Whereas benign pheochromocytomas and paragangliomas are often successfully cured by surgical resection, treatment of metastatic disease can be challenging in terms of both disease control and symptom ...control. Fortunately, several options are available, including chemotherapy, radiation therapy, and surgical debulking. Radiolabeled metaiodobenzylguanidine (MIBG) and somatostatin receptor imaging have laid the groundwork for use of these radiopharmaceuticals as theranostic agents.
I-MIBG therapy of neuroendocrine tumors has a long history, and the recent approval of high-specific-activity
I-MIBG for metastatic or inoperable pheochromocytoma or paraganglioma by the U.S. Food and Drug Administration has resulted in general availability of, and renewed interest in, this treatment. Although reports of peptide receptor radionuclide therapy of pheochromocytoma and paraganglioma with
Y- or
Lu-DOTA conjugated somatostatin analogs have appeared in the literature, the approval of
Lu-DOTATATE in the United States and Europe, together with National Comprehensive Cancer Network guidelines suggesting its use in patients with metastatic or inoperable pheochromocytoma and paraganglioma, has resulted in renewed interest. These agents have shown evidence of efficacy as palliative treatments in patients with metastatic or inoperable pheochromocytoma or paraganglioma. In this continuing medical education article, we discuss the therapy of pheochromocytoma and paraganglioma with
I-MIBG and
Y- or
Lu-DOTA-somatostatin analogs.
Pheochromocytomas and paragangliomas continue to be defined by significant morbidity and mortality despite their several recent advances in diagnosis, localization, and management. These adverse ...outcomes are largely related to mass effect as well as catecholamine-induced hypertension, tachyarrhythmias and consequent target organ damage, acute coronary syndromes, and strokes (ischemic and hemorrhagic stroke). Thus, a proper understanding of the physiology and pathophysiology of these tumors and recent advances are essential to affording optimal care. These major developments largely include a redefinition of metastatic behavior, a novel clinical categorization of these tumors into 3 genetic clusters, and an enhanced understanding of catecholamine metabolism and consequent specific biochemical phenotypes. Current advances in imaging of these tumors are shifting the paradigm from poorly specific anatomical modalities to more precise characterization of these tumors using the advent and development of functional imaging modalities. Furthermore, recent advances have revealed new molecular events in these tumors that are linked to their genetic landscape and, therefore, provide new therapeutic platforms. A few of these prospective therapies translated into new clinical trials, especially for patients with metastatic or inoperable tumors. Finally, outcomes are ever-improving as patients are cared for at centers with cumulative experience and well-established multidisciplinary tumor boards. In parallel, these centers have supported national and international collaborative efforts and worldwide clinical trials. These concerted efforts have led to improved guidelines collaboratively developed by healthcare professionals with a growing expertise in these tumors and consequently improving detection, prevention, and identification of genetic susceptibility genes in these patients.
Context:
Individual variation in the ability to convert excess calories to heat and the effects of dietary macronutrient composition are unclear.
Objective:
Stability and determinants of the energy ...expenditure (EE) response to overconsumption were assessed.
Design, Setting, and Participants:
Twenty subjects (75% male) with normal glucose regulation were evaluated during 24 hours each of energy balance, fasting, and 5 different diets with 200% energy requirements in a clinical research unit.
Interventions:
Five 1-day overfeeding diets were given in random order: high carbohydrate (75%) and low protein (3%); high carbohydrate and normal protein (20%); high fat (46%) and low protein; high fat (60%) and normal protein; and balanced (50% carbohydrates, 20% protein).
Main Outcome Measures:
The 24-hour EE, sleeping EE, and thermic effect of food (TEF) during each diet were measured with a metabolic chamber. Appetitive hormones were measured before and after the diets.
Results:
The EE response to overfeeding exhibited good intraindividual reproducibility. Similar increases above eucaloric feeding in 24-hour EE (mean 10.7 ± 5.7%, P < .001; range 2.9–18.8%) and sleeping EE (14.4 ± 11.3%, P < .001; range 1.0–45.1%) occurred when overfeeding diets containing 20% protein, despite differences in fat and carbohydrate content, but the EE response during overfeeding diets containing 3% protein was attenuated. The percent body fat negatively correlated with TEF during normal protein overfeeding (r = −0.53, P < .01). Fasting peptide YY negatively correlated with TEF (r = −0.56, P < .01) and the increase in sleeping EE (r = −0.54, P < .01) during overfeeding.
Conclusions:
There is an intrinsic EE response to overfeeding that negatively associates with adiposity, although it represents a small percentage of consumed calories.
Overall about 10 to 20% of pheochromocytomas/paragangliomas (PHEOs/PGLs) are metastatic, with higher metastatic potential observed in succinate dehydrogenase subunit B/fumarate hydratase ...(SDHB/FH)-related tumors. Due to the improved availability of biochemical and genetic testing and the frequent use of anatomical/functional imaging, there is currently a higher detection rate of metastatic PHEO/PGL.
A retrospective analysis of 132 patients (27 children, 105 adults) with metastatic PHEO/PGL diagnosed and treated from 2000 to 2014 was conducted.
Seventy-seven (58%) males and 55 (42%) females were included; 39 (30%) have died, with no sex preference. Seventy-three (55%) patients had SDHB mutations; 59 (45%) patients had apparently sporadic tumors (AST). SDHB patients had an average age at primary tumor diagnosis of 31 ± 16 years compared to 40 ± 15 years in AST patients (P<.001). The average metastatic interval (MI) decreased with increasing age in both SDHB and AST patients (P = .013 for both). Only 16% of all primary tumors were smaller than 4.5 cm. Eleven percent of patients had biochemically silent disease, more with SDHB. Of SDHB patients, 23% had metastatic tumors at first diagnosis, compared to 15% of AST patients. Five- and 10-year survival rates were significantly better for metastatic AST than SDHB patients (P = .01). Overall survival was significantly different between children and adults (P = .037); this was mostly attributed to the SDHB patients, in whom children had statistically significantly longer survival than adults (P = .006). The deceased patients all died due to the PHEO/PGL and mainly had noradrenergic phenotypes.
In children, metastatic PHEOs/PGLs are mainly due to SDHB mutations; in adults they are equally distributed between in SDHB mutations and AST, with better 5- and 10-year survival rates for ASTs. In SDHB patients, children survive longer than adults. Primary metastatic tumors, most presenting as noradrenergic PGLs, are larger than 4.5 cm in >80% of patients. The frequency of metastatic tumors from primary AST increases with age, including a decreased MI compared to SDHB tumors. These results support several recommendations that are summarized in the Discussion.
The occurrence of ≥ two distinct types of tumors, one of them paraganglioma (PGL), is unusual in an individual patient, except in hereditary cancer syndromes.
Four unrelated patients were ...investigated, with thorough clinical evaluation. Plasma and tissue catecholamines and metanephrines were measured by high-performance liquid chromatography. Anatomic and functional imaging were performed for tumor visualization. Germline and tumor tissue DNA were analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations. The prolyl hydroxylation and stability of the mutant HIF2α protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes were also investigated. Immunohistochemical staining for HIF1/2α was performed on formalin-fixed, paraffin-embedded tumor tissue.
Patients were found to have polycythemia, multiple PGLs, and duodenal somatostatinomas by imaging or biochemistry with somatic gain-of-function HIF2A mutations. Each patient carried an identical unique mutation in both types of tumors but not in germline DNA. The HIF2A mutations in these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2α interaction with the prolyl hydroxylase domain 2-containing protein, decreasing the hydroxylation of HIF2α, and reducing HIF2α affinity for the von Hippel-Lindau protein and its degradation. An increase in the half-life of HIF2α was associated with upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors.
Our findings indicate the existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia. This new syndrome results from somatic gain-of-function HIF2A mutations, which cause an upregulation of hypoxia-related genes, including EPO and genes important in cancer biology.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare chromaffin cell tumors (PPGLs) that at times raise significant challenges in clinical recognition, diagnosis, and therapy and when ...undiagnosed could associate with severe morbidity. Recent discoveries in PPGL genetics propelled our understanding in the pathophysiology of tumorigenesis and allowed the application of functional classification of pathogenetically distinct groups of PPGLs. This also resulted in a qualitative change in our approach to clinical assessment, diagnosis, and therapy of different subgroups of PPGLs. Establishment of the fact that mutations in multiple components of the PHD-VHL-HIF-2α pathway associate with pseudohypoxia-driven tumorigenesis allowed us not only to better understand the effect of this phenomenon but also to more deeply appreciate the value of functional abnormalities in the physiologic tissue oxygen-sensing mechanism. Mutations in the tricarboxylic acid cycle-related genes opened an additional window into understanding the physiology of one of the basic cellular metabolic pathways and consequences of its disruption. Mutations in the kinase signaling-related genes allow the PPGL field to join a massive innovative process in therapeutic advances in current oncology. New pathophysiologically distinct groups of mutations will widen and deepen our understanding of additional pathways in PPGL tumorigenesis and hopefully introduce additional diagnostic and therapeutic approaches. All of these developments are tremendously important in our understanding of both the normal physiology and pathophysiology of PPGLs and are strong tools and stimuli in the development of modern approaches to all components of medical management.
Context: Ectopic ACTH secretion (EAS) is difficult to diagnose and treat. We present our experience with EAS from 1983 to 2004.
Setting: The study was performed at a tertiary care clinical research ...center.
Patients: Ninety patients, aged 8–72 yr, including 48 females were included in the study.
Interventions and Outcome Measures: Tests included 8 mg dexamethasone suppression, CRH stimulation, inferior petrosal sinus sampling (IPSS), computed tomography, octreotide scan, magnetic resonance imaging, and/or venous sampling. Therapies, pathological examinations, and survival were noted.
Results: Eighty-six to 94% of patients did not respond to CRH or dexamethasone suppression, whereas 66 of 67 had negative IPSS. To control hypercortisolism, 62 patients received medical treatment, and 33 had bilateral adrenalectomy. Imaging localized tumors in 67 of 90 patients. Surgery confirmed an ACTH-secreting tumor in 59 of 66 patients and cured 65%. Nonthymic carcinoids took longest to localize. Deaths included three of 35 with pulmonary carcinoid, two of five with thymic carcinoid, four of six with gastrinoma, two of 13 with neuroendocrine tumor, two of two with medullary thyroid cancer, one of five with pheochromocytoma, three of three with small-cell lung cancer, and two of 17 with occult tumor. Patients with other carcinoids and ethesioneuroblastoma are alive.
Conclusions: IPSS best identifies EAS. Initial failed localization is common and suggests pulmonary carcinoid. Although only 47% achieved cure, survival is good except in patients with small-cell lung cancer, medullary thyroid cancer, and gastrinoma.
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest ...localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30-40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes:
,
,
,
,
,
,
,
,
,
and
; the kinase group or cluster II includes
,
,
,
and
; and the Wnt signaling group or cluster III includes
and
. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.
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