wieku rozrodczym – analiza przypadku Late ovarian cancer relapse following conservative surgery in a patient of childbearing age – a case study

Martyna Sikora, Katarzyna Kowalczyk-Amico, Jacek Suzin, Maria Szubert Received: 31.03.2016 Accepted: 19.04.2016 Published: 29.04.2016 © Curr Gynecol Oncol 2016, 14 (1), p. 63–68 DOI: 10.15557/CGO.2016.0007 Martyna Sikora, Katarzyna Kowalczyk-Amico, Jacek Suzin, Maria Szubert


INTRODUCTION
O varian cancer is responsible for the majority of deaths due to cancer of the reproductive organs, and one of the most common malignancies in women.According to the National Cancer Registry, 3544 cases and 2432 deaths due to ovarian cancer were noted in 2012.Comparing the years of 2008 and 2011, 4% increase in the age group <34 years (7% in total) may be found.Also the number of deaths in this age group increased, namely by 1% (vs.4% total decrease) (1,2) .There have been few studies devoted to risk factors for ovarian cancer in young women of childbearing age.At present, genetic factors (BRCA1, BRCA2, Lynch syndrome) are considered to play a decisive role (3) .Only regular check-up appointments with a gynecologist and ultrasound (US) scans of the reproductive organs may prevent young women from being diagnosed with the disease at a late stage, thus increasing their chances for survival and potential preservation of fertility.The mainstay of ovarian cancer treatment is radical surgery accompanied by adjunctive chemotherapy.Due to the shifting of childbearing towards higher age, an increase in the number of patients wishing to spare their fertility in spite of having developed ovarian cancer may be expected.Fertility-sparing surgery is viable in patients with a diagnosis of cancer not more advanced than FIGO stage IC1 (4,5) .Following conservative surgery, 60-90% of patients manage to conceive (5,6) .However, 9-15% of patients with a diagnosis of cancer not more advanced than FIGO stage IC1 suffer from ovarian cancer relapse following fertility-sparing treatment (4,6) .This study reflects on the management of recurring ovarian cancer in a patient diagnosed at a young age, having undergone chemotherapy and pregnancy.

CASE STUDY
In 2007, a 21-year-old female was admitted into the Clinic of Operative and Oncologic Gynecology of the Medical University of Lodz.The patient had no internal disease history, and was hospitalized to receive surgery for a cyst of the left ovary.On admission, the patient underwent a US scan of the reproductive organs and had her CA-125 level tested.The results came out negative, with no indication of malignancy.The patient was enrolled for a transverse incision procedure of the abdominal cavity and resection of the ovarian cyst.The operative course was uneventful.Intraoperative histopathological analysis suggested a benign lesion.Fourteen days after the operation, the final histopathological result was obtained, identifying the lesion to be grade 1 endometrioid cystadenocarcinoma with squamous epithelium.
The patient refused a repeat operation and an extended procedure.Since the original conservative surgery included only a resection of the cyst, adjunctive chemotherapy (taxol and carboplatin) was administered.Having received 6 chemotherapy cycles, the patient was asymptomatic.Both CA-125 level and the US scan of the reproductive organs were normal.The patient remained under the care of the hospital's outpatient centre.After a 3-year follow-up period, she was considered fit for childbearing by the oncologist in charge of her case.In February 2011, the patient was admitted for a scheduled caesarian section at 39 weeks of a normal pregnancy.A female infant was delivered, weighing 2850 g, in overall good health, Apgar score 10.While planning the delivery method, a simultaneous radical operation was suggested, but the patient refused yet one more time due to her further childbearing plans.In the course of the C-section, a remnant of the left ovary, normal contralateral ovary, and no macroscopic signs of a malignant disease in the remaining organs of the abdominal cavity were revealed.An intraoperative histopathological analysis of samples collected from both ovaries was conducted (no signs of malignancy), with greater omentum sample and peritoneal cavity lavage also collected (no signs of malignancy).
The patient remained under the care of the hospital's outpatient centre, with check-up appointments scheduled every 4-5 moths and CA-125 level tested and US scan of the reproductive organs taken at every visit.In September 2014, abnormalities were revealed.In US scan, a lesion of nonuniform echogenicity, sized 48 × 35 mm was found, confirmed in a CT scan of the abdominal cavity on the following day.No other abnormalities were identified.The patient was admitted into the ward and enrolled for a vertical incision procedure of the abdominal cavity, complete hysterectomy, bilateral oophorectomy and removal of the greater omentum.Upon opening the abdominal cavity, a tumor located on the left side, approx.10 cm large in perimeter, was found, with the remaining organs showing no lesions.An intraoperative analysis revealed the tumor to be malignant.The final diagnosis was grade 2 infiltrating endometrioid cystadenocarcinoma with squamous epithelium, FIGO stage 1A, located in the left ovary.The patient was treated with carboplatin and paclitaxel.BRCA mutation was tested, revealing no mutations typical for ovarian cancer, except for a mutation variant deemed to be insignificant (BRCA2 V387F; 1387 G>T; BRACAnalysis Rearrangement Test, BART, Myriad Genetic Laboratories, USA).At present, one year upon the completion of the second course of chemotherapy, the patient remains asymptomatic.

DISCUSSION
The risk of ovarian cancer is higher in nulliparous women, women with a family history of ovarian or breast cancer as well as those with early menarche history.The risk of ovarian cancer declines along with the decrease in the frequency of ovulations, hence it is lower in women who have born children and used hormonal contraception (7) .There is evidence for the risk factors listed above to exist for women of perimenopausal and postmenopausal age.In young women, however, it is genetic syndromes that seem to play a greater role.The patient we discuss here, when diagnosed with the disease had not been able to fulfill any of her childbearing potential.The family history showed no hereditary cancer syndromes such as Lynch syndrome or hereditary breast and/or ovarian cancer syndrome (HBOC).BRCA test showed the substitution of valine for phenylalanine at position 387 of BRCA2 gene.The risk of ovarian cancer has not been determined for such a mutation, as its impact on the function of BRCA2 protein remains unknown.It is noteworthy that BRCA2 protein is involved in DNA damage repair by facilitating recombination of both DNA strands.In 10-15% of ovarian cancer patients, BRCA mutations may be demonstrated, with a significant risk of ovarian cancer having been identified for several of them.In the Polish population (largely homogenous) the mutations include 300T>G, 4153delA, 5382insC in BRCA1 gene (8) .The majority of BRCA2 mutations present in our population are likely to be associated with a slightly elevated risk of breast cancer.With BRCA2 mutation, the risk of ovarian cancer is estimated at 11-27% (9) .Mutations of this gene are also associated with a substantial, even though not accurately determined, risk of concomitant ovarian and gastrointestinal cancer (mainly gastric cancer, colorectal cancer, and pancreatic cancer), in men and women alike (10) .Ovarian cancer is difficult to find, with even small-sized primary foci being capable of spreading to remote organs (11) .The tumor either spreads by direct extension to the neighboring organs in the peritoneal cavity, or by the lymphatic pathway, less commonly by the hematogenous route (7) .The initial symptoms are nonspecific, becoming more evident as the disease progresses (12) , and may include dysuria, flatulence, tenderness or pain felt in the lesser pelvis, and ascites.The patient whose case has been reported here was originally referred for a surgical procedure due to a cyst of the ovary, with a suspicion of a non-cancerous lesion, hence the conclusive result of the histopathological analysis came as a surprise.Multiple conversations with the patient were necessary to explain the biology of cancerous lesions and the therapeutic options available.The decision to spare the reproductive organs should in such cases invariably be made with the patient's full awareness of her circumstances, following consultations with an oncologist, gynecologist/obstetrician, and psychologist as well as with other związanych z rakiem jajnika.Finch i wsp.sugerują, iż nosicielki mutacji BRCA powinny być informowane o tym, że pod warunkiem wczesnego -około 35.roku życia -wykonania ooforektomii obustronnej można osiągnąć znaczący spadek zachorowań na nowotwór jajnika (nawet o 77%).Ponadto wczesna ooforektomia może zmniejszyć liczbę pierwotnych raków otrzewnej wykrywanych w 20-letnim okresie obserwacji u nosicielek mutacji BRCA (13) .Prawdopodobnie nowotwór ten rozwija się z subklinicznych przerzutów obecnych już w trakcie zabiegu usunięcia jajników.Im wcześniej wykonana ooforektomia, tym mniejsze ryzyko pierwotnego raka otrzewnej, którego ryzyko szacowane jest na około 4% u kobiet z mutacją BRCA1 i około 2% u kobiet z mutacją BRCA2.U nosicielek mutacji obserwacja w kierunku wystąpienia raka piersi i nowotworów przewodu pokarmowego oraz działania prewencyjne powinny być dobierane indywidualnie (14) .Kobiety młode z rozpoznanym rakiem jajnika trzeba informować, że w grupie wiekowej poniżej 55. roku życia przeżywalność jest istotnie lepsza niż wśród kobiet po menopauzie (15) .W przypadku zachorowania w wieku rozrodczym odsetek pięcioletnich przeżyć sięga 74-80% oraz poprawia się wraz z zaawansowaniem opieki medycznej i wprowadzaniem terapii indywidualnie dobranych -np.na podstawie oznaczenia mutacji BRCA (16) .family members.The patients diagnosed with the disease while in their childbearing age should be referred for testing for the most common mutations associated with ovarian cancer.Finch et al. have recommended that carriers of BRCA mutation be informed that early (around 35 years old) bilateral oophorectomy facilitates a significant decline in ovary cancer incidence (up to 77%).What is more, early oophorectomy may reduce the number of primary peritoneal cancers detected in a 20-year follow-up period in BRCA mutation carriers (13) .This cancer presumably develops from subclinical metastases already present at the time of oophorectomy.The earlier oophorectomy is performed, the lower the risk of primary peritoneal cancer, whose risk is estimated at approx.4% in women with BRCA1 mutation and approx.2% in women with BRCA2 mutation.In the mutation carriers, monitoring for breast cancer and gastrointestinal cancer as well as preventive measures should be personalized (14) .Young women with a diagnosis of ovarian cancer should be informed that in patients in the age group <55 years the survival rate is significantly higher than in postmenopausal ones (15) .In the case of ovarian cancer developed in childbearing age, the 5-year survival rate amounts to 74-80%, and has been continuously increasing along with the advances in available medical care and the introduction of individually-matched therapies, e.g. based on the identification of BRCA mutations (16) .

SUMMARY
Women in childbearing age with diagnosed ovarian cancer should be tested for BRCA mutations and consulted by the oncologist.As 9-15% of patients who undergo fertilitysparing surgery ultimately relapse, hysterectomy and salpingo-oophorectomy should be suggested as soon as they consider their childbearing complete.Oncology consultation should be based on the available epidemiologic data as well as incidence and survival rates.The counseling should also be extended to cover the patient's female relatives, especially in the case of early-onset and confirmed BRCA mutationrelated ovarian cancer.