1. Radiation Injury Can Mimic Tumor Progression Following Proton Radiotherapy for Atypical Teratoid Rhabdoid Tumor in Pediatric Patients M Chang 1, F Perez 1,2, J Nixon 1,2, D Shaw 1,2, R Ermoian 1,2, S Leary 1,2, G.E. Ishak 1,2 1 University of Washington, Seattle, WA. 2 Seattle Children’s Hospital, Seattle, WA. Control # 647 Poster # EP-132

2. Introduction Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors mostly affecting infants and young children with a historically dismal prognosis. Proton beam radiation therapy is a promising treatment for pediatric ATRT due, in part, to more specific delivery of radiation dose to the tumor with decreased dose to normal surrounding tissues; however, radiation injury can still occur. The imaging and clinical characteristics of proton beam radiation injury in pediatric patients have not been described well.

3. Atypical Teratoid Rhabdoid Tumors  Aggressive, rare WHO Grade IV tumor  Median age of presentation less than 3 years  50% are infratentorial  Presence of rhabdoid cells differentiate ATRT from medulloblastoma  22q11 chromosome deletions present in many ATRT with loss of INI1 protein expression  Poor prognosis (median survival 17 months)

4. Imaging Features of ATRT’s  CT: isodense to gray matter, heterogeneous enhancement, calcification is common  MRI: T1 iso to mildly hyperintense, T2 hyperintense, heterogeneous enhancement, restricted diffusion FLAIRT1 + GADADC

5. Proton Radiotherapy  A form of external beam radiotherapy  Protons exhibit less scatter than photons due to their relatively large mass, so dose to surrounding non-targeted tissues is lower (particularly important for patients under 3 years of age due to risk of radiation related neurocognitive deficits)  Early studies suggest favorable outcomes for ATRT patients treated by proton therapy.

6. Radiation Injury in Brain  Can be observed after partial or whole brain irradiation  Manifests in clinical symptoms as well as imaging abnormalities  Can be classified based on time of onset  acute (during or shortly after exposure)  subacute (<12 weeks)  delayed (months-years)  Acute and subacute injuries: associated with vasodilation and blood brain barrier disruption, resulting in edema and increased contrast enhancement.  Late delayed injuries: associated with vessel damage, ischemia/necrosis (microhemorrhages)

7. Materials and Methods  Retrospective imaging and clinical review of a cohort of ATRT patients treated with proton therapy at three proton treatment centers who developed radiation injury.  The cohort consisted of 5 patients with ATRT, four of whom developed neurologic symptoms and associated abnormal imaging findings.

8. Results  The 4 symptomatic patients (age 4 months to 4 years) were treated with two cycles of induction chemotherapy (including methotrexate) followed by proton therapy (50.4- 54 Gy in 1.8 Gy fractions) and three cycles of consolidation chemotherapy (including thiotepa).  These patients developed acute neurological symptoms (for example, seizure, hemiparesis, or eye deviation) at 4 to 7 months following proton therapy and underwent MRI evaluation.  The distinguishing feature of the fifth (asymptomatic) patient was an older age of 13 years, raising the possibility of age related susceptibility to radiation/treatment related injury.

9. Results (cont’d)  In all four cases, MRI findings raised the possibility of local tumor recurrence, including FLAIR hyperintensity, enhancement, and diffusion restriction similar to the original ATRT.  In three of four cases, CT or MRI demonstrated formation of parenchymal calcifications as early as 6 months following proton therapy.  Symptoms and imaging findings improved with supportive care and steroids, without re-initiation of oncologic treatment, suggestive of radiation injury rather than tumor progression.

10. Summary of Cases Age at diagnosisTumor locationTreatmentSubsequent symptoms Case 1 1 yrPosterior fossa All patients:  Surgical tumor resection.  Two cycles of induction chemotherapy (including methotrexate)  Proton therapy (50.4-54 Gy in 1.8 Gy fractions)  Consolidation chemotherapy (including thiotepa) Vomiting and lethargy 1 month post proton therapy, then bilateral weakness, inability to sit/stand. Case 2 4 yrSupratentorialProgressive hemiparesis 6 months post proton therapy. Case 3 4 moPosterior fossa Acute eye deviation, 4 months post proton therapy. Case 4 3 yrSupratentorial Seizure, right sided weakness, irritability, inability to ambulate, 7-8 months post proton therapy.

11. Post-Proton Therapy Radiation Injury: CASE 1 FLAIR T1+Gad ADC Initial tumor.1 month post proton radiation treatment (RT). No suspicious findings. 4 months post RT. Symptom onset. New FLAIR signal and contrast enhancement. 5 months post RT. New restricted diffusion. 12 months post RT. Imaging findings improve. Calcifications evident on SWI. SWI

12. Post-Proton Therapy Radiation Injury: CASE 2 Initial Tumor 3 month post RT. Minimal white matter FLAIR hyperintensity. 7 months post RT. Symptom onset. Increased FLAIR signal and new patchy enhancement and restricted diffusion. 10 months post RT. Decreased restricted diffusion. Calcifications on SWI. FLAIR T1+Gad ADC SWI

13. Post-Proton Therapy Radiation Injury: CASE 3 FLAIR T1+Gad ADC Initial Tumor 3 month post RT. No suspicious findings. DWI/ADC non-diagnostic due to VP shunt artifact. 6 months post RT. Symptom onset. New FLAIR signal and contrast enhancement. Calcifications on CT. 12 months post RT. Decreased FLAIR and contrast enhancement. CT

14. Post-Proton Therapy Radiation Injury: CASE 4 FLAIR T1+Gad ADC Initial Tumor3 month post RT. No suspicious abnormality. 7 months post RT. Worsening symptoms. Increased FLAIR signal, restricted diffusion, and contrast enhancement in multiple areas. Calcifications seen on SWI. 17 months post RT. Decreased restricted diffusion. Calcifications on SWI. SWI

15. Potential Discriminators of ATRT Recurrence vs Radiation Injury ATRT: well defined margins, solid enhancement, mass effect. Radiation injury: ill defined lesions confined to white matter, relatively little mass effect, patchy enhancement, calcifications.

16. Conclusions  Proton beam radiation therapy is a promising treatment for pediatric ATRT, with the potential for improved survival and decreased treatment complications, but radiation injury remains a possibility.  Following proton therapy for ATRT, we observed MRI abnormalities which mimicked tumor progression, but spontaneously improved, suggestive of radiation injury (possibly potentiated by intense chemotherapy)

17. Conclusions  MRI findings of patchy enhancement, ill defined margins, and parenchymal calcification as early as 6 months after treatment, are suggestive of radiation injury.  Recognition of radiation injury is important since misinterpretation as tumor progression can lead to unnecessary toxic therapies in this vulnerable pediatric population.