Pheochromocytomas (PCCs) and paragangliomas (PGLs; together PPGLs) are uncommon neuroendocrine tumors arising from adrenal medullary chromaffin cells and sympathetic/parasympathetic paraganglia. Though PPGLs predominate in adult populations, pediatric cases of PPGLs represent more aggressive disease outcomes with 12% being diagnosed as metastatic. Metastatic disease (spread to bone, lung, lymph nodes, or liver) occurs in a subset of PPGLs, ranging from 15% to 17% depending on the underlying pathogenic variants. Historically, pulmonary metastases present clinically as multiple small lesions; however, cases of PPGLs with innumerable small metastases (a miliary pattern) overwhelming lung parenchyma define a novel yet exceptionally challenging disease presentation. This pattern of pulmonary lesions upon treatment and/or cellular lysis may lead to both respiratory decompensation as well as prolific catecholamine release, incurring significant morbidity and mortality if not appropriately managed. Of the 2,649 PPGL patients enrolled in our protocol from January 1, 2000, to April 30, 2023, 500 had metastatic disease, 122 were children/adolescents, and 3 of the 122 children/adolescents had extensive pulmonary metastatic disease. All three adolescent patients with extensive pulmonary metastases had cluster 1 PPGLs and suffered hypoxemia (due to pulmonary metastases) leading to overactive hypoxia signaling and catecholamine-induced signs and symptoms [among them hypertension and/or tachyarrhythmia(s)]. Interventions including surgery, chemotherapy, and radiotherapy were pursued. Two patients achieved disease stability, while one patient succumbed to disease. Ultimately these divergent outcomes emphasize the importance of recognizing poor prognostic factors and aggressive disease early, to select appropriate treatments. Optimal management of these patients must consider complications of catecholamine excess and the profound influence of hypoxia. Herein, we describe three adolescent cases of extensive pulmonary metastatic PPGL and the unique clinical challenges faced in treating these tumors alongside relevant literature to provide guidance on appropriate interventions (ClinicalTrials.gov identifier: NCT00004847).

To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)–related spinal bone metastases. Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7 • Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. • [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7

We present a unique case of primary intraosseous paraganglioma (PGL) originating from maxillary bone. PGL is a neurosecretory neoplasm that arises from cells believed to originate from the neural crest. A 30-year-old woman presented with right facial pain and swelling, along with palpitations. Computed tomography (CT) imaging revealed a 3.3 × 3.1 × 2.3 cm mass in the anterior maxilla, and biochemical results showed elevated plasma dopamine, 3-methoxytyramine, and chromogranin A levels. Biopsy confirmed a PGL, with positive expression of synaptophysin, chromogranin A, and GATA-3. Whole-body positron emission tomography/computed tomography (PET/CT) scans showed avidity on 18F-fluorodopa (18F-FDOPA), 68Ga-DOTA(0)-Tyr(3)-octreotate ​​ (68Ga-DOTATATE), and 18F-fluorodeoxyglucose (18F-FDG). No other lesions (primary or metastatic) were found. Proton beam therapy was chosen over surgery due to potential complications and patient's preference. Following radiotherapy, she experienced symptom relief, with dopamine levels decreasing and chromogranin A normalizing, with the lesion remaining stable on 11-month follow-up imaging. This case highlights the rarity of primary bone PGLs and underscores the importance of comprehensive diagnostic approaches combining physical examinations, biochemical testing, functional imaging, and histopathological analysis properly guiding personalized treatment strategies. Additionally, proton beam therapy emerges as a highly suitable treatment option for head and neck paragangliomas (HNPGLs), offering effective tumor control with minimal complications.

BACKGROUND:Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS:Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS:In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION:Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Chronic granulomatous disease (CGD) is a rare inborn error of immunity, resulting from a defect in nicotinamide adenine dinucleotide phosphate oxidation and decreased production of phagocyte reactive oxygen species. The main clinical manifestations are recurrent infections and chronic inflammatory disorders. Current approaches to management include antimicrobial prophylaxis and control of inflammatory complications. Hematopoietic stem cell transplantation or gene therapy can provide definitive treatment. Gastrointestinal and hepatic manifestations are common in CGD and include structural changes, dysmotility, CGD-associated inflammatory bowel disease, liver abscesses, and noncirrhotic portal hypertension. The findings can be heterogeneous, and the management is complex in light of the underlying immune dysfunction. This review describes the various clinical findings and the latest studies in management of gastrointestinal and hepatic manifestations in CGD, as well as the management experience at the National Institutes of Health.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

CONTEXT:The skeletal phenotype of patients with MEN2B has been described but fracture risk in these patients has not yet been evaluated.OBJECTIVE:This work aims to better delineate fracture risk in patients with multiple endocrine neoplasia type 2B (MEN2B).METHODS:This case series with chart review was conducted at the National Institutes of Health, Pediatric Oncology Branch. A total of 48 patients with MEN2B were identified, with an age range of 5 to 36 years, median of 19; 24 of 48 (50%) patients were female. Medical records, demographic information, available imaging, and laboratory results were reviewed. History up to age 19 was included in the statistical analyses.RESULTS:Of the 48 patients with MEN2B, 20 patients experienced at least one fracture. The majority (n = 18) experienced their first fracture at or before age 19. The observed frequency of fracture occurrence throughout childhood (0-19 years) was 38%, with very little difference between males and females. This frequency is higher than the 9.47 to 36.1 fractures per 1000 persons per year that has been reported in healthy pediatric cohorts in the United States. Less common sites of fracture including vertebral compression fracture and pelvic fractures were observed in patients with MEN2B.CONCLUSION:In this group of patients with MEN2B, there was an increased overall risk of fracture compared to general pediatric cohorts in the United States. Less common sites of fracture were also observed. This suggests a possible effect of an activating RET mutation on bone physiology and warrants further investigation.

BACKGROUND. Recent professional society guidelines for radionuclide imaging of sporadic pheochromocytoma (PHEO) recommend F-18-fluorodihydroxyphenylala-nine (F-18-FDOPA) as the radiotracer of choice, deeming Ga-68-DOTATATE and FDG to be second- and third-line agents, respectively. An additional agent, F-18-fluorodopamine (F-18-FDA), remains experimental for PHEO detection. A paucity of research has performed head-to-head comparison among these agents. OBJECTIVE. The purpose of this study was to perform an intraindividual comparison of Ga-68-DOTATATE PET/CT, FDG PET/CT, F-18-FDOPA PET/CT, F-18-FDA PET/CT, CT, and MRI in visualization of sporadic primary PHEO. METHODS. This prospective study enrolled patients referred with clinical suspicion for sporadic PHEO. Patients were scheduled for Ga-68-DOTATATE PET/CT, FDG PET/CT, F-18-FDOPA PET/CT, F-18-FDA PET/CT, whole-body staging CT (portal venous phase), and MRI within a 3-month period. PET/CT examinations were reviewed by two nuclear medicine physicians, and CT and MRI were reviewed by two radiologists; differences were resolved by consensus. Readers scored lesions in terms of confidence in diagnosis of PHEO (1-5 scale; 4-5 considered positive for PHEO). Lesion-to-liver SUVmax was computed using both readers' measurements. Interreader agreement was assessed using intraclass correlation coefficients (ICCs) for SUVmax. Analysis included only patients with histologically confirmed PHEO on resection. RESULTS. The analysis included 14 patients (eight women, six men; mean age, 52.4 +/- 16.8 [SD] years) with PHEO. Both Ga-68-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, F-18-FDOPA PET/CT in 11, F-18-FDA PET/CT in 7, CT in 12, and MRI in 12. Mean conspicuity score for PHEO was 5.0 +/- 0.0 for F-18-FDOPA PET/CT, 4.7 +/- 0.5 for MRI, 4.6 +/- 0.8 for F-18-FDA PET/CT, 4.4 +/- 1.0 for Ga-68-DOTATATE PET/CT, 4.3 +/- 1.0 for CT, and 4.1 +/- 1.5 for FDG PET/CT. The positivity rate for PHEO was 100.0% (11/11) for F-18-FDOPA PET/CT, 100.0% (12/12) for MRI, 85.7% (6/7) for F-18-FDA PET/CT, 78.6% (11/14) for FDG PET/CT, 78.6% (11/14) for Ga-68-DOTATATE PET/CT, and 66.7% (8/12) for CT. Lesion-to-liver SUVmax was 10.5 for F-18-FDOPA versus 3.0-4.2 for the other tracers. Interreader agreement across modalities ranged from 85.7% to 100.0% for lesion positivity with ICCs of 0.55-1.00 for SUVmax measurements. CONCLUSION. Findings from this small intraindividual comparative study support F-18-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PHEO. CLINICAL IMPACT. This study provides data supporting current guidelines for imaging evaluation of suspected PHEO.

Although rare, a metastatic renal cell carcinoma could present with 68Ga-DOTATATE avidity. A 66-year-old man with von Hippel-Lindau syndrome (VHL) presented with 68Ga-DOTATATE uptake in the pancreatic head, splenic hilar region, and multiple osseous sites, including the right lateral portion of the T9 vertebrae. Biopsy of the T9 lesion confirmed metastatic renal cell carcinoma. Various VHL-associated cancers may display 68Ga-DOTATATE avidity, which can change and guide clinical decisions for the patient.

Somatostatin receptor (SSTR) imaging has brought about impactful changes in clinical management of neuroendocrine tumors (NETs), including pheochromocytoma and paraganglioma (PPGL) ([ 1 ][1] , [ 2 ][2]). It allows tumor detection and disease characterization and is mandatory for selecting patients

DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.

The study identifies the importance of positron emission tomographic (PET) and anatomic imaging modalities and their individual performances in detecting succinate dehydrogenase A (SDHA)-related metastatic pheochromocytoma and paraganglioma (PPGL). The detection rates of PET modalities—68Ga-DOTATATE, 18F-FDG, and 18F-FDOPA—along with the combination of computed tomography (CT) and magnetic resonance imaging (MRI) are compared in a cohort of 11 patients with metastatic PPGL in the setting of a germline SDHA mutation. The imaging detection performances were evaluated at three levels: overall lesions, anatomic regions, and a patient-by-patient basis. 68Ga-DOTATATE PET demonstrated a lesion-based detection rate of 88.6% [95% confidence interval (CI), 84.3–92.5%], while 18F-FDG, 18F-FDOPA, and CT/MRI showed detection rates of 82.9% (CI, 78.0–87.1%), 39.8% (CI, 30.2–50.2%), and 58.2% (CI, 52.0–64.1%), respectively. The study found that 68Ga-DOTATATE best detects lesions in a subset of patients with SDHA-related metastatic PPGL. However, 18F-FDG did detect more lesions in the liver, mediastinum, and abdomen/pelvis anatomic regions, showing the importance of a combined approach using both PET modalities in evaluating SDHA-related PPGL.

Abstract Background Within a spectrum of cancers implicated by VHL germline pathogenic variants, one rare cancer which may present in patients are pheochromocytomas (PHEOs). These tumors occur in the adrenal glands and predispose patients to a variety of morbid clinical symptoms due to the excess secretion of catecholamines. As a part of these patients’ management, imaging is important to localize the tumors of which there are both morphologic (CT and MRI) and molecular (PET/CT with 18F-FDG, 68Ga-DOTATATE, 18F-DOPA, and 18F-DA) imaging modalities. Purpose To determine which imaging modalities provided the optimal detection of VHL-related PHEO. Methods The study compared detection of 19 PHEOs (18 histologically proven and 1 is a contralateral tumor awaiting resection) in 12 patients. The CT and MRI were evaluated by a body radiologist and the PET/CT of18F-FDG, 68Ga-DOTATATE, 18F-DOPA, and 18F-DA were evaluated by a nuclear medicine physician in a blinded fashion. Both experts graded using a five-point Likert scale (1 – not PHEO and 5 – PHEO). For analysis, the Likert scale was dichotomized with 1-3 designating negative for PHEO and 4-5 positive for PHEO. The findings were reported as detection rates of positive PHEOs found on imaging to the gold standard of pathologically (aside from one contralateral PHEO awaiting surgery) proven PHEOs. The McNemar test was performed to compare the statistical relevance of detection rates between histology and the imaging modalities. Two-sided p values <0.05 were considered significant. Results The detection rates were CT 17/19 [89.5%, 95% CI = 66.9%-98.7%], MRI 17/17 [100%, 95% CI = 80.5%-100%], 18F-FDG PET/CT 16/17 [94.1%, 95% CI = 80.5%-100%], 68Ga-DOTATATE 5/9 [55.6%, 95% CI = 21.2%-86.3%], 18F-DOPA 12/14 [85.7%, 95% CI = 57.2%-98.2%], and 18F-DA 4/6 [66.7%, 95% CI = 22.3%–95.7%]. All McNemar tests showed p-values greater than 0.05, which were not statistically significant. Conclusion The study was performed in a small patient set with VHL-related PHEO showed MRI, with the highest detection percent followed by 18F-FDG PET/CT. More trials with a larger patient set are needed to support the statistical relevance as it was not seen in this study. Furthermore, performing a study on a patient cohort with additional VHL associated cancers could prove clinically beneficial for patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:18 p.m. - 1:23 p.m.

BackgroundPancreaticneuroendocrine tumors (PNETs) are a rare, understudied form of cancer with few curativeoptions, and their occurrence isrising. Withapproximately 4,000 newcasesdiagnosedperyearintheUS,anda5-yearrelativesurvivalrateof54%,it’simperativetounderstandthemolecularmechanismsgoverningPNETcarcinogen-esis.Todate,moststudiesusedwhole-tumorsequencingtocharacterizePNETs,whichhampersthediscoveryoftheirmicroenvironment,cellularcomposition,and celloforigin.Inthisstudy,weusedsingle-cellassaysoncryopreservedprimaryPNETsthatvaryingrade,stage,andmetastasisstatustocharacterizethechromatin andtranscriptomesofsinglecellsobtainedfromresectedtumors. MethodsAssayforTransposaseAccessibleChromatinsequencing(ATAC-seq)isarobustmethodtoprobeareasofaccessiblechromatinwhichlikelyfunctionasregulatory genomicregionscalledenhancers.Weusedanucleiisolationprotocoldesignedtorecovernucleifromcryopreservedtissueforsingle-cellassays.Weperformed single-nucleusATAC-seqandRNA-sequsinga10xgenomicsmultiomicsplatform.Wethenusedasuiteofbioinformatictoolstoperformclustering, marker gene identification, and molecular pathway analysis. ResultsWeidentified several distinct cell populations within PNETs, including cancer associated fibroblasts, immune cells, and cancer cell populations. Our preliminary analysis suggests there is little to no heterogeneity within individual tumorcells. In contrast, each tumor is significantly