The ABC Cafe: Adult Bone Cancer Survivors Support Forum

The Sept. issue (2008) of Pediatric Oncology/Hematology published an interesting "case review" paper: "Late Recurrence of Ewing Sarcoma During Pregnancy: A Report of 2 Cases" by DuBois, Steven G. MD*; Perez-Atayde, Antonio R. MD†; McLean, Thomas W. MD‡; Grier, Holcombe E. MD§ from
*Department of Pediatrics, University of California, San Francisco, CA
†Department of Pathology, Children's Hospital
§Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA
‡Department of Pediatric Hematology/Oncology, Wake Forest University School of Medicine, Winston-Salem, NC

From the Abstract: "We report 2 patients with a history of Ewing sarcoma who were diagnosed with recurrent tumor during or immediately after pregnancy. To determine whether the hormonal milieu of pregnancy might have contributed to recurrence, we performed immunohistochemistry for estrogen and progesterone receptors on available tumor tissue. These receptors were not detected by immunohistochemistry. Increased medical surveillance during pregnancy may have resulted in ascertainment of recurrence in these 2 patients."

Here are the case histories of both female patients:
Patient 1:
"Patient 1 was a 9-year-old girl when she presented with hip pain and a palpable thigh mass. Imaging revealed a large mass centered at the right ischium. Biopsy of the mass demonstrated Ewing sarcoma. Metastatic evaluation showed multiple bilateral pulmonary metastases. She received vincristine, actinomycin, and cyclophosphamide every 3 to 4 weeks for a total of 24 months. After 4 months of therapy, her chest radiograph and pelvic ultrasound were both normal. At that time, she started radiation therapy and received 5620 cGy to the right pelvis. The patient remained free of disease until approximately 9.3 years from the initial diagnosis when she developed enlarging soft tissue masses on her arms and thighs during the third trimester of her first pregnancy. Imaging at that time demonstrated 2 pulmonary nodules, a soft tissue mass on the anterior abdominal wall, and a hemorrhagic lesion in the left frontal lobe. The baby was delivered by caesarian section. Immediately after the successful delivery of the baby, the maternal left frontal lobe lesion was resected. The frontal lobe lesion showed Ewing sarcoma by histopathology. Molecular confirmation was not performed. The placental pathology was normal. The patient received cranial radiation and chemotherapy with vincristine, doxorubicin, and cyclophosphamide for approximately 8 months. Shortly after completing chemotherapy, the soft tissue masses on her thighs recurred. No further follow-up is available."
Patient 2:
"Patient 2 was a 15-year-old girl when she presented with chest pain and fever. She was found to have a mass arising from the left 11th rib. The rib and soft tissue mass were resected, but residual tumor remained. Pathologic diagnosis was Ewing sarcoma. Metastatic evaluation was negative. She received 24 months of vincristine, actinomycin, and cyclophosphamide given every 3 weeks. She also received 5200 cGy radiation to the area of initial tumor involvement. Approximately 5.7 years from initial diagnosis, the patient developed new chest pain 2 days after the uncomplicated delivery of her first child. Imaging revealed a mass involving the hilum of the right lung. Biopsy showed Ewing sarcoma by histopathology without molecular confirmation. Metastatic evaluation was again negative. She received 3 months of vincristine, doxorubicin, and cyclophosphamide given every 3 weeks. At the completion of chemotherapy, she received 1500 cGy of radiation to the right lung with an additional 3500 cGy directed at the hilum of the right lung. The patient remained free from cancer until 10 years from first recurrence when she developed papillary thyroid carcinoma. At her last follow-up visit 13 years from first recurrence, she remained free of Ewing sarcoma."

Next, the authors examined the tumor specimens from both patients: "Tumor samples from the initial diagnosis of patient 1 and from the recurrence of patient 2 were available for immunohistochemical staining for estrogen and progesterone receptors. Neither tumor had detectable receptor expression by immunohistochemistry".

The mostly interesting part here is the Discussion:
DISCUSSION

Ewing sarcoma has only rarely been reported during pregnancy. Diagnosis of recurrent Ewing sarcoma during pregnancy seems to be particularly uncommon, with only 2 previous reports.4,6 One patient had a combined local and distant relapse 1 year from initial diagnosis.4 The outcome of this pregnancy was not reported. The second patient had a distant relapse, including placental metastasis, 2 years from initial diagnosis.6 Despite metastasis to the placenta, the child born to this mother was healthy and without evidence of cancer. In both of the patients described here, the presence of recurrent cancer did not adversely affect the outcome of the pregnancy.

In contrast to the previously reported patients with recurrent Ewing sarcoma during pregnancy, both patients reported here developed distant metastases more than 5 years from initial diagnosis. Most recurrences of Ewing sarcoma occur within the first 2 years after diagnosis.10–13 However, approximately 20% of patients surviving 5 years from initial diagnosis will ultimately recur.14 Several reports have indicated that patients who recur after 2 years from initial diagnosis have a more favorable outcome compared with patients having early relapse.10–13

The diagnosis of recurrent Ewing sarcoma around the time of pregnancy may have been solely owing to increased contact with medical providers during pregnancy and the immediate postpartum period. Alternatively, one might speculate that the hormonal milieu of pregnancy stimulated the growth of quiescent Ewing sarcoma cells. The absence of appropriate receptor expression suggests that estrogen and progesterone were not directly stimulating tumor growth in these cases. This result is consistent with previous reports demonstrating absent or minimal estrogen and progesterone receptor expression in Ewing sarcoma cells.15,16 An indirect effect of estrogen and/or progesterone on tumor growth in these cases can not be ruled out based on the data available. Additional hormonal pathways, such as the insulin-like growth factor-1 (IGF-1) pathway, may have contributed to these relapses during pregnancy. The IGF-1 pathway is particularly interesting because IGF-1 levels increase in maternal plasma during pregnancy and the IGF-1 receptor seems to be almost universally expressed on Ewing sarcoma cells.17–19

One of the reasons recurrent Ewing sarcoma has been noted only rarely during pregnancy may be due to impaired female fertility after Ewing sarcoma therapy. Analyses from the Childhood Cancer Survivor Study indicate that female survivors of childhood cancer have a significantly increased risk of premature ovarian failure.20 This risk increases with exposure to alkylating agents and pelvic radiation, the 2 treatments frequently employed in the treatment of Ewing sarcoma.20

In conclusion, the diagnosis of late recurrent Ewing sarcoma around the time of pregnancy is rare, likely owing to the relative rarity of late recurrence in Ewing sarcoma and the impaired fertility after Ewing sarcoma therapy. The timing of relapse in the patients reported here may be due to increased medical surveillance during pregnancy. Whether the hormonal environment of pregnancy indirectly promotes tumor growth remains unclear from these 2 cases.