Mrs X

Clear Cell Ovarian Carcinoma post Right Cystectomy in Pregnancy

Case Discription

Patient came for her antenatal visit with no complain on her pregnancy. The last menstrual period September 28 September 2016. She had positive pregnancy test November 2^nd, 2016. Patient underwent cystectomy 5 months ago at hermina hospital depok with PA result of endometriosis on the right ovary with suspected clear cell ovarian carcinoma foci. Review on pathologic result showed clear cell carcinoma and endometriosis, as well as IHC result right ovarian cyst.

Physical Exam February 2^nd, 2017

CM. BP: 110/75 HR 84 bpm, RR 20x/m,  T:36,2 C

General status:

Good appearence, compos mentis

No lymph nodes palpable

Abdomen:  supple, Fundal height at navel, FHR 168 bpm

Gynecology status:

Inspection: no vaginal bleeding, vulva & external urethral orifice were normal

Inspekulo: smooth portio, smooth vaginal wall, no fluor albus,

PA Result August 19^th, 2016

Macroscopic

received 1 piece of tissue, with a right ovarian cyst information, such as tissue, the cyst wall has been split, size 2,5x1,5x1,2 cm, wall thickness 0,5 cm, chewy chocolate, all printed one cassette

Microscopic

preparations derived from right ovarian cysts, shows the cyst wall consists of a tissue fibrovaskuler, most seemed coated piston epithelial layer, showing atypical nucleus and most erosive, stroma containing hemosiderofag. Focus stroma was found to contain glands, lined epithelium partially overlap with the core pleomorphic, hyperchromatic, eosinophilic cytoplasm, mostly clear, desmoplastik stroma, surrounding stroma inflammatory cells and looked hemosiderofag.

Conclusion:

Histology according to endometriosis cyst with focus suspected clear cell carcinoma.

METHODS

Search strategy

The search was conducted on Pubmed, Science Direct, and Uptodate  on February 6^th 2017, using the search tool containing the keyword “clear cell ovarian carcinoma in pregnancy” (Table 1). Search results were filtered by the engine according to the following criteria : articles published in the past 10 year, human species, and English language.

Discussion

A gynecologic malignancy is estimated to complicate four to eight of every 100,000 pregnancies. Unfortunately, the data on the effects of antineoplastic drugs administered during pregnancy have largely been derived from case reports, small case series, and collected reviews of pregnant women treated for a variety of cancers. There are even less data on long-term outcomes in offspring.

The finding of early-stage epithelial ovarian cancer (EOC) is occasionally made during surgery for an emergent (eg, torsion) or benign (ie, ovarian cystectomy) indication. In these cases, women will not have undergone surgical staging and technically speaking would be considered to have apparent early but unstaged ovarian cancer. For women with unstaged apparent early EOC, we suggest staging because both prognosis and adjuvant treatment options are tied to disease stage. Often this surgery can be performed through a minimally invasive approach. Alternatively, some evidence suggests that surgery may not be required if adjuvant chemotherapy is administered:

·         As described above, the Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) trial of adjuvant chemotherapy versus observation highlighted the importance of complete surgical staging in patients with early stage EOC. In this trial, the benefit of adjuvant chemotherapy was limited to patients with incomplete staging:

·         For the 297 women who were not completely staged, adjuvant chemotherapy was associated with significant improvement in recurrence-free survival (Hazard Ratio [HR] 1.78, 95% CI 1.15-2.77) and overall survival (HR 1.75, 95% CI 1.04-2.95) compared with observation.

·         For the 224 women enrolled in to the observation arm, complete staging was associated with a significant improvement in recurrence-free (HR 1.82, 95% CI 1.02-3.24) and overall survival (HR 2.31, 95% CI 1.08-4.96) over incomplete staging.

·         For the 151 women who were completely staged, chemotherapy was not associated with a recurrence-free or overall survival advantage over observation.

·         In a retrospective study of 88 patients with early stage ovarian cancer (36 unstaged), all of whom received adjuvant chemotherapy, there was no difference in outcomes among women who underwent staging after a diagnosis of EOC and those who did not undergo a second surgery for staging. The estimated rates of five-year progression free survival were 85 and 80 percent, respectively, with corresponding rates of overall survival of 85 and 88 percent.

·         In a separate series of 138 patients with tumor confined to the ovary, 53 underwent adjuvant chemotherapy (34 after staging, 19 without staging performed). The relapse rate at a median follow-up of 58 months was 32 percent among staged patients and 42 percent among unstaged patients.

While these underpowered studies suggest that it might be safe to omit formal surgical staging after a woman has been diagnosed with apparent EOC, prospective studies are needed to confirm this finding before incorporating this into standard practice. For women who choose not to undergo formal surgical staging, we recommend adjuvant chemotherapy. With grade 3 or clear cell tumors, where chemotherapy will be administered regardless of staging outcome, there may be less impetus for a secondary procedure.

There are several different histologic types of malignancy that can arise within the ovary including epithelial ovarian cancer (EOC), ovarian germ cell tumors, and sex-cord stromal tumors. In some series of women presenting with an ovarian malignancy while pregnant, germ cell tumors predominate, while others report a higher frequency of EOC.

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, 5-fluorouracil and methotrexate) and alkylating agents (eg, busulfan, chlorambucil, cyclophosphamide), 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

Following surgery, the indications for adjuvant treatment of epithelial ovarian cancer (EOC) are similar for pregnant and non-pregnant women. However, administration of chemotherapy during the first trimester should be avoided. We 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

As with non-pregnant women, we recommend the use of a platinum drug (with or without a taxane) for women with EOC in pregnancy because, in general, this combination results in the best survival outcomes. For women diagnosed during pregnancy, we prefer carboplatin to cisplatin because it is a better tolerated agent. There are little data to guide the use of taxanes in pregnancy, although it has also been used to treat breast cancer in pregnancy without apparent adverse events. However, if a taxane is administered, we prefer paclitaxel rather than docetaxel because it is less myelotoxic in general.

All women with EOC in pregnancy should be informed of the limited data on maternal and fetal outcomes associated with treatment.

Clear cell carcinomas are associated with poorer responses to platinum-based chemotherapy compared with serous adenocarcinomas. This was shown in one retrospective study that reported on the outcomes of women with a clear cell carcinoma (n = 101) versus serous carcinomas (n = 235). Compared with women with serous carcinomas, clear cell carcinomas were associated with:

·         A significantly lower response rate to platinum-based therapy (11 versus 72.5 percent).

·         Lower duration of overall survival in those patients with stage I/II (31.8 versus 42.3 months), or stage III disease (12.7 versus 26.8 months), although it was only significant for patients with stage III disease. However, overall survival was similar among patients who presented with stage IV disease (17.8 versus 19.4 months).

Because of the relatively poor prognosis for patients with a clear cell ovarian cancer, we prefer treatment on a clinical trial exploring alternative or novel agents.

Conclusion

Based on the reviewed article patient should be observed until birth and and start chemotheraphy after ward. If there is fact of new development of mass, the recommendation in favof of platinum-based chemotherapy during pregnancy compare to waiting until after delivery.