Biochemically normal adrenal pheochromocytoma following extensive central necrosis in a child with von Hippel-Lindau (VHL) gene mutation

Pheochromocytomas are rare in children. The diagnosis is usually established from a raised urinary or plasma catecholamine or their metabolites. We present a girl aged 11 years who manifested with a hypertensive crisis secondary to an adrenal tumour but with unexpectedly normal urinary metanephrine and catecholamine results. She improved spontaneously following the crisis and underwent surgery later. The histopathological study confirmed a pheochromocytoma with large central necrosis. Her genetic screening reported a pathogenic von Hippel-Lindau gene mutation. Surveillance scan postsurgery detected no other tumours. Following the catecholamine crisis, an acute infarct occurred, resulting in extensive tumour necrosis and subsequent rapid remission of symptoms and paradoxically normal biochemical markers. Although not unheard of in adults, we believe this is the first reported case of an extensive spontaneous necrosis resulting in a biochemically normal pheochromocytoma in a child.

TMOD-16. HYPOXIA RESHAPES THE GLIOBLASTOMA MICROENVIRONMENT INVOKING NECROSIS AND TRIGGERING DISEASE PROGRESSION

Emerging necrosis within solid tumors corresponds with malignant progression. Current tumor model systems fail to adequately mimic the magnitude of post-necrotic restructuring within the microenvironment and remain overly reliant on post-mortem and descriptive analyses, obligating researchers to extrapolate causal relationships between necrosis and progression phenomena that emerge during tumor evolution. In glioblastoma (GBM; WHO grade 4), the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. Despite extensive genetic characterization in GBM, mechanisms enabling selective fitness within a hypoxic/anoxic setting remain poorly understood. Persistent nutrient deprivation culminates in necrosis, dramatically altering the tumor microenvironment (TME). We established mouse models that more aptly capture events found in human gliomas, exposing the dynamic temporal and spatial changes that facilitate expansive progression while including unique microenvironmental stressors typically absent from GBM animal models, specifically central necrosis. This model combines hypoxia-induced focal necrosis within GBM with real time intravital microscopy to capture TME restructuring and elucidate its impact on glioma progression. Our studies use genetically characterized patient-derived orthotopic GBM xenografts, alongside an immunocompetent RCAS/tv-a model, to determine how these processes impact disease progression and outcomes across multiple GBM molecular subtypes. Simultaneously, we employ in vitro models to scrutinize how hypoxia-related crosstalk between GBM, microglia and circulating monocytes alter tumor-associated macrophage (TAMs) recruitment and reprogramming. Our preliminary data suggests microenvironmental cues significantly alter microglia behavior and have demonstrated increased 3D invasion under hypoxic conditions as compared to normoxia. Monocyte invasion varies based on signals emanating from specific GBM subtypes, yet the signaling events that elicit differential responses remains unknown. However, exposure to any GBM conditioned media uniformly upregulates immunosuppressive TAM programming. Our ongoing investigations seek to uncover the mechanisms driving post-necrotic GBM evolution and reactive neuroinflammation

The Influence of the Exclusion of Central Necrosis on [18F]FDG PET Radiomic Analysis

Background: Central necrosis can be detected on [18F]FDG PET/CT as a region with little to no tracer uptake. Currently, there is no consensus regarding the inclusion of regions of central necrosis during volume of interest (VOI) delineation for radiomic analysis. The aim of this study was to assess how central necrosis affects radiomic analysis in PET. Methods: Forty-three patients, either with non-small cell lung carcinomas (NSCLC, n = 12) or with pheochromocytomas or paragangliomas (PPGL, n = 31), were included retrospectively. VOIs were delineated with and without central necrosis. From all VOIs, 105 radiomic features were extracted. Differences in radiomic features between delineation methods were assessed using a paired t-test with Benjamini–Hochberg multiple testing correction. In the PPGL cohort, performances of the radiomic models to predict the noradrenergic biochemical profile were assessed by comparing the areas under the receiver operating characteristic curve (AUC) for both delineation methods. Results: At least 65% of the features showed significant differences between VOIvital-tumour and VOIgross-tumour (65%, 79% and 82% for the NSCLC, PPGL and combined cohort, respectively). The AUCs of the radiomic models were not significantly different between delineation methods. Conclusion: In both tumour types, almost two-third of the features were affected, demonstrating that the impact of whether or not to include central necrosis in the VOI on the radiomic feature values is significant. Nevertheless, predictive performances of both delineation methods were comparable. We recommend that radiomic studies should report whether or not central necrosis was included during delineation.

Lupus miliaris disseminatus faciei: A report with a new dermoscopy finding

Lupus miliaris disseminatus faciei (LMDF) is a rare inflammatory disorder characterized by asymptomatic papular lesions mainly over the central part of the face, common in young adults and with a spontaneously resolving course. Its exact etiology remains unknown, its treatment is problematic, and there is a lack of controlled studies on LMDF. Histopathology shows dermal epithelioid granulomas with central necrosis and surrounding lymphocytic infiltrate with multinucleate giant cells. Dermoscopic findings published show discrete focal orangish structureless areas located around follicular openings with whitish keratotic plugs. Herein, we report a case of LMDF with dermoscopy showing stellate scar signs and structureless white areas.

TAMI-56. HYPOXIA-DRIVEN NECROSIS DRIVES DYNAMIC TUMOR PROGRESSION IN GLIOBLASTOMA

The onset of necrosis correlates with aggressive malignant progression in solid tumors. Whether necrosis arises from or promotes accelerated tumor proliferation and progression remains unknown, primarily due to inadequate models systems that fail to induce or capture these dynamic changes as they develop. In glioblastoma (GBM; WHO grade IV), the most malignant primary brain tumor, vascular pathology and central necrosis precedes rapid, radial expansion resulting in patient mortality. While genetic alterations in GBM have been highly characterized, biological adaptations arising from sustained hypoxia/anoxia require further mechanistic investigation. This sustained nutrient deprivation leads to necrosis which dramatically changes the tumor microenvironment (TME). To reveal the dynamic temporal and spatial changes promoting expansive progression, we are generating mouse models that more appropriately capture events found in human gliomas, accounting for unique microenvironmental stressors often lacking in GBM animal models, specifically central necrosis. Combining hypoxia-induced focal necrosis within high grade gliomas with intravital microscopy captures TME restructuring to understand its impact on glioma progression. Our studies use both genetically characterized patient-derived orthotopic GBM xenografts, alongside an immunocompetent RCAS/tv-a model, to determine how antagonizing these processes impacts disease progression and outcomes across multiple GBM subtypes. Complementary to this, we are investigating how increasing hypoxia and necrosis-driven signaling events promotes tumor-associated macrophages (TAMs) influx and reprogramming during glioma progression. Our preliminary data indicate substantial differences pre- and post-necrosis regarding TAM enrichment, immunosuppressive phenotypic conversion and their biological impact, however these mechanisms have not yet been elucidated. Our models capture glioma growth dynamics, reactive neuroinflammation and therapeutic resistance, facilitating innovative pre-clinical interventions to improve patient outcome.

TMOD-37. INTRAVITAL MONITORING DYNAMIC TUMOR MICRO-ENVIRONMENTAL EVOLUTION FOLLOWING HYPOXIA-INDUCED NECROSIS IN GLIOBLASTOMA

The onset of necrosis correlates with malignant progression in virtually all human cancers. Whether necrosis arises from or promotes rapid tumor expansion remains unknown, primarily due to insufficient model systems necessary for capturing these dynamic changes as they develop. In glioblastoma (GBM; WHO grade IV), the most malignant primary brain tumor, the development of central necrosis precedes rapid, radial expansion precipitously leading to patient mortality. While genetic alterations in GBM have been highly characterized, the resultant biological adaptations leading to accelerated tumor growth require further mechanistic investigation. The onset of necrosis dramatically changes the tumor microenvironment (TME), evolving from a sheet-like growth of infiltrating malignant cells undergoing gradual expansion to a complex 3-D microsystem comprising diverse cell types and spatially segregated signaling networks. To reveal the dynamic temporal and spatial changes promoting progression, we are generating mouse models that more appropriately capture events found in human gliomas, accounting for unique microenvironmental stressors often lacking in GBM animal models, specifically central necrosis. We developed a novel method combining hypoxia-induced focal necrosis within high-grade gliomas with intravital microscopy to study TME restructuring and its impact on glioma progression in real time. As translational applications, we are investigating how hypoxia and necrosis promote glioma stem cell (GSC) enrichment in their peri-necrotic niche and how the massive influx of tumor-associated macrophages (TAMs) promotes glioma progression. Our studies use both genetically characterized patient-derived orthotopic GBM xenografts in humanized mice, alongside an immunocompetent RCAS/tv-a model, to determine how antagonizing these processes impacts disease progression and outcomes across multiple GBM subtypes. Our preliminary data indicate substantial differences pre- and post-necrosis regarding GSC and TAM enrichment and their biological impact, however, these mechanisms have not yet been studied. Our models capture glioma growth dynamics, GSC enrichment, and TAM influx, facilitating innovative therapeutic interventions to improve patient outcome.

Sclerosing angiomatoid nodular transformation of the spleen

The authors described a case of sclerosing angiomatoid nodular transformation of the spleen (SANT) in a 50-year-old woman presented with persistent neutrophilia and unintentional weight loss. An incidental splenic mass was initially found on abdominal ultrasound. It was found to be progressive in size and with high likelihood of central necrosis on further CT of abdomen and pelvis. The patient subsequently underwent an uneventful laparoscopic splenectomy. The splenic specimens were sent for laboratory analysis and the histopathological findings were highly suggestive of SANT. The patient then had routine surgical follow-ups and was eventually discharged with no further clinical concern.