diagnosis: 63 (55 – 64) years
 Median age of death: 71 (65 – 74) years

Risk factor
 Genetics
 Germline BRCA 1 (3.6 %), BRCA 2 (3.3 %) mutation
 Germline + sporadic BRCA 1 / 2 (10-20 % cases)
 44 % risk at age of 70 year
 Homolog recombination pathway gene mutation
 BRIP1 (5.8 % lifetime risk),
 RAD1C (5.2 % lifetime risk)
 RAD1D (12 % lifetime risk)

Risk factor
 Genetics
 Family history (3 - 4 fold increase risk)
 Lynch Syndrome (HNPCC) DNA mismatch repair gene
 MLH1, MSH2, MSH6, PMS2
 Single nucleotide polymorphism (SNPs)

Risk factor
 Ethnicity
 Non-Hispanic Caucasian > Hispanic, Asian, African
American
 Reproductive / Hormonal
 Early menarche
 Late menopause
 Nulliparity
 Ovulatory cycles

Protective factor
 Pregnancy
 Breast feeding
 Tubal ligation
 Salpingoophorectomy (BRCA 1 / 2 mutant )
 Combination OCP
 Wild type p53
 Functionally normal homolog recombination DNA
repair pathway

Clinical Presentation

Clinical Presentation
 History
 Variable and nonspecific symptoms
 Abdomen/pelvis examination
 Abdominal or pelvic masses
 bilateral, solid-cystic, firm, fix, irregular surface,
nodularity of pouch of Douglas

Dissemination
 Direct dissemination
 Exfoliation of tumor cells in peritoneal cavity
(Transcoelomic)
 Lymphatics
 Hematogenous (rare)

Screening
 No effective screening strategy for early detection
of ovarian cancers
 PLCO Screening trail (CA 125, TVS)
 Promising result in early detection
 Failure to improve patient outcomes (survival)
 Genetic testing may be helpful
 Family history
 Prophylactic oophorectomy (BRCA 1 / 2; 80-90 %
reduction)

Diagnosis
 Tumor marker
 CA-125
 50 % early stage, 80 % late
 Diagnostic and prognostic
 Imaging
 US/CT/MRI/PET-CT
 Laparoscopy (staging/diagnostic)

Staging

Treatment
 Early stage EOC (FIGO I and II)
 Surgical staging
 Midline/laparoscopy (selected cases)
 Peritoneal washings
 Systemic exploration of all abdominal surfaces and
viscera in a clockwise fashion
 Any suspicious area / adhesion on peritoneum should be
biopsied

Treatment
 Random blind peritoneal biopsies (if normal
peritoneal surface)
 Right and left paracolic recesses
 Right and left pelvic side walls
 Right hemidiaphragm
 Urinary bladder recession
 Cul-de-sac

Treatment
 Hysterectomy + BSO
 Omentectomy
 Retroperitoneal space dissected and explored to
evaluate pelvic LNs.
 Para aortic area should be explored

Treatment
 Advanced EOC (FIGO III and IV)
 Mainstay = Debulking/cytoreductive surgery +
chemotherapy
 Types of debulking surgery
 Immediate primary
 Delayed primary (interval)
 Secondary

Treatment
 Factors impacting probability and extent of surgery
 Patient related factors
 Age
 Performance status
 Comorbidities
 Non acceptance of blood transfusion and stoma
formation

Treatment
 Factors impacting probability and extent of surgery
 Disease related factors
 Involvement of SMA
 Diffuse deep infiltration of proximal small bowel mesentery
 Diffuse carcinomatosis infiltration of small bowel
 Multiple liver parenchymal pulmonary metastases
 Brain metastases
 Tumor infiltration of hepatoduodenal ligament/celiac trunk
 Extensive lymphadenopathy extending into chest

Treatment
 Aim of cytoreduction
 Removal of primary and all metastatic tumor
 No visible (R1) tumor after surgery
 Rationale of cytoreduction
 Physiologic benefit of tumor mass excision
 Enhanced immunologic response
 Improve tumor perfusion and growth fraction and
better response to chemotherapy

Treatment
 Standard procedures in cytoreduction
 Hysterectomy + Oophorectomy
 Pelvic , para-aortic LND
 ESMO (LION Trial) recommends PLND if LN
bulky/suspicious
 Routine LND not recommended

Treatment
 Standard procedures in cytoreduction
 Omentectomy
 Bowel resection (if involved)
 Non standard procedures in cytoreduction

Treatment

Quantitative Prognostic Indicators
 Prior Surgical Score (PSS)
 Peritoneal Cancer Index (PCI)
 Complete Cytoreduction (CCR) Score

 Prior Surgical Score (PSS)
 PSS 0: No previous abdominopelvic (AP) surgery
 PSS 1: 1 AP region dissected
 PSS 2: 2-5 AP regions dissected
 PSS 3: ≥ 6 AP regions dissected
 Low PSS associated with good median survival

PCI score Median Survival 5 year survival rate
< 10 80 months 65 %
> 10 38 months 29 %

 Complete Cytoreduction (CCR) Score
Median survival
Adequate / Optimal CC-0 to CC-2 (1 cm) 55 months
Suboptimal CC-3 8 months

Treatment
 Bevacizumab
 Humanized monoclonal anti- VEGR antibody
 ICON-7 and GOG218 trials
 Recommended as 1st line therapy of advanced stage
EOC to be used along side chemotherapy and
continued for 15 months as maintenance therapy.

Treatment
 Intraperitoneal chemotherapy
 Delivers higher amount of chemotherapy
intraperitoneally as compare to IV route
 NCCN recommends it as potential option for stage II or
III EOC after optimal debulking surgery
 Based on improved survival outcome reported in
GOG172 RCT.

Treatment
 HIPEC (Hyperthermic Intraperitoneal
Chemotherapy)
 OVIHIPEC-1: Significant improved OS/PFS
 Korean Trail: No improved OS/PFS
 Not recommended as 1st line treatment option.
 Need further Phase III RCT

Follow-up / Surveillance

Prognosis

Recurrent disease
 Platinum sensitive
 If ovarian cancer recur ≥ 6 months of platinum based
therapy
 Platinum resistant
 If ovarian cancer recur < 6 months of platinum based
therapy.

Recurrent disease

Recurrent disease
 PARPI (Poly(ADP-Ribose) Polymerase Inhibitors)
 Olaparib, Niraparib, Rucaparib, veliparib
 Dramatic change in outcome of stage III-IV HGSOC in
BRCA mutant and Homologous recombinant deficient
(HRD) tumor
 20 % HGSOC: Somatic / germline mutation in BRCA 1
and 2 genes.
 50 % HGSOC: HRD deficient

Summary
 Inspite of Uncommon incidence, OC still represents a silent public health concern due to
dismal long term survival outcome.
 HGSOC is most common and by far the deadliest.
 Unspecific symptoms and few early warning signs , rarely diagnosed at an early stage.
 Few recurrent driver mutations in p53, genomic instability and gene number alterations.
 Mainstay of treatment is debulking surgery and platinum-based chemotherapy
 Despite excellent response to platinum-based chemotherapy, recurrence occurs and that
response to PARP inhibitors and bevazicumab.

References
 Textbook of Gynecological Oncology (European Society of Gynecological Oncology)
 Berek & Hacker ‘s Gynecologic Oncology (6th edition)
 NCCN guidelines (version 1.2021)
 Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical
and therapeutic standpoints. Int J Mol Sci. 2019 Feb 22;20(4):952. PMID: 30813239. DOI:10.3390/ijms20040952.
 Mahmood RD, Morgan RD, Edmondson RJ, Clamp AR, Jayson GC. First-Line Management of Advanced High-
Grade Serous Ovarian Cancer. Curr Oncol Rep. 2020 Jun 4;22(6):64. PMID: 32494876. DOI: 10.1007/s11912-020-
00933-8.
 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020:
GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021 May;71(3):209-249. PMID: 33538338DOI: 10.3322/caac.21660. Epub 2021 Feb 4.

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High Grade Serous Ovarian Cancer

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