British Journal of Radiology 75 (2002),543-547 © 2002 The British Institute of Radiology
Peripheral primitive neuroectodermal tumour during pregnancy
H Varveris, MD, PhD1,
M Mazonakis, MSc, PhD2,
J Damilakis, MSc, PhD2,
K Stefanaki, MD, PhD3,
E Lyraraki, MD1,
S Kachris, MD1,
E Orfanoudaki, MD4,
P Prassopoulos, MD, PhD1 and
G Samonis, MD, PhD5
Departments of 1 Radiotherapy & Oncology, 2 Medical Physics, 3 Histopathology, 4 Obstetrics and Gynecology and 5 Clinical Oncology, Iraclion University Hospital, School of Medicine, 71110 Iraclion, Crete, Greece
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Abstract
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The case of a 25-year-old primipara in the second trimester of pregnancy, suffering from a peripheral primitive neuroectodermal tumour (pPNET) diagnosed by bone biopsy, is described. External irradiation was initially performed because of Jacksonian seizures due to a lesion in the right cerebral hemisphere. Appropriate shielding was used to reduce fetal exposure during brain radiotherapy. Caesarian delivery at the 27th week of gestation was performed because of tumour progression. The neonate had no evidence of disease and survived for 1 month. However, the placenta and ovaries showed metastases from the maternal pPNET. The patient died 14 months after initial diagnosis owing to the aggressiveness of the tumour, the rapid and extensive semination (bone marrow, lung, liver, craniospinal axis involvement) and the inability to adequately treat the patient with appropriate doses of chemotherapy.
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Case report
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A 25-year-old primipara, at the 24th week of gestation, was urgently admitted to hospital with Jacksonian seizures, lumbar pain, weight loss, headache, anaemia and thrombocytopenia. A peripheral primitive neuroectodermal tumour (pPNET) was diagnosed after bone marrow biopsy. On immunohistochemical examination using the streptavidin-biotin peroxidase method, the tumour cells were positively stained for neuron-specific enolase, neurofilaments, MIC-2 (O-13), ß2-microglobulin and vimentin. The tumour cells showed no immunoreactivity to CD-56/NCAM, synaptophysin, keratin MNF-116, cytoceratin KL-1 or EMA. Molecular cytogenetic techniques were not available in our hospital for further examination and detection of the t(11, 22) translocation typically associated with pPNETs. The trephine bone marrow biopsy and placenta were sent to the laboratory in formalin.
MRI of the brain revealed an extensive mass invading the right hemisphere (Figure 1
), but investigations (MRI of the lung, abdomen and pelvis) did not reveal any other metastases. It would have been possible to start treating the patient with polychemotherapy because of disease dissemination, knowing that judicious use of some of the relevant chemotherapeutic agents is feasible during the second trimester of pregnancy [1]. However, we decided to proceed to cranial irradiation because of the initial epileptic seizures. External irradiation of the brain was given with a 6 MV linear accelerator (SL 75/5; Philips, UK) with two lateral opposed fields of 19.3 cm x 19.8 cm. Lead blocks protected the lens but no wedges were used, and both fields were treated with daily fractions of 2 Gy, 5 days per week. A total dose of 50 Gy was planned. A special shield was used to protect the fetus, which comprised a mobile support consisting of a bridge over the patient's body to hold 5.1 cm of lead, independent of the treatment couch [2].
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Figure 1. Sagittal T1 weighted MR image after intravenous contrast medium. An extensive enhancing lytic mass is shown in the skull in the parietal-occipital region. The lesion infiltrates the meninges (which are enhanced) and invades the right hemisphere (arrowhead).
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Fetal dose was measured using calcium fluoride thermoluminescent dosemeters (TLD-200; Harshaw, Salon, OH) and a modified Rando anthropomorphic phantom (Alderson Research Laboratories, Stanford, CA) simulating the geometry of the pregnant woman [2]. The upper, middle and lower fetal levels were located, respectively, 50 cm, 61 cm and 72.5 cm inferior to the field isocentre. The position of the above levels was determined by ultrasound. For a treatment course delivering 50 Gy to the tumour, it was found that the radiation dose to the shielded fetus at the upper, middle and lower fetal level was 51.7 mGy, 29.9 mGy and 14.7 mGy, respectively. These fetal doses were much lower than the threshold value of 100 mGy.
After 24 Gy, the patient showed symptoms suggesting progressive spinal cord and cauda equina compression. A Caesarian section was performed at 27 weeks gestation. The newborn, a 650 g female without abnormalities, died 4 weeks later from cardiopulmonary insufficiency. Biopsies taken from the placenta, ovaries and omentum showed infiltration from the maternal pPNET (Figures 2 and 3).
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Figure 2. Diffuse infiltration of small round cells within the intervillous space without any infiltration of the decidua. Homer–Wright rosettes are seen, H-E stain at x 200 magnification.
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Figure 3. Diffuse, strong membrane expression of CD-99/MIC-2 (O-13) in the neoplastic cells invading the placenta. Streptavidin-biotin peroxidase stain at x 400 magnification.
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CT of the lungs and abdomen at this time showed lung, liver and bone metastases, while spinal MRI revealed bone marrow and subarachnoid space infiltration (Figure 4). Cytological examination of the cerebrospinal fluid (CSF) established the diagnosis of carcinomatous meningitis.
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Figure 4. (a) Sagittal T2 weighted and (b) post-gadolinium T1 weighted MR images of the lumbar spine. The patchy areas of high signal on T2 weighted images (a) in vertebral bodies correspond to bone marrow infiltration and oedema, with enhancement on post-gadolinium images (b). Enhancement of the meninges and small epidural soft tissue masses (arrowheads) show extension into the spinal canal.
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Concurrent craniospinal irradiation and chemotherapy began 1 week after Caesarian section. Radiotherapy included the entire subarachnoid space, using lateral helmet fields (whole brain) and spinal fields (inferior neuraxis). The patient was treated in the prone position with the medulloblastoma technique [3]. The whole subarachnoid space received 40 Gy in 1.8 Gy fractions, 5 days per week, followed by a boost (shrinking fields, isocentric technique) to the parieto-occipital region, up to a total dose of 54 Gy (including the initial 24 Gy).
Two cycles of chemotherapy were given simultaneously with irradiation every 21 days, consisting of ifosfamide (1 g m-2) with intravenous (iv) mensa (1 g m-2) uroprotection, combined with etoposide (50 mg m-2) and actinomycin-D (0.5 mg m-2) in the first and second cycle, respectively. Regarding the above used EICESS 92 protocol [4], some drugs were omitted and doses were reduced, except that of actinomycin-D, because they were being given concurrently with radiotherapy and as radiosensitizing agents. Another six cycles were given after irradiation, consisting of ifosfamide and mensa (2 g m-2), actinomycin-D (0.5 mg m-2; days 1–3, cycles four and six), doxorubicin (20 mg m-2; days 1–3, cycles three and five) and vincristine (1.4 mg m-2; day 1), every 21 days over 6 months [4]. Intrathecal chemotherapy with methotrexate (12 mg per dose) or cytarabine (ara-c 50 mg per dose) was not used because of the unwillingness of the patient to accept an Ommaya reservoir to permit intraventricular drug administration. Nevertheless, the CSF cytology returned to normal and total disappearance of lung and liver metastases was confirmed by CT. However, the above VAIA (vincristine actinomycin-D, ifosfamide, doxorubicin, chemotherapy regimen did not succeed in clearing the bone marrow, as shown by a biopsy of the iliac crest at the end of chemotherapy.
Asthenia, malaise and lung infection caused a treatment delay of 1 month. During the third month after the end of chemotherapy, i.e. 12 months after disease presentation, the patient developed severe lumbar pain. MRI scans showed vertebral osteolysis, T12, L1, L2 and L3 paravertebral soft tissue masses invading the lumbosacral area and infiltrates of the dura mater along the whole craniospinal axis and right sincipital bone. The PCV (procarbazine, CCNU, vincristine) regimen was used with concomitant external irradiation to the spine as a palliative measure, aiming to keep the doses below the maximum spinal cord tolerance of 50 Gy. This regimen was chosen as it is effective in recurrent medulloblastoma [5] and brain tumours [6], and owing to the failure of the previously used standard chemotherapy schedules. The patient died 14 months after initial diagnosis owing to disseminated intravascular coagulation. No autopsy was performed.
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Discussion
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PNET and Ewing's sarcoma are closely related tumours that may occur as skeletal or extraskeletal soft tissue neoplasms.
During the last two decades, small blue round cell tumours arising in the bone and soft tissues of the periphery have been described, representing a common clinical and pathological entity. They occur predominantly in older children and adolescents and follow a more aggressive clinical course than other small round cell tumours, i.e. Ewing's sarcoma and neuroblastoma.
The peripheral tumours (Ewing's sarcoma of bone, extraosseous Ewing's sarcoma and Askin's tumour) have all been recognized as members of the Ewing's family of tumours. Evidence for this association is the result of the expression of the MIC-2 antigen [7] and the demonstration that the pPNET contain the same t(11,22) translocation [8] that is found in the great majority of classical Ewing's sarcoma [8] of bone. There is no evidence of this translocation, or the histochemical reaction used for recognition of expression of the MIC-2 protein, in PNET of the central nervous system [9].
This paper describes a pPNET in a 25-year-old primipara in the second trimester of pregnancy. It was not entirely clear where the primary site of the tumour was, although it seems probable that it arose in the parietal-occipital region of the skull. Bone and lung metastases were shown immediately after the Caesarian delivery. Dildy et al [10] found 52 cases of maternal malignancy that had metastasized to the placenta and/or the fetus reported over the last 120 years. Most cases were maternal melanomas [11], followed by lymphomas and leukaemias [10]; in only 13 cases were fetal metastases confirmed. Only one other case of placental metastasis has been reported from a maternal pPNET, in a 33-year-old Japanese woman at 33 weeks gestation with a pPNET of the vagina/rectum [12]. There was no fetal involvement in any of the patients reported, as in this case.
Immunohistochemically, pPNETs are linked by shared positivity for the MIC-2 protein best demonstrated by the antibodies HBA-71 or O-13 [13]; these two antibodies are in fact the same. In previous series, 16 (84%) of 19 pPNETs [14] and 33 (97%) of 34 pPNETs [7] reacted with the above antibody. The diagnosis of pPNET was made in this case by the histological features of the tumour including the Homer–Wright type rosettes in combination with the characteristic immunophenotype. The immunohistochemical expression of MIC-2 (using the O-13 antibody) and ß2-microglobulin, in conjunction with immunoreactivity to two neural markers (NSE, neurofilaments), were used in favour of a diagnosis of pPNET rather than the Ewing's sarcoma family or other small round blue cell tumours. In addition, the histological examination of the placenta demonstrated intervillous metastases, but no direct infiltration of the tumour into the villi was observed in our patient, nor in that of Sakurai et al [12]. Because of haematogenous metastatic spread, placental metastases are usually associated with the death of the affected mother, as happened in this case.
Recent results of institutional and multicentre trials [15, 16] have demonstrated the importance of a multidisciplinary approach to the treatment of Ewing's sarcoma and primitive neuroectodermal tumours in children and young adults. Furthermore, they have shown the advantage of incorporating etoposide and ifosfamide into chemotherapy regimens for recurrent and advanced disease.
Received for publication March 26, 2001.
Revision received November 20, 2001.
Accepted for publication February 27, 2002.
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