NFOG - Nordic Federation of Societies of Obstetrics and Gynecology

49. Tubo- ovarian cancer and Borderline tumors

Take home messages

Epithelial tubo-ovarian-peritoneal cancers have a high incidence in Nordic countries and a lower incidence in the Asian populations
10-15% are linked to hereditary mutations
70% are diagnosed at stages with advanced disease and 5-year survival is approximately 50%
Treatment is extensive surgery followed by chemotherapy or vice versa
Borderline tumors do not infiltrate the underlying stroma and have a good prognosis

Introduction to all gynecological cancers

Gynecological cancers are classified according to FIGO (International Federation of Gynecology and Obstetrics, see Table 1), rather than
the traditional TNM-classification. Localized/small tumors (FIGO stage I) have significantly better survival than tumors with distant spread
(Typically FIGO stage IV). Cancers that generally are detected early (such as endometrial cancer after postmenopausal bleeding) have a
mostly good prognosis, while ovarian cancer with few early signs are mostly diagnosed late and thus have a poorer overall survival rate.
The only preventable gynecological cancer (HPV-vaccination, see Chapter Premalignant lesions of the uterine cervix) is also the only one
with a good screening option (cervical smear/HPV-test, described in the Approach to the patient chapter, part Performing cervical
cytology). Following mass vaccination the incidence of cervical cancer will likely decrease in the coming decades. Endometrial cancer on
the other hand has displayed an increased incidence due to the general aging of the population in combination with obesity.

The different cancers and their treatment are described in the specific sub-chapters. The Nordic countries have guidelines that differ
slightly. Links to specific Nordic/European guidelines are displayed in the FIGO table (Table 1).

Table 1. FIGO (International Federation of Gynecology and Obstetrics) classification of gynecological cancer (Click to enlarge)

Epithelial ovarian cancer

Introduction
Ovarian cancer refers to a group of malignancies (Figure 1), traditionally developed from one of three cell types: epithelial cells
(carcinomas), non-epithelial cells (non-epithelial cancers) such as sex cord-stromal cells (including granulosa, theca, and hilus cells), and
germ cells (oocytes). The non-epithelial cancers represent less than 10%, while the carcinomas represent a major public health problem
because of late diagnosis and a high mortality rate. This chapter describes only the carcinomas.

Figure 1a. Ovarian cancer originating from the ovary. (Click to enlarge)

Figure 1b. Ovarian cancer originating from the tube. (Click to enlarge)

Recent advances in pathology and genetics of the carcinomas have identified five histological types (high-grade serous carcinoma
(HGSC), low-grade serous, endometroid, mucinous and clear cell carcinomas) (Figure 2). The term “ovarian cancer” has been used for all
adnexal malignancies, however, as the HGSC constitutes 70% of the carcinomas, and originate in the fallopian tube rather than the ovary,
make the term “tubo-ovarian cancer” more accurate.

Figure 2. Epithelial ovarian cancer, proportion of histopathologic types. (Click to enlarge)

High grade serous carcinomas (HGSC) represent 70% of carcinomas and originate from cells in the tubal fimbria and spread rapidly from
the fimbria to the ovary and the peritoneal cavity. They are characterized by abnormal tumor protein 53 (TP53) expression and germline
and/or somatic breast cancer gene (BRCA) mutations (see Genetics part). More than 70% are diagnosed in advanced stages and are
chemotherapy sensitive. The origin in the fimbria means that these carcinomas may potentially be reduced with simple salpingectomy,
and women with genetically high risk of cancer (BRCA1-2 mutation carriers) may be offered salpingectomy after completing
childbearing and delay the oophorectomy closer to natural menopause, and thus experience less side effects than at currently
recommended age (ongoing study; ClinicalTrials.gov (NCT02321228 )) .
Low grade serous carcinomas represent less than 5% of the carcinomas and may develop from borderline tumors in the ovary.
Endometrioid (10%), clear cell (<10%) and mucinous carcinomas (3%) may develop from endometriosis lesions (cells from the
endometrium implanted outside the uterine cavity). These carcinomas are more often diagnosed in early stages.

Epidemiology

The distribution of tubo-ovarian cancer is highest in Caucasian and lowest in Asian populations. It is the sixth most common cancer
among women in middle- and high-income countries and is the deadliest of the gynecological malignancies. The Nordic countries are
among those with highest incidence rates; in 2020 the age-standardized rate was lowest in Sweden with 9.8 per 100,000 and highest in
Denmark with 12.5 per 100,000. The median age is about 68 years. The 5-year survival is 50%, depending mostly on FIGO stage (See
FIGO addendum in the reference list), as most cases are diagnosed after spread.
There has been a decline in the incidence over the last decade, especially in younger age groups, which may be due to a protective effect
from the use of oral contraceptives. Genetic testing for BRCA1-2 mutations and medical follow-up of healthy female family members of
mutation carriers adds to this.

Figure 3. The Nordic Countries: 2016 age standardized incidence rate 14.5 per 100 000 (Click to enlarge)
Risk Factors
Personal or family history of ovarian, breast or colon cancer (BRCA1-2 mutation carriers and Lynch syndrome) (see Genetics).
Increasing height and body mass index (BMI).
Suppression of ovarian cyclical activity protects against neoplastic change. Thus, early menarche and a late natural menopause
increase the risk, while pregnancies, breastfeeding and use of oral contraceptives reduce the risk.
Tubal ligation, hysterectomy and low-dose aspirin are associated with a reduced risk.

Symptoms
Early-stage disease is often asymptomatic and symptoms are unspecific. Most patients have more than one of the following symptoms
at the time of diagnosis:
Abdominal distension or increased girth
Abdominal pain or bloating
Change in bowel or urination pattern
Loss of appetite
A weakened general health state
Shortness of breath (due to pleural effusion)
Deep vein thrombosis in the lower limbs

Diagnosis
Gynecological examination and vaginal ultrasound findings of: complex cysts, papillary projections, solid contents, vascularity,
ascites and extra-ovarian lesions.
Blood test/tumor markers: CA125, HE4 and CEA (to exclude colorectal cancer).
If the Risk of Malignancy Index (RMI)>200, the patient should be referred to a national gynecologic-oncology center. The algorithm
combines 3 factors: CA125 value, menopausal status (M) and ultrasound score (U). RMI = U x M x CA125
Imaging: CT thorax, abdomen and pelvis or MRI of the pelvis and PET-CT.
Testing for BRCA1-2 mutations in tumor for treatment options, and testing for BRCA1-2 mutations in germline to identify families
with hereditary risk of breast and ovarian cancer for referral to genetic assessment.

Treatment
Treatment is centralized to national gynecologic oncology centers.
Standard of care is dependent on FIGO stage

From Table 1: Ovarian cancer classification (Click to enlarge)

Preservation of fertility (removing one ovary only) may be discussed at younger ages, if early stage and low-grade disease.

The standard treatment is surgery (removing adnexa, uterus, omentum and pelvic/paraaortic lymph nodes, and if advanced
disease, enlarged lymph nodes and all metastatic tissue) followed by adjuvant chemotherapy.
In patients with non-resectable disease or poor general condition the treatment is primary chemotherapy (neo-adjuvant
chemotherapy) followed by surgery or palliative treatment.
Various new types of maintenance treatments and targeted therapies are available or offered in medical trials for specific
subtypes, such as:
Vascular Endothelial Growth Factor (VEGF) is one of the primary regulators of angiogenesis, and the angiogenesis inhibitor
bevacizumab are typically combined with chemotherapy in advanced cases.
Poly-ADP ribose polymerase (PARP) is an important protein involved in DNA repair, and PARP inhibitors is especially useful in
cases with BRCA1-2 mutations in tumor.
Immunotherapy (to stimulate the immune system to recognize and destroy cancer cells more effectively) is recommended for
certain subtypes.
Figure 4. High grade serous ovarian cancer surgery: Uterus, adnexa and pelvic peritoneum with typical carcinomatosis resected in one
bloc. (Click to enlarge)

Fig. 5: Carcinomatosis on peritoneum and small bowel (Click to enlarge)

Figure 6. Pelvis after radical ovarian cancer tumor dissection and removal. (Click to enlarge)

Figure 7. High grade serous ovarian cancer after paraaortic lymph node dissection. (Click to enlarge)

Figure 8. Ovarian cancer surgery needs access by midline incision from symphysis to processus xiphoideus for complete staging or in
advanced cases. (Click to enlarge)
Figure 9. Mucinous ovarian cancer are often large tumors confined to one ovary. (Click to enlarge)

Relapse
Most patients experience several relapses, which may be treated with surgery and/or medical therapies or offered participation in
medical trials.

Prognosis
The best predictor regarding survival is if the patient is free from tumor after primary surgical therapy. This is mostly achieved for
patients with early-stage disease (FIGO stage I), thus their 5-year overall survival is ~90%. However, most cases are diagnosed with
advanced disease (stages III-IV) with a 5-year overall survival ~50%. .

Genetics
Hereditary tubo-ovarian cancer syndromes exhibit an autosomal dominant pattern of transmission:
Hereditary breast- and tubo-ovarian cancer syndrome
10-15% of tubo-ovarian cancers are caused by mutations in the tumor suppressor genes BRCA1 or BRCA2. BRCA1 mutation carrier state
confers a 40-45% risk of tubo-ovarian cancer and the risk of breast cancer is 65-85%. The mean age for diagnosis is 54 years. BRCA2
mutations carriers have a 10-20% risk of tubo-ovarian cancer and the risk of breast cancer by age 70 is 40-85%. The mean age is 59
years.
Referral criteria for genetic assessment are one first degree relative with tubo-ovarian cancer and/or two with breast cancer.
The Lynch syndrome
Approximately 4% of tubo-ovarian cancers are caused by Lynch syndrome (mutations in the mismatch repair (MMR) genes MLH1, MSH2,
MSH6, PMS2), which confer a 9-12% risk of tubo-ovarian cancer, 80% risk of colorectal and a 40% risk of endometrial cancer and a lesser
risk for biliary and urinary tract cancers. The mean age of tubo-ovarian cancer detection in Lynch syndrome is 48 years. Mutations in the
MMR genes lead to microsatellite instability (MSI) and multiple DNA mutations.
Referral criteria for genetic assessment: three relatives with colorectal or related cancers (tubo-ovarian, endometrial, small bowel,
urinary, biliary, stomach).
Other rare syndromes with a link to tubo-ovarian cancer are Peutz-Jaegers syndrome and Cowden syndrome.

Borderline ovarian tumors (BOTs)

Introduction
BOTs are epithelial tumors with a low malignant potential, but which may develop into a low-grade ovarian cancer. Most frequent are
serous- (~50%) and mucinous (~40%) BOT.

Epidemiology
The incidence is 1.47/100.000 women. The 5-year overall survival is 90–100% depending on FIGO stage (see FIGO addendum in the
references list), histologic type and age at diagnosis, and most cases are diagnosed before metastatic spread.

Diagnosis
These tumors differ from benign tumors by proliferation of atypical cells. Contrary to invasive tumors, they are localized on the
inside of ovarian cysts and have not infiltrated the capsule or stroma.
They occur more frequent in younger women.
On ultrasound they are often unilocular cysts with or without septae and papillary projections into the cyst lumen.
They are often limited to the ovary, although they can spread with implants in the peritoneal cavity.
Treatment
Surgery is the standard of care: inspection of the peritoneum and appendix, resection of metastatic lesions, peritoneal staging
biopsies, bilateral salpingo-oophorectomy, omentectomy and hysterectomy. No lymph nodes are sampled/removed.
Fertility preservation of at least part of one ovary and the uterus is the standard approach in young patients.
There is no indication for chemotherapy.

Keywords: Epithelial ovarian cancer, fallopian tube cancer, peritoneal cancer, ovarian borderline tumor, BRCA mutation.

Test yourself
Click at NFOG-MCQ  and then at chapter 49

References

Literature
NORDCAN 2022 
FIGO addendum 
WHO Classification of Tumours Editorial Board. Female Genital Tumours. WHO Classification of Tumours. Vol 4. 5th ed. IARC; 2020.
Singh N, et al. High-grade serous carcinoma of tubo-ovarian origin: recent developments. Histopathology 2017; 71(3): 339–356.
Sutcliffe S, et al. Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer. Int. J. Cancer 2000;
87: 110-117

Relevant guidelines regarding gynecological cancer:

ESGO: European Society of Gynecologic Oncology 

NSGO: Nordic Society of Gynecologic Oncology 
National guidelines
DGCG: Dansk Gynekologisk Cancer Gruppe 
Finland:  Finnish 
NFGO: Norsk Forening Gynekologisk Onkologi 
Sweden: Regionala Cancercentrum i Samverkan-Gynekologisk cancer 

Authors
Anne Dørum , MD, PhD, Norway

Last edited 28.08.2020

Published by:
NFOG - Nordic Federation of Societies of Obstetrics and Gynecology
Ole Mogensen Department of Obstetrics and Gynecology - Aarhus University Hospital
8200 Århus N

Telephone: +45 30 71 45 62
nfogtextbook@nfog.org