Phe ochromocytomas and paragangliomas (PPGLs) are rare neural crest-derived tumors with malignant potential and a highly variable natural history, where some patients achieve a cure through surgical resection, while others experience an aggressive and protracted disease course characterized by recurrence and metastasis. While currently no definitive curative treatment exists for metastatic PPGLs, ongoing trials and advances in biology of the disease present a beacon of hope. We present a case that illustrates a 15-year treatment journey, illustrating the complexity of metastatic PPGL treatment with different modalities, each with distinct efficacy and toxicity profiles. The choice of treatment is often an art, as much as it is based on evidence, as the clinician must balance among several factors, including tumor-related (pace of progression, tumor burden) and patient-related (functional status, symptoms, general health) ones. Through a stepwise approach, this discussion aims to provide insights into the evolving landscape of metastatic PPGL management.

• Keywords
• Lutathera, catecholamines and metanephrines, chemotherapy, fumarate hydratase, genetics, metastatic disease, neuroendocrine tumors, peptide receptor radionuclide therapy, pheochromocytoma and paraganglioma, tyrosine kinase inhibitor,
• MeSH
• Pheochromocytoma * diagnosis   pathology   secondary   therapy   MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Adrenal Gland Neoplasms * diagnosis   pathology   therapy   MeSH
• Paraganglioma * diagnosis   pathology   secondary   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Studies on HIF-2α variants have shed light on genotype-phenotype correlations in Pacak-Zhuang syndrome. Here, we propose the combination of the timing of variant acquisition and molecular pathogenicity into a schema to understand phenotypic severity, with implications for other diseases.

Alkassi, Cole et al. provide a conceptual framework for understanding how the molecular characteristics and spatiotemporal distribution of HIF2α variants impact the disease phenotype in Pacak–Zhuang Syndrome. This schema has application not only to this syndrome, but also hereditary cancer syndromes and other mosaic diseases.

• Publication type
• Journal Article MeSH

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are rare endocrine tumors that frequently produce catecholamines. Catecholamine-induced cardiometabolic complications substantially contribute to increased morbidity and mortality in PPGL patients prior to surgical resection. OBJECTIVE: To determine whether markers of elevated cardiometabolic risk persist in patients following PPGL resection. METHODS: In this retrospective analysis of a multicenter cohort of patients with PPGLs participating in the prospective ProsPheo study and the ENS@T registry, cardiometabolic risk factors, including glycemic status, dyslipidemia, and body mass index (BMI), were assessed in patients with PPGL at diagnosis and during follow-up. Patients with a history of resected PPGL were compared to a control group with nonfunctioning adrenal adenomas from the ENS@T registry. RESULTS: Patients with a present PPGL or a history of PPGL (n = 188), a metastatic PPGL (n = 27), or a known susceptibility gene pathogenic variant (PV) for the development of PPGL without a history of PPGL (n = 44) were included. We compared the asymptomatic PV carriers to patients with a history of PPGL: those with a history of PPGL showed a significantly higher prevalence of hyperglycemic disorders (P = .013) compared with asymptomatic PV carriers. In patients with a history of PPGL and at least 12 months of follow-up post surgery (n = 113), the prevalence of hyperglycemic disorders (P < .001), as well as the mean HbA1c (5.63%, SD 0.43%), were significantly higher, compared to a control group with nonfunctioning adrenal adenomas (n = 76) of similar age and BMI (HbA1c 5.45%, SD 0.40%; P = .004). CONCLUSION: Glycemic disturbances persist long-term after the resection of PPGL.

• Keywords
• HbA1c, cardiometabolic risk, diabetes, glucose intolerance, paraganglioma, pheochromocytoma,
• MeSH
• Adult MeSH
• Pheochromocytoma * surgery   complications   epidemiology   pathology   MeSH
• Cardiometabolic Risk Factors MeSH
• Blood Glucose analysis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adrenal Gland Neoplasms * surgery   complications   epidemiology   pathology   MeSH
• Follow-Up Studies MeSH
• Paraganglioma * surgery   complications   epidemiology   pathology   MeSH
• Prospective Studies MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Names of Substances
• Blood Glucose MeSH

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

• Keywords
• B cells, cytokine storm, intratumoral immunotherapy, melanoma, pheochromocytoma,
• MeSH
• B-Lymphocytes * immunology   physiology   MeSH
• Pheochromocytoma * immunology   therapy   pathology   MeSH
• Immunotherapy * methods   MeSH
• Interleukin-6 MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Adrenal Gland Neoplasms * immunology   therapy   pathology   MeSH
• Tumor Necrosis Factor-alpha immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Interleukin-6 MeSH
• Tumor Necrosis Factor-alpha MeSH

Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.

• Keywords
• GATA3, Hand2, Neuroendocrine tumors, Paraganglioma, Phox2B, dHand,
• MeSH
• Immunohistochemistry MeSH
• Humans MeSH
• Carcinoma, Neuroendocrine * pathology   MeSH
• Neuroendocrine Tumors * pathology   MeSH
• Paraganglioma * diagnosis   pathology   MeSH
• Transcription Factors metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Transcription Factors MeSH