Rapid Fatal Progression of Cervical Cancer during Pregnancy Treated by Neoadjuvant Chemotherapy

C l i n M e d International Library Citation: Naoura I, Selleret L, Selle F, Daraï E (2016) Rapid Fatal Progression of Cervical Cancer during Pregnancy Treated by Neoadjuvant Chemotherapy. Int J Cancer Clin Res 3:060 Received: April 27, 2016: Accepted: June 27, 2016: Published: June 29, 2016 Copyright: © 2016 Naoura I, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Naoura et al. Int J Cancer Clin Res 2016, 3:060


Case
A 30-year-old woman, gravida 1 para 0, was referred to the expert centre of pregnancy associated cancers (CALG) at Tenon Hospital for a cervical cancer diagnosed at 19 weeks of pregnancy.The Papanicolaou (Pap) smear test carried out at the first prenatal visit because of vaginal bleeding was negative although only endocervical cells were detected.Hence, vaginal bleeding during the first trimester of pregnancy was attributed to cervical ectropion.
At the visit corresponding to the 19 th week of gestation, the physician diagnosed an exophytic cervical lesion measuring at least 4 cm without invasion of parametrium corresponding to IB2 FIGO stage.A cervical biopsy was performed and histology revealed an undifferentiated squamous cell carcinoma.Immunohistochemistry showed that cervical lesion was positive for p16 and p63 protein as well as for KL1 and CD 5/6 cytokeratin confirming the diagnosis of squamous cell carcinoma.No chromogranin, CD 56 neither synaptophysin expression was observed ruling out the neuroendocrine origin.

Introduction
Cervical cancer is the first gynaecological cancer diagnosed during pregnancy [1] but most cases (70%) are diagnosed at an early stage thanks to routine cervical screening in prenatal care.
Abnormal cervical cytology is encountered in around 5% of pregnant women whereas invasive cervical cancer affects only 1 to 2 women among 10 000 pregnancies [2,3].Some authors report that maternal outcome is not worsened by pregnancy in particular for squamous cell types [2,4].

ISSN: 2378-3419
Naoura et al.Int J Cancer Clin Res 2016, 3:060 intra-uterine growth restriction.After two cycles of chemotherapy, physical examination found an increase in tumour size confirmed by MRI showing a tumour of 8 cm of diameter with bilateral ureteral dilatation (Figure 2).In this context, preterm birth by caesarean section was organized at 29 weeks of gestation after foetal lung maturation (bethamethasone, 12 mg per day during 2 days).The infant girl weighed 1525 grams and had an Apgar score of 10 at 1 minute which decreased to 2 at 5 minutes justifying intubation for respiratory assistance.She remained in the hospital intensive care unit until she was 27 weeks old.Today the child is 4 months old and healthy.PET-FDG performed on the mother during the early postpartum period revealed a suspicious pelvic node but no uptake in the paraaortic areas.An extraperitoneal para-aortic lymphadenectomy was performed 2 weeks after the caesarean section and histology revealed metastases in 6 of the 16 lymph nodes.Exclusive concomitant radiochemotherapy was consequently recommended (external beam radiotherapy: 45 Grays on the pelvis and a complement of 10 Grays on each iliac site associated with Cisplatin 30 mg/m² weekly during 2 weeks then Topotecan, 4 mg/m², one cycle).
However, despite treatment, the patient developed intraperitoneal carcinomatosis with ascites, hydrodronephrosis and pulmonary embolism 11 weeks after the birth.The patient died of tumor progression 5 months after the initial diagnosis and 11 weeks after giving birth.

Discussion
Several studies have reported that pregnancy does not affect prognosis or survival of patients with early stages of cervical cancer justifying postponing treatment until after delivery [5][6][7].However, this case report suggests that neoadjuvant chemotherapy administered during pregnancy is not always effective and can affect thus the prognosis compared to non pregnant patient.For pregnant patients with a tumour stage greater than IB1, guidelines for treatment differ from country to country [1,8] (Figure 3).The trimester during which the cancer is diagnosed and lymph node status are essential to determine therapeutic strategy.In the case reported here, two major arguments justified the decision to delay surgical lymph node staging: MRI did not show any suspicious lymph nodes; the pregnancy was in the 2 nd trimester and the uterus was enlarged with numerous leiomyomas which may have compromised the feasibility of laparoscopic lymphadenectomy and increased maternal and foetal morbidities.
While a couple is more likely to accept termination of pregnancy when the cancer is diagnosed during the 1 st trimester, physicians accept to delay treatment if the cancer is diagnosed during the last trimester [9].However, when the cancer is diagnosed in the 2 nd trimester, as in our case, the situation is less clear-cut and several ethical issues arise.Lymph node status assessment may help to make a decision but PET-FDG and MRI with gadolinium are not recommended during pregnancy.Although some authors have suggested that the 6mSv dose exposure delivered during PET-FDG exam at the 2 nd trimester is acceptable for foetus [8], animal studies have demonstrated that foetal elimination of fluorine-18-labelled fluorodeoxyglucose is long [1,10].MRI could be useful in evaluating tumour response to chemotherapy but it lacks accuracy in detecting lymph node metastasis [11].Finally, the main challenge is evaluating the feasibility of para-aortic lymphadenectomy when the couple is not sure about preserving or terminating the pregnancy.In this specific setting, Alouini et al. reported good pregnancy outcome after para-aortic lymphadenectomy [11].For patients with positive lymph nodes, termination of the pregnancy is mandatory as the optimal therapeutic option is concomitant radio-chemotherapy that is lethal for the foetus [12].However, when the lymph nodes are negative, neoadjuvant chemotherapy is an option to reach foetal maturity.French recommendations accept to postpone optimal treatment for 6 to 8 weeks after diagnosis when the pregnancy term is over 22 weeks of gestation [13].However, in the present case report, the couple's decision was clear in opting for conservative treatment which explains why no paraaortic lymphadenectomy was proposed.
Another major issue is how to evaluate whether the cervical tumour is chemosensitive.
Classic squamous cell type, especially undifferentiated as in the current case report, is more likely to respond to chemotherapy.Several cases of neoadjuvant chemotherapy for advanced stage cervical cancer during pregnancy with good outcome have been published [1,[14][15][16].However, there might be a publication bias leading to an overestimation of the safety and efficacy of chemotherapy for cervical cancer during pregnancy.In a review of 13 cases of stage IB2 cervical cancer diagnosed during pregnancy and treated with neoadjuvant chemotherapy, Morice et al. reported a recurrence rate of 54% [16].
It is impossible to know if the outcome of our patient would have been better if the pregnancy had been terminated at diagnosis.This underlines the need to identify additional predictive factors such as Ki-67, p53, p16, CK7 expression [17].However, the fact that the tumour failed to respond to radio-chemotherapy after the birth and that there was rapid progression with development of peritoneal carcinomatosis, would suggest chemoresistance of the tumour.
Finally, the present case report underlines the risk of misinterpretation of Pap smear during pregnancy due to anatomic cervical transformation.In the present case report, the absence of squamous cell should have motived the physician to repeat cervical screening either by performing a Pap test ensuring that junction cells were collected or performing a colposcopy.
Pap smear currently has a sensitivity for detecting high-grade cervical neoplasia in non-pregnant patients in 70% to 80% [18].In a study including 1593 pregnant compared to 214 375 non-pregnant patients, accuracy of Pap smear was not different between the population (27.6% for non-pregnant vs. 45% for pregnant patient) even there were more an overestimation of abnormal test during pregnancy [19].This could be explained by large ectropion, frequent inflammation, presence of confusing decidual cells during pregnancy that could mimicked atypia.In the current case, the patient had effectively an ectropion and Pap smear did not note the presence of glandular cells.This underlines quality criteria of Pap smear imposing detecting both the presence of glandular and squamous cells.
The current case report highlights that, although neoadjuvant chemotherapy is an option to treat cervical cancer during pregnancy, chemotherapy is not always effective and maternal outcome could potentially be compromised.There is hence a need to identify predictive factors of chemo-sensitivity of cervical cancer to better select patients that could benefit from this therapeutic strategy.

Figure 1 :
Figure 1: At 19 weeks of pregnancy, magnetic resonance imaging detected a cervical cancer lesion of 65mm exhibiting an extension to internal os of the cervix corresponding to IB2 FIGO stage.

Figure 2 :
Figure 2: Magnetic resonance imaging: cancer progression after neoadjuvant chemotherapy at 29 weeks of pregnancy with a cervical lesion of 8 cm.

Figure 3 :
Figure 3: Management of cervical cancer during pregnancy.