Abstract
We report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.
1. Case Presentation
A 25-year-old G3P0202 presented at 22w3d gestation for evaluation of a newly discovered retroperitoneal mass found during workup for abdominal pain. The patient had experienced one year of ongoing, worsening abdominal pain. She had a history of two prior preterm deliveries at 36 weeks gestation but otherwise was healthy with no chronic medical conditions.
Magnetic resonance imaging (MRI) evaluation revealed a 13 cm transverse by 8 cm anterior-posterior by 9 cm craniocaudal smoothly marginated mass inferior to the pancreas which encased the left renal vessels, displaced the inferior vena cava (IVC) anteriorly, and partially encased the abdominal aorta (Figure 1). A computerized tomography (CT) guided biopsy was unable to be performed due to the surrounding anatomy and gravid uterus; therefore, a laparoscopic biopsy was planned. CT of the chest was performed showing no evidence of metastatic disease. The patient was readmitted for planned laparoscopic biopsy at 27w2d gestation. She was given corticosteroids for fetal lung maturity prior to the procedure due to the increased risk of preterm birth. Continuous fetal monitoring was performed throughout the surgery and was noted to be reassuring for the gestational age.
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Histopathology from the retroperitoneal biopsy demonstrated high-grade spindle cells with areas of herringbone pattern and small round blue cells (Figure 2). Frequent mitoses were noted (8/HPF). Immunohistochemistry (IHC) revealed tumor cells to be CD56+, bcl-2+, weakly TLE1+, partially CD34+, and focally S100+. Cells were negative for pankeratin, CAM 5.2, EMA, CD99, SOX10, SMA, desmin, synaptophysin, SALL4, CD10, CD31, CD117, WT1, and estrogen receptor. Fluorescence in situ hybridization (FISH) was positive for SYT (SS18) gene rearrangement. While the IHC profile was not specific, the morphologic features and positive SYT rearrangement result were consistent with a diagnosis of poorly differentiated synovial sarcoma, clinically staged IIIB (T3N0M0).
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The case was discussed at a multidisciplinary sarcoma tumor board in consultation with Surgical Oncology, Medical Oncology, Radiology, Pathology, Teratology, and Maternal-Fetal Medicine with decision for neoadjuvant chemotherapy with doxorubicin and ifosfamide with modified dosing during the prepartum period as described in Mir et al [1]. The patient was admitted at 29w6d for cycle 1 of chemotherapy and at that time had a repeat baseline MRI which redemonstrated the now cm mass encasing right renal pelvis and aorta, displacing left renal vessels posteriorly and IVC anterolateral (Figure 1). She received doxorubicin (50 mg/m2 day 1) and ifosfamide (2.5 g/m2/day, days 1-2) with standard mesna rescue without notable maternal side effects or fetal complications. She continued to follow closely for prenatal care and serial fetal growth ultrasounds. The timing for delivery was determined through multidisciplinary discussion with neonatology, maternal-fetal medicine, and oncology. Fetal antenatal testing was overall reassuring with normal fetal growth; however, the amniotic fluid index (AFI) was found to be borderline low (5.9 cm, with maximum vertical pocket (MVP) of 2.3 cm) and decreased from an AFI of 15.3 cm with an MVP of 5.7 cm prior to cycle 1 of neoadjuvant chemotherapy. Further, the patient had a prior history of two spontaneous preterm deliveries at approximately 36 wks. There was therefore a concern that delaying delivery for a second cycle of chemotherapy could result in a spontaneous delivery close to the administration of the chemotherapeutic agents which theoretically would increase the risk of neonatal adverse effects. Given the above considerations, the decision was made to proceed with a scheduled induction of labor (IOL) 3 wks after cycle 1 of neoadjuvant chemotherapy and to proceed with the remaining cycles postpartum. She was given a second course of corticosteroids for fetal lung maturity prior to her IOL, and she then underwent an uncomplicated IOL resulting in a vaginal delivery of a 1870 g (32nd percentile) male neonate with APGAR scores of 8 and 9 at 1 and 5 minutes, respectively. The patient had an uncomplicated postpartum course and was discharged home. The neonate’s NICU course was complicated by mild respiratory distress syndrome requiring continuous positive airway pressure (CPAP) on admission which was weaned to room air by day of life (DOL) 7 as well as hyperbilirubinemia requiring 2 days of phototherapy. Otherwise, he had an uncomplicated NICU stay, was advanced to full PO feeds, monitored for temperature stability and adequate weight growth, and was discharged home on DOL 20 (corrected gestational age 36w0d).
The patient continued with neoadjuvant chemotherapy with cycle 2 beginning 1 week postpartum. She received doxorubicin (25 mg/m2/day, day 1-3) and ifosfamide (2.5 g/m2/day, day 1-4) with standard mesna rescue for the postpartum cycles. Restaging CT was performed following cycle 3 demonstrating marked decrease in the size of the retroperitoneal mass (Figure 1). She went on to complete three additional neoadjuvant chemotherapy cycles (6 total) without significant complication with restaging imaging again demonstrating substantial reduction in tumor size, then measuring cm in greatest dimension (Figure 1).
Following completion of neoadjuvant chemotherapy, she received neoadjuvant external beam radiation therapy consisting of 5750 cGy in 25 fractions, which was completed without significant complication. She then went on to undergo radical resection of the retroperitoneal tumor including en bloc resection of infrarenal IVC and aorta and portion of omentum with mm aortic reconstruction with tube graft and omental flap coverage of aortic prosthetic reconstruction. Her surgical recovery was unremarkable except for requirement of packed red blood cell transfusion twice for asymptomatic anemia with gm/dL on postoperative day numbers 3 and 7 with adequate response. She was discharged on postoperative day number 7 in good condition.
Pathology from the resection specimen demonstrated a 6 cm mass that on histologic evaluation exhibited marked treatment effect with only microscopic foci of residual synovial sarcoma in a background of necrosis, pigment deposition, histiocytic infiltrate, and inflammatory cells (Figure 2). The tumor focally invaded the soft tissue surrounding the proximal aortic resection margin with all other margins uninvolved by tumor.
Following resection of her sarcoma, the patient was followed with routine surveillance CT imaging including the chest, abdomen, and pelvis at 3-month intervals. Unfortunately, she developed an isolated pelvic recurrence 13-month postresection. As of this writing, she is undergoing salvage chemotherapy with neoadjuvant intent. Her 23-month-old son is healthy and has achieved appropriate developmental milestones.
2. Discussion
Synovial sarcomas (SS) are mesenchymal neoplasms that can occur throughout the body and account for 5-10% of all soft tissue sarcomas [2]. SS occur most common in the adolescent and young adult (AYA) age range with peak incidence in the third decade and hence can affect women of childbearing age. Presenting symptoms, particularly for retroperitoneal primary site locations, can often be vague and predate the diagnosis by years [2].
For nonmetastatic synovial sarcoma, surgery is the mainstay of therapy and only curative treatment. For higher risk tumors, traditionally defined by cm and high histologic grade, adjuvant or neoadjuvant therapy with radiation and/or systemic therapy is often considered for risk reduction of recurrence. Neoadjuvant treatment is increasingly utilized over adjuvant owing to the advantages of improved chance of conservative surgery as well as the ability to assess treatment response [3]. Regarding systemic therapy, synovial sarcoma is considered one of the most chemosensitive sarcoma subtypes and has among the strongest evidence for adjuvant/neoadjuvant chemotherapy use [4]. In the case described, even outside of the pregnancy considerations, there were strong indications for neoadjuvant chemotherapy given the high-risk features of the tumor and extensive visceral involvement complicating an initial surgical approach.
In review of the literature, there have been 13 previous cases on synovial sarcoma associated with pregnancy reported [5–18]. These patients, their treatment, and outcomes are summarized in Table 1. These cases occurred in various anatomical locations with two noted originating from soft tissue of the lower extremities, two from the oral cavity, three from the kidneys, one from the abdominal wall, and five from the chest. To our knowledge, ours is the first case reporting a synovial sarcoma originating in the retroperitoneum distinct from the renal structures during pregnancy. In only one of the previous reports was neoadjuvant chemotherapy administered antepartum.
For women diagnosed with malignancy during pregnancy, treatment decisions must balance optimal oncologic management with the interventional risks to both the mother and fetus. Regarding systemic chemotherapy, best available data suggests that the majority of agents evaluated do not appear to increase the risk of maternal or fetal complications when administered after the first trimester, nor appear to have long-term effects on children that were exposed in utero [19, 20]. Anthracycline-based chemotherapy combinations in particular have been fairly widely studied owing to their common use in the management of breast cancer and are considered relatively low risk for maternal and fetal complications [21]. Specific to sarcoma, prior literature regarding the use of neoadjuvant anthracycline plus ifosfamide chemotherapy is limited to one small series, suggesting this approach to be feasible and safe [1].
Systemic chemotherapy is often considered for treatment of malignancy in pregnancy, especially during the second and third trimesters after organogenesis is completed [22]. However, there are still risks of obstetric complications despite the completion of the majority of organogenesis including preterm delivery, fetal growth restriction, and intrauterine fetal demise [22]. While fetal growth restriction has been demonstrated in cases of malignancy in pregnancy, data are limited in suggesting whether the cause is related to toxicity of the systemic cytotoxic treatment or simply the pathophysiology of the disease itself. Van Calsteren et al. demonstrated higher rates of small for gestational age neonates in patients receiving cytotoxic treatment compared to those without (20.4 vs. 9.2%) [23]; however, Cardonick did not show increased rates of fetal growth restriction with cytotoxic treatment in their cohorts (7.6 vs. 7.1%) [24]. Data regarding ifosfamide use in pregnancy is particularly limited; however, Mir et al.’s review of ifosfamide use in pregnancy noted oligohydramnios in 5 of the 11 patients given this drug at various doses [1], suggesting this as a potential fetal toxicity and is notable in light of the borderline low AFI observed in our case that developed post-ifosfamide therapy. Among the cases of synovial sarcoma in pregnancy, two experienced fetal growth restriction [6, 9], and one was delivered for oligohydramnios with nonreassuring fetal monitoring [11]. These constellations of findings emphasize the importance of frequent fetal monitoring during treatment in order to detect potential obstetrical complications and modify delivery planning as indicated.
In summary, we report a unique case of a large, borderline resectable retroperitoneal synovial sarcoma presenting in a pregnant woman in the second trimester. This case highlights the need for multidisciplinary management in this high-risk scenario and argues for an aggressive treatment approach including administration of systemic chemotherapy in the antepartum setting to achieve optimal oncologic and maternal-fetal outcomes. This case, along with previous small series, suggests the potential for decreased amniotic fluid volumes associated with the use of ifosfamide, and therefore, frequent fetal monitoring in this scenario is recommended.
Consent
Consent for publication of the case was provided by the patient.
Conflicts of Interest
All authors declare no competing interests related to this report.