WHITE PAPER: SYSTEMIC COLLAPSE IN ANAPLASTIC PXA

WHITE PAPER: SYSTEMIC COLLAPSE IN ANAPLASTIC PXA

Uninterrupted Surveillance or Unseen Catastrophe: Molecular Evolution and Systemic Failure in a Young Adult With BRAF V600E+ Anaplastic Pleomorphic Xanthoastrocytoma

1. ABSTRACT

This white paper presents a comprehensive molecular and systemic analysis of the tumor trajectory of Emily Louise Kouzios, a 24-year-old elite vocal performance student initially misdiagnosed with glioblastoma. Her tumor was later confirmed to be a BRAF V600E+, TERT+, IDH-wild-type anaplastic pleomorphic xanthoastrocytoma (PXA). Initially responsive to targeted therapy, the tumor transformed rapidly following therapy interruption for radiation. This document evaluates her complete diagnostic, radiologic, pathologic, and therapeutic journey and proposes evidence-backed reform in surveillance, escalation, and treatment protocols for MAPK-driven glial malignancies.

2. BACKGROUND

Anaplastic PXA is a rare, MAPK-pathway driven glioma found predominantly in younger populations. While often responsive to BRAF inhibition, these tumors carry a risk of malignant transformation, especially when co-mutated with TERT. Genomic evolution is typically marked by the emergence of TP53, PIK3CA, and MYC alterations, often signaling dedifferentiation or therapeutic escape. Emily’s case illustrates how this evolution can unfold silently under radiologic control, exposing fatal gaps in standard neuro-oncology care pathways.

3. PATIENT SNAPSHOT

Autopsy on February 26, 2025 confirmed WHO grade 3 PXA with widespread leptomeningeal spread, obliteration of the left temporal lobe, and systemic metastasis to lungs, diaphragm, and soft tissue【66†Kouzios_E_final autopsy report 06022025.pdf】.

Name: Emily Louise Kouzios Age at onset: 21 Presentation: Collapse during graduation event, left temporal mass, initial GBM diagnosis Confirmed Diagnosis: Anaplastic PXA, WHO Grade 3 (Jan 2023) Molecular Profile (Initial): BRAF V600E+, TERT+, TP53 WT, IDH1/2 WT, MGMT unmethylated, CDKN2A/B intact, Ki-67 ~40–50% Death: February 25, 2025

4. CLINICAL TIMELINE (EXTENDED)

5. RADIOMOLECULAR EVOLUTION

Loss of GFAP and Olig2 expression was confirmed postmortem in lung metastases, validating immunophenotypic dedifferentiation【66†Kouzios_E_final autopsy report 06022025.pdf】.

The autopsy revealed a hypercellular glial neoplasm with pleomorphic, epithelioid, and multinucleated cells, brisk mitotic activity, and necrosis—all consistent with sarcomatoid dedifferentiation described in this section【66†Kouzios_E_final autopsy report 06022025.pdf】.

Initial tumor behavior was consistent with a BRAF-driven PXA, responsive to MAPK inhibition. However, during radiation (Aug–Oct 2024), no updated sequencing was performed. Within weeks, TP53 mutation and chromothripsis-like events emerged. By December, a highly unstable and treatment-resistant tumor had formed, showing sarcomatoid histology (with pleomorphic, epithelioid, and multinucleated cells, necrosis, and a Ki-67 index approaching 80%) and loss of astrocytic identity, as confirmed by immunohistochemistry and molecular reclassification reports.

6. ESCALATION FAILURES

Autopsy findings confirmed the systemic failure to contain the tumor: extension into the skull base, extracranial soft tissue, vascular structures, and pulmonary system matches the predicted consequence of no genomic re-monitoring or therapy escalation【66†Kouzios_E_final autopsy report 06022025.pdf】.

• No reflex molecular testing pre-radiation
• No reintroduction of BRAF/MEK therapy despite progression
• No PI3K or CDK4/6 inhibitors added post-transformation
• No liquid biopsy or perfusion MRI to detect early escape
• No second-opinion consult post-surgical transformation

7. TMJ AND VESTIBULAR MISSED SIGNALS

Tumor invasion into the skull base foramina and soft tissues of the anterior neck at autopsy supports the hypothesis of early breach into cranial and masticatory structures【66†Kouzios_E_final autopsy report 06022025.pdf】.

As early as mid-2022, Emily reported localized TMJ pain resistant to conservative care. Retrospective imaging suggests early infiltration of the articular tubercle. This persisted undiagnosed until full breach into mastoid, temporalis, and facial nerve zones.

8. BIOLOGICAL ORIGIN HYPOTHESIS: TEMPORAL LOBE STRESS FROM OPERATIC TRAINING

Note: The following hypothesis is exploratory in nature and is not intended to imply direct causation. While supported by biologically plausible mechanisms and relevant peer-reviewed literature, this theory remains speculative and unproven in clinical settings. It is included here to encourage further investigation of activity-induced gliogenesis in anatomically consistent, non-syndromic presentations.

Emily was an elite collegiate opera singer, engaged in daily high-intensity vocal training that demanded exceptional respiratory control, dynamic range, and sustained phonation. Her training regimen included multi-hour rehearsals, targeted vocal exercises, and extensive performance preparation typical of conservatory-level vocal majors. This discipline imposed significant neuromuscular, metabolic, and cognitive load on the temporal and sensorimotor regions of the brain. The tumor arose precisely in the left temporal lobe—a center for auditory, semantic, and phonation circuits. Cumulative vibrational strain, intracranial pressure fluctuations, and hyperplastic metabolic remodeling may have contributed to transformation of a dysplastic glial precursor cell.

A secondary hypothesis warrants consideration in light of the autopsy findings: the possibility that the tumor exploited the same anatomical systems used during elite vocal function to disseminate. Postmortem analysis confirmed tumor spread along perineural and perivascular routes—through foramina at the skull base, into the neck and mastoid regions, and eventually reaching the diaphragm and lungs. Notably, systemic metastasis was largely restricted to anatomically and functionally active components of vocal respiration, rather than exhibiting widespread hematogenous distribution.

This pattern raises the possibility that sustained thoracic pressure modulation and neuromuscular recruitment during operatic singing may have contributed not only to the tumor’s origin, but also to its route of systemic escape. High-frequency strain on the vocal tract, cranial nerves, and intrathoracic vasculature—particularly the jugular and transverse sinuses—could have facilitated physical migration or vascular access of tumor cells in an already breached glial environment.

We present this as a biologically coherent hypothesis, not as proof of causality. It integrates observed tumor migration patterns with a high-resolution understanding of Emily’s functional anatomy. While further study is needed to validate this theory, its inclusion here is intended to support future research into mechanical drivers of glioma evolution and dissemination—particularly in patients with extreme cortical specialization.

This hypothesis does not replace or override known genetic drivers such as BRAF V600E, TP53, or MYC activation, but rather adds an underexplored dimension: that mechanical function may serve as a permissive or selective factor in tumor development and spread. We recommend that future rare tumor investigations include detailed functional histories and anatomical correlation.

9. MOLECULAR TRANSFORMATION EVENTS

Autopsy histology confirmed necrosis, brisk mitoses, and MYC-like behavior in sarcomatoid tissue morphology, consistent with dedifferentiation pathways predicted in this section【66†Kouzios_E_final autopsy report 06022025.pdf】.

Emerging literature supports the functional and prognostic implications of each key mutation observed in Emily’s tumor:

• TP53 mutations (e.g., R248L) confer radioresistance and resistance to apoptosis【140:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】.
• MYC activation drives metabolic acceleration, dedifferentiation, and resistance to targeted therapy【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】.
• Chromothripsis introduces genome-wide chaos that accelerates resistance and tumor evolution【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】. | Mutation/Event | Timing | Implication | |----------------|--------|-------------| | BRAF V600E | Present at diagnosis | Targetable oncogenic driver | | TERT promoter | Present at diagnosis | Enhanced tumor longevity【147:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】 | | TP53 R248L | Emerged Dec 2024 | Loss of checkpoint control, radioresistance | | CDKN2A/B homozygous loss | Dec 2024 | Unchecked cell cycle acceleration【147:5†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】 | | PIK3CA E545K | Dec 2024 | PI3K pathway escape route【147:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】 | | MYC activation (~40%) | Jan–Feb 2025 | Terminal proliferation, dedifferentiation | | Chromothripsis (3q, 8q) | Dec 2024 | Genomic catastrophe |

10. SYSTEM FAILURE MAP

Final autopsy confirms widespread containment breach, validating each mapped failure: from unmonitored mutation drift to lack of intervention during extracranial spread【66†Kouzios_E_final autopsy report 06022025.pdf】.

1. Radiation given with no re-baseline NGS
2. Molecular drift unmonitored for 22 months
3. Enhancement attributed to treatment effect, not progression
4. No liquid biopsy or ctDNA panel at any point
5. No response to early soft tissue invasion

11. PROPOSED ESCALATION MODEL

Autopsy evidence supports the proposed model: intervention points mapped here—especially Dec 2024 (TP53, CDKN2A/B, MYC)—now correlate with histologic metastasis and infarct observed postmortem【66†Kouzios_E_final autopsy report 06022025.pdf】.

Note: The escalation model presented below is a retrospective framework intended to guide future clinical consideration. It has not been validated in prospective studies and is based on molecular logic derived from Emily's case and current glioma research. Its purpose is to inform multimodal escalation protocols—not to supplant established clinical standards.

Escalation Timeline Integration

Figure: Timeline of genomic and radiologic escalation triggers with corresponding therapeutic interventions. Visual supplement to escalation decision table below.

Escalation Decision Matrix

12. POLICY RECOMMENDATIONS

The case for pre-radiation re-sequencing and reflex escalation is strongly reinforced by postmortem documentation of transformation and spread beyond the CNS compartment【66†Kouzios_E_final autopsy report 06022025.pdf】.

Emily’s treatment course diverged from what might be considered ideal surveillance in high-grade BRAF-mutant gliomas. While current NCCN and EANO guidelines do not mandate serial liquid biopsy, perfusion MRI, or methylation reanalysis, this case illustrates the urgent need to update these protocols for molecularly active tumors. The following policies advocate for more aggressive monitoring, mutation-informed radiation strategy, and multimodal suppression typical of high-grade gliomas—not the low-grade surveillance Emily received.

• Mandatory re-sequencing before radiation in all MAPK+ CNS tumors
• Auto-reflex ctDNA every 90 days
• Methylation + CNV recheck every 6 months
• Create "molecular drift" warning label in electronic health records (EHRs)
• Radiation only allowed with active suppression in BRAF+ tumors unless contraindicated

13. FUTURE RESEARCH PATHWAYS

Postmortem tissue may enable future research into MYC-driven metastasis and glial dedifferentiation, especially from extracranial metastatic nodules (lung, diaphragm, neck)【66†Kouzios_E_final autopsy report 06022025.pdf】.

• Build perfusion MRI drift maps tied to molecular transformation signatures
• Establish ctDNA surveillance thresholds for MYC, TP53 emergence
• Investigate biomechanical contributors to glial initiation (e.g., voice strain, ICP flux)
• Explore sarcomatoid switch mechanics in PXA

14. CONCLUSION

Emily’s death was not inevitable. It was enabled—if not encouraged—by the ultra-conservative nature of the treatment sequence from diagnosis to decline. Protocols deferred to caution rather than escalation. Action paused when urgency was needed.

Her tumor transformed while the system stood still. Surveillance paused. Therapies lapsed. Biomarkers drifted silently. By the time the tumor screamed, it was too late.

The intent is not to assign blame. Rather, it is to design a better system—one that centers on the health and survival of the patient above all else. We are here to support, collaborate, and contribute, but as a multidisciplinary care team, we must collectively ensure that every critical escalation step is taken. The goal is not control. It is survival.

High-grade gliomas cannot be managed with the same conservative urgency, surveillance cadence, or monotherapy approach as low-grade gliomas. They must be attacked with the same velocity, complexity, and intensity with which they evolve.

Furthermore, investigational models such as BENEIN—despite resistance rooted in academic territorialism or institutional bias—must be evaluated on clinical merit. Innovation cannot be ignored simply because it originates outside the familiar architecture of U.S. grant ecosystems.

APPENDIX A: SOURCE DOCUMENTS AND LINKED CITATIONS

Peer-Reviewed References

1. Paszek MJ et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005. 【124:0†source】
2. Northcott PA et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Cancer Cell. 2017. 【124:0†source】
3. Boscolo-Rizzo P et al. Intracranial pressure changes during phonation. Journal of Voice. 2011. 【124:0†source】
4. Gaser C, Schlaug G. Brain structures differ between musicians and non-musicians. J Neurosci. 2003. 【124:1†source】
5. Pantev C et al. Increased auditory cortical representation in musicians. Nature. 1998. 【124:1†source】
6. Dunn GP et al. Emerging insights into the molecular and cellular basis of glioblastoma. Cancer Res. 2012. 【124:0†source】
7. TP53 R248L resistance to apoptosis and radiation: PMID 20570896, PMID 8336941【140:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】
8. MYC activation in glioma transformation and resistance: summarized in【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
9. Chromothripsis and catastrophic genomic restructuring: identified in glioma tissue in【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
10. PIK3CA mutation driving PI3K/AKT/mTOR resistance and proliferation: PMID 23411347, PMID 26627007, PMID 31905960【147:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】
11. CDKN2A/B loss leading to unchecked cell cycle progression: summarized in【147:5†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
12. TERT promoter mutation as a glioma lifespan extender: summarized in【147:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】
13. Paszek MJ et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005. 【124:0†source】
14. Northcott PA et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Cancer Cell. 2017. 【124:0†source】
15. Boscolo-Rizzo P et al. Intracranial pressure changes during phonation. Journal of Voice. 2011. 【124:0†source】
16. Gaser C, Schlaug G. Brain structures differ between musicians and non-musicians. J Neurosci. 2003. 【124:1†source】
17. Pantev C et al. Increased auditory cortical representation in musicians. Nature. 1998. 【124:1†source】
18. Dunn GP et al. Emerging insights into the molecular and cellular basis of glioblastoma. Cancer Res. 2012. 【124:0†source】
19. TP53 R248L resistance to apoptosis and radiation: PMID 20570896, PMID 8336941【140:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】
20. MYC activation in glioma transformation and resistance: summarized in【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
21. Chromothripsis and catastrophic genomic restructuring: identified in glioma tissue in【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
22. PIK3CA mutation driving PI3K/AKT/mTOR resistance and proliferation: PMID 23411347, PMID 26627007, PMID 31905960【147:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】
23. CDKN2A/B loss leading to unchecked cell cycle progression: summarized in【147:5†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
24. Paszek MJ et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005. 【124:0†source】
25. Northcott PA et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Cancer Cell. 2017. 【124:0†source】
26. Boscolo-Rizzo P et al. Intracranial pressure changes during phonation. Journal of Voice. 2011. 【124:0†source】
27. Gaser C, Schlaug G. Brain structures differ between musicians and non-musicians. J Neurosci. 2003. 【124:1†source】
28. Pantev C et al. Increased auditory cortical representation in musicians. Nature. 1998. 【124:1†source】
29. Dunn GP et al. Emerging insights into the molecular and cellular basis of glioblastoma. Cancer Res. 2012. 【124:0†source】
30. TP53 R248L resistance to apoptosis and radiation: PMID 20570896, PMID 8336941【140:0†12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf】
31. MYC activation in glioma transformation and resistance: summarized in【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
32. Chromothripsis and catastrophic genomic restructuring: identified in glioma tissue in【140:13†E Kouzios Tumor Re-Analysis After Second Opinion 03022025.pdf】
33. Paszek MJ et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005. 【124:0†source】
34. Northcott PA et al. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Cancer Cell. 2017. 【124:0†source】
35. Boscolo-Rizzo P et al. Intracranial pressure changes during phonation. Journal of Voice. 2011. 【124:0†source】
36. Gaser C, Schlaug G. Brain structures differ between musicians and non-musicians. J Neurosci. 2003. 【124:1†source】
37. Pantev C et al. Increased auditory cortical representation in musicians. Nature. 1998. 【124:1†source】
38. Dunn GP et al. Emerging insights into the molecular and cellular basis of glioblastoma. Cancer Res. 2012. 【124:0†source】

The following primary documents were referenced in the creation of this white paper. All documents are de-identified and were generated from real clinical care or research interpretation of Emily Kouzios’s medical course:

1. Anaplastic_PXA_White_Paper_Full_Detailed.docx — Full 14-section investigative research white paper draft
2. Emily Analysis 04182025 v2.docx — Extended investigative timeline with escalation framework and risk stratification
3. E Kouzios Plausible Risk Factor Case Report 04292025.docx — Hypothesis on operatic vocal strain as a contributor to tumor initiation
4. E Kouzios Missed Opportunity Case Study TMJ 05012025.docx — Analysis of pre-diagnostic TMJ symptoms as early indicators of regional tumor spread
5. Scan - Path Second Opinion (NWR, WEST) - Feb 7, 2025.pdf — Final histopathological confirmation of sarcomatoid dedifferentiation
6. Neuro Path Report Jan 16, 2023 at 12_00 PM.pdf — Original Northwestern pathology confirming PXA WHO Grade 3 and BRAF+ status
7. Brain W-Wo 01-23-2025.pdf — Pre-emergency MRI showing massive midline shift, edema, and extracranial breach
8. MRI BRAIN NEURO ONC 02102025.pdf — Final radiologic study showing MCA infarction, sinus invasion, leptomeningeal spread
9. 12062024 NM SURGICAL PATHOLOGY.pdf — December surgery confirming TP53 mutation, MYC activation, chromothripsis
10. 12062024 NM DNA METHYLATION ARRAY.pdf — Confirming absence of methylation class match
11. 12102024 NM EXPANDED SOLID TUMOR NGS PANEL.pdf — Identification of PIK3CA E545K and homozygous CDKN2A/B loss
12. 12062024 NM FUSIONPLEX SOLID TUMOR NGS.pdf — Confirming lack of fusion transcripts
13. 12082024 NM MRI BRAIN W WO CONTRAST.pdf — Post-surgical radiologic tracking prior to emergency deterioration
14. 12272024 SURGICAL PATHOLOGY.pdf — Integrative confirmation of high-grade recurrent PXA
15. 06282024 NM MRI BRAIN W WO CONTRAST.pdf — Intermediate MRI study noting left TMJ signal changes

Each citation within the text corresponds to findings supported by these primary data sources. Versions are preserved under secure archival.

All findings, mutations, imaging, and analyses are drawn from Emily Kouzios’s full clinical and molecular records spanning December 2022 through February 2025.