Case Conference April 4th 2018

04-Apr-2018, Divisi Ginekologi Onkologi RSCM

 

CASE CONFERENCE

 

April 5th, 2018

 

Mrs D, 28 yo, 427-14-34

 

Ovarian cyst in pregnancy

 

 

 

Case Description

 

Patient visited Hasanah Graha Afiah Hospital to do regular antenatal care. Found fetus intrauterine and adnexal mass, suspected malignant ovarian cyst. She then referred to Fetomaternal, to confirm the mass and the pregnancy. Then she referred to Oncogynaecology Division of RSCM. Physical examination found fundal height 3 fingers above symphisis. Ultrasound examination, found fetus with positive FHB, CRL correspond to 14 weeks; left ovary with cystic mass Ø 6 cm (contain papillary growth with neovascularization).

 

This is first pregnancy, has been married for 6 months. LMP 25 November 2017. No history of medical illness. She has no complain before about the mass.

 

 

 

Physical Examination on April, 2nd 2018

 

General status:

 

CM. BP: 100/70 mmHg, HR: 82 x/min, T: 36.8°C, RR: 18 x/min, weight: 50 kgs, height 160 cm.

 

Head                : pale conjunctiva (-/-) icteric sclera (-/-)

 

Thorax             : symmetry shape and movement of hemithorax

 

Lung                : vesicular breath sound on both lungs, neither wheezing nor rhales

 

Cardia              : no murmur, no gallop

 

Extremity         : warm, no oedema

 

Obstetric status:

 

Abdomen         : fundal height as high as navel

 

Inspection        : vulva normal

 

 

 

Work Up

 

Laboratory Result, RSCM, February 28th, 2018:

 

CBC                             : 10.6/33.5/6990/288000

 

PT                    : 9.7 (11.0)                               APTT               : 31.1 (31.1)

 

SGOT/PT         : 19/11                                     Blood Glucose : 89

 

Albumin          : 4.26

 

Ur/Cr               : 23/0.60        

 

Na/K/Cl           : 140/4.44/102.2

 

CA 125                        : 59.1

 

 

 

US FM, RSCM, March 6th 2018

 

Description: uterus shaped was normal, size was enlarge with uterine cavity contained a gestational sac, fetal echo (+). CRL: 83 mm, fetal heart beat: 157 bpm, appropriate to 14 weeks gestational age. Normal embryo morphology and activity. Endocervix and portio were normal.

 

Right ovary was normal.

 

Left ovary was enlarge, contain cyst mass with homogeneous echointerna. The mass sized 61x50 mm, contain precipitate and papillary growth (neovascularization +). The mass derived from neoplasm.

 

Conclusion: Intrauterine pregnancy, correspond to 14 weeks gestational age. Embryo was normal. Neoplasm with papillary growth of the left ovary, suspicious malignancy (clear cell carcinoma?)

 

 

 

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IOTA Adnex Score : Risk of Malignancy 13.5%

 

                                 Chance of Benign Tumor 86.5%

 

                                   

 

 

 

US FM, April, 3rd 2018

 

 

 

Fetal biometry ~ 18 wga, the left ovary was enlarged, contain cyst mass with homogenous echointern material. The mass sized 67 mm, containing papillary deposits and growth containing neovascular. The mass derived from neoplasm

 

Conclusion: pregnancy matched with 18 weeks gestasional age, with normal fetal activity. Cyst neoplasm with papillary growth of the left ovary, suspicious malignancy (clear cell carcinoma?)

 

 

 

 

 

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Introduction

 

The advent of ultrasound use in early pregnancy for assessing fetal viability, growth and anomalies, have been an important advance in obstetric care. It has, however, resulted in increased detection of ovarian masses, which previously would not have been clinically apparent. Most ovarian masses in early pregnancy are physiological and resolve spontaneously, but some persist and the management of such cysts is variable. Masses persisting after the first trimester or found during the second trimester are generally excised to prevent torsion or rupture during pregnancy or possible obstruction during labour, and to exclude malignancy. The incidence of adnexal masses during pregnancy is estimated to be 0.2-2% depending on the stage of pregnancy. With a 1-6% malignancy rate, the vast majority of these masses are benign.

 

Most ovarian masses in early pregnancy are physiological and resolve spontaneously, but some persist and the management of such cysts is variable. Masses persisting after the first trimester or found during the second trimester are generally excised to prevent torsion or rupture during pregnancy or possible obstruction during labour, and to exclude malignancy The risk of ovarian malignancy is rare in pregnancy, with a reported incidence between one in 12,000 and 47,000. Nevertheless it is the second most common gynaecological malignancy in pregnancy.

 

 

 

Problem to be discussed

 

1.    Timing to do surgery of adnexal masses during pregnancy

 

2.    Need of frozen section in the surgery of adnexal masses during pregnancy

 

3.    Chemotherapy during pregnancy

 

 

 

Discussion

 

1.    Treatment guidelines of adnexal masses during pregnancy.

 

Ovarian enlargement less than 6 cm diameter is usually due to corpus luteum formation. Resection of all suspected cysts at risk of rupture or undergoing torsion is recommended. Cysts measuring 10 cm in diameter should be resected due to increased risk of cancer in the large cysts, while cysts less than 5 cm could be left alone, and indeed, most undergo spontaneous resolution. Management of cysts between 5 and 10 cm in diameter remains controversial. Some clinicians recommend that these cysts be managed expectantly if they have cystic appearance. Others believe that if they contain septae, nodules, papillary excrescences, or solid component, resection is recommended. Surgical management is encouraged when there is concern that the persistent or larger ovarian mass will place the patient at higher risk for an acute abdomen, ovarian torsion, or rupture. Up to 10% of persistent complex ovarian masses will ultimately be diagnosed as malignancy, implying that observation may not be appropriate. Where cancer of the ovary is found, treatment should be individualized and consideration should be given to the type and stage of the cancer, women desire to continue with the pregnancy, and the risk of modifying or delaying treatment.

 

Patients with asymptomatic cysts over five centimetres or with a less reassuring appearance must be reviewed after 16 weeks of pregnancy. If these cysts are persistent, further follow-up is advised to determine the need for surgical exploration.

 

The optimal time for semi-elective surgery during pregnancy is after the first trimester for a number of reasons:

 

-       Almost all functional cysts will have resolved by this time.

 

-       Organogenesis is mostly complete, thus minimizing the risk of drug-induced teratogenesis.

 

-       The hormonal function of the corpus luteum has been replaced by the placenta, so reduction in progesterone secretion from oophorectomy or cystectomy does not result in loss of the pregnancy if not replaced.

 

-       Spontaneous pregnancy losses due to intrinsic fetal abnormalities are likely to have already occurred and will not be erroneously attributed to the surgery.

 

 

 

Data regarding timing of surgery were not available for one study. For the remaining studies with 70 patients, surgery was performed in T1 in 17 (24.2%), T2 in 19 (27.1%), T3 or at caesarean in 20 (28.5%) and postpartum in 14 (20%) cases.

 

 

 

 

 

2.    Need of frozen section in the surgery of adnexal masses during pregnancy

 

The ideal procedure for a suspicious adnexal mass during pregnancy is peritoneal cytology and unilateral salpingo-oophorectomy of the affected side with frozen- section analysis. Results of the frozen section should guide further surgical management.  For invasive epithelial ovarian carcinoma, grade I and diagnosed at FIGO stage Ia, fertility- and pregnancy preserving management can also be performed. Restaging after delivery may be considered because of occult extra-ovarian disease, which may not be assessed adequately during pregnancy. Non-epithelial tumours (germ-cell and sex-cord stromal tumours), which frequently present as bulky masses, are over 90% diagnosed at FIGO stage Ia and therefore are also treated by a resection and surgical staging. For high- grade stage I and any stage II disease, standard adjuvant chemotherapy (carboplatin-paclitaxel) can be considered. When there is a high probability of advanced stage ovarian cancer, further imaging besides ultrasound is required to evaluate the stage. The use of MRI after the first trimester is considered safe and allows accurate evaluation of the mass and its possible spread. the performance of complete cytoreductive surgery for advanced stage invasive (FIGO stage III) ovarian cancer is not possible during pregnancy. In most reported cases of ad-vanced invasive disease, patients chose to terminate pregnancy when diagnosis has been made early in the first trimester of pregnancy. When the patient wants to proceed the pregnancy, neoadjuvant chemotherapy (carboplatin and paclitaxel) until fetal maturity and complete cytoreductive surgery after delivery is recommended from midpregnancy onwards.

 

 

 

 

 

 

 

 

 

3.        Chemotherapy during pregnancy

 

Concerns about the administration of cytotoxic chemotherapy during pregnancy arise because chemotherapy preferentially kills rapidly proliferating cells, and the fetus represents a rapidly proliferating cell mass. All chemotherapy agents used in the treatment of epithelial and nonepithelial ovarian cancers are pregnancy category D, meaning that fetal exposure to individual chemotherapeutic agents have resulted in adverse effects including intrauterine growth restriction, prematurity, and low birth weight in the infants. Chemotherapy may also cause fetal toxicities similar to those observed in the mother (eg, bone marrow suppression).

 

The risks of spontaneous abortion, fetal death, and major malformations vary depending on the agent used and the trimester of pregnancy. These risks must be weighed against the benefits of immediate versus delayed (ie, postdelivery) chemotherapy for the mother. Ethical considerations of treatment during pregnancy have emphasized the role of patient autonomy and the concept of beneficence and nonmaleficence for both the mother and fetus.

 

Although previous data suggested that the administration of chemotherapy increased the risk of fetal malformations, most data suggest this is not the case. It is now believed that the impact of chemotherapy during pregnancy is predominantly dependent on when treatment is administered:

 

-       During the first four weeks of gestation (first two weeks post conception) the embryo is undifferentiated. Fetal exposure to cytotoxic agents at this point results in "all or none" phenomena: either the pregnancy is lost or it continues with no apparent adverse effect.

 

-       Organogenesis occurs during weeks 5 to 10 weeks of gestation. The administration of cytotoxic drugs, particularly antimetabolites (eg, fluorouracil and methotrexate) and alkylating agents (eg, busulfanchlorambucilcyclophosphamide), during this period carries an increased risk of fetal malformations. In a review of the literature, rates of adverse pregnancy outcomes (APOs) for anti-neoplastic agents in single and combination therapy were 33, 27, and 25 percent for the first, second, and third trimesters. Rates of congenital malformations (included in the APOs) were 16, 8, and 6 percent for the first, second, and third trimesters. The majority of stillborn infants and infants with chromosomal or congenital abnormalities occur when chemotherapy is administered in the first trimester.

 

-       When chemotherapy is delivered to the mother during the second and third trimesters of pregnancy, the risk of fetal malformation is lower. First trimester exposure poses a larger and more permanent risk to the fetus. Administration of chemotherapy within three weeks of anticipated delivery or beyond 35 weeks of gestation may induce neonatal myelosuppression and complicate delivery due to adverse effects of treatment on bone marrow reserves. This includes potential complications such as bleeding, sepsis, and death. Additionally, neonatal toxicity may be higher if chemotherapy is administered peripartum because placental drug clearance is generally more effective than either hepatic and/or renal drug clearance in the neonate

 

-       In practice, it is possible to administer chemotherapy from 14 weeks gestational age onwards with specific attention to prenatal care. To allow the bone marrow to recover and to minimize the risk of maternal and fetal sepsis and hemorrhage, delivery should be planned at least 3 weeks after the last cycle of chemotherapy, and chemotherapy should not be given after 35 weeks since spontaneous labor becomes more probable.

 

 

 

 

 

EPITHELIAL OVARIAN CANCER

 

Indications — Following surgery, the indications for adjuvant treatment of epithelial ovarian cancer (EOC) are similar for pregnant and nonpregnant women. However, administration of chemotherapy during the first trimester should be avoided. Some experts recommend chemotherapy for:

 

-       Women with early-stage EOC if any of the following high-risk features is present: stage IA/IB, grade 2/3; stage IC or II (any histology); serous or clear cell carcinoma (stage IA, IB, IC, or II)

 

-       Women with stage III or IV EOC

 

Regimen — As with nonpregnant women, recommend the use of a platinum drug plus taxane for women with EOC in pregnancy because, in general, this combination results in the best survival outcomes. For women diagnosed during pregnancy, prefer carboplatin to cisplatin because it is a better tolerated agent and reduces the risk of long-term side effects (eg, renal and neurotoxicity). Although there are few data to guide the use of taxanes in pregnancy, it has been used to treat breast cancer in pregnancy without apparent adverse events. Some experts prefer paclitaxel rather than docetaxel because it is generally less myelotoxic. In the absence of data on the use of bevacizumab, some experts recommend not using it in pregnancy.

 

All women with EOC in pregnancy should be informed of the limited data on maternal and fetal outcomes associated with treatment. In one of the largest cohort studies of pregnant women with all types of cancer treated at multiple institutions, 84 were exposed to taxanes and 74 were exposed to platinum-based chemotherapy. Both drugs were associated with an increased risk of delivery of a small for gestational age infant: platinum odds ratio (OR) 3.12, 95% CI 1.45-6.70 and taxanes OR 2.07, 95% CI 1.11-3.86. However, it was not possible to determine whether these findings were related to in-utero drug exposure or to other factors, such as effects of other medications, maternal stress, lack of adequate gestational weight gain, and other prenatal factors.

 

Administration — Patients can be treated with single agent carboplatin or a combination of carboplatin and a taxane. A decision should be made on an individual basis taking into account potential risks and benefits of treatment.

 

 

 

 

 

Timing of chemotherapy

 

Early-stage disease — For pregnant women with high-risk, early-stage EOC, suggest initiation of chemotherapy following completion of the first trimester. The approach is similar to the treatment of nonpregnant women with early-stage EOC. For women who prefer not to receive treatment during pregnancy due to concerns for fetal safety, it may be reasonable to delay adjuvant chemotherapy until after delivery. The evidence to support this comes from two studies that evaluated the impact of a treatment start delay. In these trials, 271 nonpregnant women with high-risk stage I EOC were randomly assigned treatment with adjuvant cisplatin versus observation (trial 1) or P-32 (trial 2). In both trials, women who were not treated with cisplatin received cisplatin at the time of relapse. The main results were:

 

-       Administration of cisplatin reduced the risk of relapse in both trials (compared with observation, hazard ratio [HR] 0.35, 95% CI 0.14-0.89; compared with P-32, HR 0.39, 95% CI 0.19-0.77).

 

-       There was no difference in five year overall survival (88 and 82 percent with cisplatin or observation; HR 1.15, 95% CI 0.44-2.98; 81 and 79 percent with cisplatin or P-32; HR 0.72, 95% CI 0.72, 95% CI 0.37-1.43).

 

Advanced-stage disease — Women with advanced disease should begin chemotherapy as soon as they are out of the first trimester and have recovered from surgery. We generally prefer to initiate treatment in two to four weeks after surgery for ovarian cancer. The approach to treatment is similar to that for nonpregnant women with advanced EOC. Although dose-dense (weekly) paclitaxel has been reported to improve progression-free survival, other groups have been unable to duplicate these data.

 

 

 

GERM CELL TUMORS — Most germ cell ovarian malignancies occur in young women and are limited to one ovary. Maximal surgical cytoreduction is usually undertaken initially. Despite being diagnosed at a relatively early stage, recommend adjuvant chemotherapy for most women with completely resected malignant ovarian germ cell tumors except those with stage IA dysgerminoma or stage I grade one immature teratoma. When indicated, chemotherapy should be delayed at least until completion of the first trimester of pregnancy. The most commonly used regimen is bleomycinetoposide, and cisplatin (BEP). In other series, use of etoposide during pregnancy has been associated with growth restriction and neonatal bone marrow suppression. Etoposide is teratogenic in mice and rats at doses much lower than the human dose and should not be used in the first trimester. A consensus report suggested paclitaxel-carboplatin or cisplatin-vinblastine-bleomycin as alternatives to BEP in pregnancy.

 

Timing of chemotherapy — Given that germ cell neoplasms are exquisitely sensitive to platinum-based chemotherapy, several investigators have published case reports addressing a treatment delay until after the completion of the pregnancy.

 

 

 

Conclusion

 

1.        For this case, should be accurately evaluate to decide the most appropriate treatment option. Ultrasound and MRI are safe and allow distinguishing between benign and malignant lesions. A wait-and-see strategy is advised for an ovarian cyst with benign features. Masses with septa, solid components, papillae or nodules, or when persisting after 16 weeks of pregnancy should be further investigated.

 

2.        Treatment options including surgical procedures should be discussed for this patient individually. Both open surgery and laparoscopy can be performed considering the tumour diameter, gestational age and surgical expertise.

 

3.        When advanced stage invasive ovarian cancer is diagnosed, termination of pregnancy may be considered in early pregnancy, other- wise chemotherapy can be administered during second and third trimester. When there is high sus- picion of malignancy, a multidisciplinary approach is necessary, and preferably patients should be referred to centres with specialized experience.

 

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