Pheochromocytoma is a neuroendocrine neoplasm that originates from chromaffin cells of the adrenal medulla. Langerhans cell histiocytosis (LCH) is a proliferative disease of histiocyte-like cells, often associated with activating mutations of the mitogen-activated protein kinase (MAPK) pathway. We present a case of a 49-year-old male with a history of pheochromocytoma, which metastasized to the inferior vena cava eight years after left adrenalectomy. At the same time, it was found that the pheochromocytoma in the metastasis was complicated with LCH, a combination that has not been previously reported. Genetic analysis was carried out by next-generation sequencing (NGS) technology. Somatic mutations of BRAF and RAD54B were detected in Langerhans cells and EPAS1 in pheochromocytoma.

Pheochromocytomas and paragangliomas are rare chromaffin cell-derived tumors characterized by catecholamine-secreting activity. Pheochromocytomas account for 1.7% of pediatric hypertension cases. Surgical resection, the definitive pheochromocytoma treatment, carries risks of hemodynamic instability and cardiovascular complications. Nevertheless, mortality rates decreased significantly in the latter half of the 20th century due to effective perioperative blood pressure (BP) management. The literature on BP management tailored to pediatric pheochromocytoma is limited, while the sustained hypertension rate in this population is high (up to 90%) and related to a high risk of intraoperative complications. In this narrative review, we provide up-to-date recommendations regarding BP management to minimize perioperative comorbidities in children with pheochromocytoma.

Antihypertensive agents, primarily alpha (α)-blockers, should be promptly administered for suspected pheochromocytoma. Beta (β)-blockers may be introduced thereafter to counteract reflex tachycardia. The patient must be salt- and water-replete preoperation. Intraoperatively, stable hemodynamics should be ensured during anesthesia and surgery, and short-acting intravenous medications and resuscitation fluid should be supplied. Postoperatively, patients should be admitted to the pediatric intensive care unit for close monitoring for at least 24-48 h. Genetic testing is recommended for all pheochromocytoma patients. Identifying underlying mutations, like in succinate dehydrogenase subunit B, which is linked to a higher risk of multifocality and metastasis, is imperative for tailoring treatment strategies and prognostication.

Achieving optimal outcomes in pediatric pheochromocytoma relies on preoperative BP optimization with appropriate antihypertensive agents, intraoperative hemodynamic stability, and postoperative routine long-term follow-up to monitor for complications, recurrence, and metastasis. Future research should prioritize well-designed prospective multicenter studies with adequate sample sizes and, where feasible, randomized controlled trials with standardized protocols and appropriate endpoints. These studies should focus on the efficacy and safety of preoperative nonselective versus selective α-blockers, whether as monotherapy or combined with other medications (e.g., calcium channel blockers and/or β-blockers), or treatment without preoperative anti-hypertensives.

Paediatric phaeochromocytomas and paragangliomas (PPGLs), though rare tumours, are associated with significant disability and death in the most vulnerable of patients early in their lives. However, unlike cryptogenic and insidious disease states, the clinical presentation of paediatric patients with PPGLs can be rather overt, allowing early diagnosis, granted that salient findings are recognized. Additionally, with prompt and effective intervention, prognosis is favourable if timely intervention is implemented. For this reason, this review focuses on four exemplary paediatric cases, succinctly emphasizing the now state-of-the-art concepts in paediatric PPGL management.

The aim of this study is comparison the effectiveness of stereotactic, hypofractionated and conventional radiotherapy assessed by the tumor volume changes of paraganglioma located in the head and neck region concerning fractional and total doses.

We analyzed 76 patients after radiotherapy due to paraganglioma who were assigned to 3 groups considering fractional (≤2 Gy, 3-5.5 Gy, ≥6 Gy) and total (≤20 Gy, 21-40 Gy, >40 Gy) doses. The volumes of irradiated tumors were measured and compared based on diagnostic images performed before and after the treatment.

The mean tumor volume after the treatment with the lowest fractional dose (≤2 Gy) was decreased by 14.4 cm3. In patients treated with higher fractional doses (>2 Gy), the mean tumor volumes decreased by less than 1 cm3 for hypofractionated and stereotactic radiotherapy. 15.9 cm3 reduction of the mean tumor volume after the treatment with the highest RT total dose (>40 Gy) was stated. In patients treated with total doses ≤20 Gy and 21-40 Gy, the mean tumor volume was stable and reduced by 1.15 cm3, respectively. The analysis demonstrates a statistically significant (p < 0.05) treatment advantage in patients after the lowest fractional and highest total doses.

The reduction of the tumor's volume was reported after conventional and unconventional radiotherapy. The most significant depletion of the paraganglioma volume was noted after a factional dose ≤2 Gy and a total dose >40 Gy.

Paraganglioma (PGL) is rare, and PGL that arises from the urogenital system is even rarer. Here we report a case of PGL in spermatic cord and review the relevant literatures. We encountered a 15-year-old boy with a history of hypertension for almost 2 years, accompanied with headache and palpitations. His serum and urine catecholamines were elevated, but no adrenal lesions were detected, suggesting the existence of PGL. Upon physical examination, a painless nodule adherent to the spermatic cord in the right scrotum was found. A systemic Ga68 DOTATATE PET-CT was then performed, and it revealed a mass with high DOTATATE uptake in the right scrotum. The CT, MRI, and ultrasound images showed the abundant blood supply to the tumor. Based on the above-mentioned imaging and biochemical information, a diagnosis of PGL was made prior to surgery. After 2 weeks of preparation with Cardura, an open surgery was performed to remove the tumor together with the right testis and right epididymis. The blood pressure increased to 180/100 mmHg when the tumor was touched intraoperatively and decreased to 90/55 mmHg after the tumor was removed. Post-operative pathology confirmed our diagnosis of PGL originating from the spermatic cord. Immunohistochemical (IHC) staining showed SDHB (+), CgA (+), synaptophysin (+), GATA3 (+), CD56 (+), sertoli cells S-100 (+), and Ki67 (5%). Genetic testing revealed a missense mutation in the SDHA gene. Only 16 cases of spermatic cord PGL have been reported to date. Although it is easy to diagnose by histology and IHC examinations, preoperative diagnosis is quite important as it can actually reduce intraoperative complications.

Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment.

This work aimed to evaluate a novel PET radiotracer, 3-[18F]fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL.

3-[18F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.6 ± 17.6 years; range, 19-74 years) with pathologically confirmed or clinically diagnosed PCC/PGL. After intravenous administration of 304 to 475 MBq (8.2-12.8 mCi) of 3-[18F]pHPG, whole-body PET scans were performed at 90 minutes in all patients. 3-[18F]pHPG PET was interpreted for abnormal findings consistent with primary tumor or metastasis, and biodistribution in normal organs recorded. Standardized uptake value (SUV) measurements were obtained for target lesions and physiological organ distributions.

3-[18F]pHPG PET showed high radiotracer uptake and trapping in primary tumors, and metastatic tumor lesions that included bone, lymph nodes, and other solid organ sites. Physiological biodistribution was universally present in salivary glands (parotid, submandibular, sublingual), thyroid, heart, liver, adrenals, kidneys, and bladder. Comparison [68Ga]DOTATATE PET/CT was available in 10 patients and in all cases showed concordant distribution. Comparison [123I]meta-iodobenzylguanidine [123I]mIBG planar scintigraphy and SPECT/CT scans were available for 4 patients, with 3-[18F]pHPG showing a greater number of metastatic lesions.

We found the kinetic profile of 3-[18F]pHPG PET affords high activity retention within benign and metastatic PCC/PGL. Therefore, 3-[18F]pHPG PET imaging provides a novel modality for functional imaging and staging of malignant paraganglioma with advantages of high lesion affinity, whole-body coregistered computed tomography, and rapid same-day imaging.

We seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL).

This single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy.

76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p<0.0001). Across PPGL, SIZEPASS >1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P<0.001). It retained an accuracy >90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status.

The SIZEPASS>1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status.

Pheochromocytoma/neuroblastoma composite tumors are rare entities for which little is known. We report an atypical case of a 39-year-old man with secondary bone locations of a composite tumor, 7 years after resection of adrenal neuroblastoma, with constitutional alteration of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 whose role is unknown. The diagnosis of a peripheral neuroblastic tumor in adulthood is difficult and even more so when it is a composite tumor. In the absence of a standard of care, management is varied and discussions about treatment modalities for these patients are complex.

Embolization in pediatric patients encompasses a large spectrum of indications, ranging from the elective treatment of congenital diseases of the cardiovascular system to the urgent management of acute hemorrhagic conditions. In particular, the endovascular treatment of central and peripheral vascular malformations and hypervascular tumors represents a wide chapter for both congenital and acquired situations. Thanks to the progressive availability of low-profile endovascular devices and new embolic materials, the mini-invasive approach has gradually overtaken surgery. In this review, the main embolization procedures will be illustrated and discussed, with a focus on clinical indications and expected outcomes. The most recent mini-invasive techniques will be described, with hints on the cutting-edge devices and embolic materials.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with metastatic potential. Both 68Ga-DOTATATE and 18F-FDG PET/CT scans have been demonstrated to have important roles in imaging PPGLs, but less is known about the performance of PET/MRI for PPGLs. The study is aimed to investigate whether diffusion-weighted imaging-MRI (DWI-MRI) has an added value to PET imaging in the identification of PPGL lesions by means of integrated PET/MRI.

Eleven patients who underwent both 18F-FDG and 68Ga-DOTATATE PET/MRI within 2 weeks were retrospectively included in the study. A total of 56 PPGL lesions were analyzed, and lesion-based detection rates of 68Ga-DOTATATE PET, 18F-FDG PET, DWI-MRI, and PET/MRI were calculated and compared, respectively.

68Ga-DOTATATE PET was superior to 18F-FDG PET and DWI-MRI in imaging PPGLs with a lesion-based detection rate of 96.4% (54/56) (95% confidence interval [CI], 87.7%-99.6%), 85.7% (48/56) (95% CI, 76.3%-95.2%), and 89.3% (50/56) (95% CI, 80.9%-97.6%), respectively. PET/MRI with DWI could improve the detection rate of 68Ga-DOTATATE and 18F-FDG PET alone up to 100% in metastatic PPGLs. Lesions of PPGL demonstrated markedly higher tracer uptake in 68Ga-DOTATATE PET than in 18F-FDG PET (P = 0.009 for primary lesion, P = 0.033 for metastases).

68Ga-DOTATATE PET showed a higher detection rate than 18F-FDG for PPGLs. In integrated PET/MRI, MRI had an added value to 18F-FDG PET but not much to 68Ga-DOTATATAE PET in identifying PPGL lesions.

Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient's tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.

Peptide receptor radionuclide therapy (PRRT) is used to treat patients with advanced malignant pheochromocytomas (PCCs) and paragangliomas (PGLs). Patients are at risk of a PRRT-induced catecholamine crisis, and standard guidelines regarding the prevention and management of infusion reactions are lacking. In this case series, the institutional experience of five sequential patients with metastatic PCCs and PGLs receiving PRRT on an outpatient basis is described, of which four had symptomatic tumors and three had a high burden of disease. All patients with symptomatic tumors were treated with preventive management prior to the initiation of PRRT, and no infusion reactions or catecholamine crises were documented. PRRT may be delivered safely on an outpatient basis for patients with metastatic PCCs and PGLs with the involvement of an interdisciplinary team.

The presence or future development of metastatic pheochromocytomas or paragangliomas (mPPGLs) can be difficult to diagnose or predict at initial presentation. Since production of catecholamines from mPPGLs is different from non-metastatic tumors (non-mPPGLs), this study aimed to clarify whether presenting catecholamine-related signs and symptoms (cSS) might also differ.

The study included 249 patients, 43 with mPPGL and 206 with non-mPPGL. Clinical data at the time of biochemical diagnosis (i.e. at entry into the study) were used to generate a cumulative score of cSS for each patient.

Patients with mPPGL were significantly younger (43.3 ± 14 vs. 48.9 ± 16.1 years) and included a lower proportion of females (39.5% vs. 60.7%) than patients with non-mPPGLs. Frequencies of signs and symptoms did not differ between the two groups. Patients with mPPGLs had lower (P < 0.001) urinary excretion of epinephrine (3.5 (IQR, 1.9-6.5) µg/day) than those with non-mPPGLs (19.1 (IQR, 4.3-70.2) µg/day). There was no difference in urinary excretion of norepinephrine. In patients with mPPGLs a high cSS score was associated with high urinary excretion of norepinephrine and normetanephrine. In contrast, in patients with non-mPPGLs, a high cSS was associated with high urinary excretion of epinephrine and metanephrine.

Although presenting signs and symptoms were associated with production of norepinephrine in patients with mPPGLs and of epinephrine in patients with non-mPPGLs, there were no differences in signs and symptoms between the two groups. Therefore, consideration of signs and symptoms does not appear helpful for distinguishing patients with and without mPPGLs.

Pheochromocytomas and paragangliomas are rare tumors arising, respectively, from the adrenal medulla and extra-adrenal sympathetic or parasympathetic paraganglia. The main therapeutic objectives in case of metastatic disease are the reduction of tumor burden and the control of symptoms resulting from excessive catecholamine secretion. Treatment choices constitute not only a wait and see attitude, locoregional approaches, chemotherapy regiments but also radiopharmaceutical agents, and they should be discussed in a specialized multidisciplinary board. This review will briefly discuss the radiopharmaceutical modalities in patients with pheochromocytomas and paragangliomas (I-MIBG and PRRT).

I-MIBG (Azedra) has received FDA approval for patients with iobenguane-scan-positive, unresectable, locally advanced or metastatic pheochromocytomas and paragangliomas who require systemic anticancer therapy, whereas peptide receptor radionuclide therapy using radiolabelled somatostatin analogues is currently performed in compassionate use, with very promising results. No prospective head-to-head comparison between the modalities has been conducted to date.

Promising results have been reported for both radiopharmaceutical agents, mostly in the setting of retrospective series. No prospective head-to-head comparison between the modalities is yet available.

To compare metastatic pheochromocytoma/paraganglioma (MPP) patients with germline SDHB mutations (SDHB MPP) and without SDHB mutations (non-SDHB MPP) in terms of baseline clinical manifestations, tumor characteristics, and outcomes.

Clinical data were retrospectively reviewed in 101 MPP patients, including 34 SDHB MPP patients and 61 non-SDHB MPP patients.

SDHB MPP patients presented at a younger age at onset, diagnosis, or metastasis (25 ± 16 vs 36 ± 14, 28 ± 17 vs 38 ± 15, and 31 ± 17 vs 44 ± 14 years old, respectively, P < .01 for all) than non-SDHB patients. Compared with their non-SDHB counterparts, SDHB patients were more likely to have paragangliomas (83% vs 47%, P < .05), synchronous metastases (44% vs 23%, P < .05), bone metastases (80% vs 48%, P < .01), and a shorter progression-free survival (3 years vs 5 years, P < .01). The Ki-67 index was higher in SDHB tumors (P < .05). The 5- and 10-year survival rates were 79% and 74%, respectively, in all patients. Seventeen patients died from MPP, and the time from metastasis to death in patients who had received systemic therapy was significantly longer than in those who had not (3.1 ± 1.5 vs 1.4 ± 0.7 years, P < .01).

Compared with MPP patients without SDHB mutations, MPP patients with SDHB mutations were younger at onset, diagnosis, or metastasis; had a higher incidence of synchronous metastases, higher ratio of paraganglioma, and higher Ki-67 index; had a shorter postoperative progression-free survival; and were more likely to develop bone metastasis or sole liver metastasis. Our results suggest that patients with SDHB mutations should be identified early and monitored regularly to achieve optimal clinical outcomes.

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype-phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.

Pheochromocytoma (PC) and paraganglioma (PGL) are rare neuroendocrine tumors that occur throughout the body from the base of the skull to the pelvis. Sympathetic catecholamine-secreting tumors may be associated with hyperadrenergic symptoms and long-term morbidity if they are untreated. Typically biochemically silent, head and neck PGLs may result in cranial nerve palsies and symptoms due to localized mass effect. Tumors can arise sporadically or as part of an inheritable PC-PGL syndrome. Up to 40% of tumors are recognized to be associated with germline mutations in an increasing array of susceptibility genes, including those that appear to arise sporadically. Most commonly, up to 25% of all PC-PGLs are associated with mutations in one of the succinate dehydrogenase (SDH) enzyme subunit genes. The resulting familial PC-PGL syndrome varies according to the affected enzyme subunit (most commonly SDHB and SDHD mutations) with respect to tumor prevalence, location, age of onset, and risk of malignancy. Patients with SDH enzyme mutations have increased lifetime risk of developing multifocal tumors and malignancy. Early recognition of individuals at high risk, genetic testing, screening of family members, and lifelong surveillance programs are recommended, but not without health, economic, and psychologic implications. Anatomic and functional imaging is key to diagnosis, staging, treatment planning, and lifelong surveillance of these individuals. Radiologists must be aware of the imaging appearance of these varied tumors.^©RSNA, 2019.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare, heterogeneous neuroendocrine neoplasms of the autonomous nervous system of chromaffin cell origin that may arise within the adrenal medulla (PCCs) or the sympathetic and parasympathetic paraganglia (PGLs). Currently referred to by the umbrella term pheochromocytomas-paragangliomas (PPGLs), these distinct tumors are characterized by specific histopathology as well as biological and clinical profiles. PPGLs may occur as part of hereditary syndromes (40% of cases) or as sporadic tumors. Currently, there are 12 different hereditary syndromes with characteristic genetic abnormalities, at least 15 well-characterized driver genes and distinct tumor metabolic pathways. Based on the Cancer Genome Atlas (TCGA) taxonomic schemata, PPGLs have been classified into three main clusters of specific genetic mutations and tumor pathways with clinical, biochemical, and prognostic implications. Imaging plays a pivotal role in the initial diagnosis, tumor characterization, evaluation of treatment response, and long-term surveillance. While MDCT and MRI help in the anatomic localization, SPECT, and PET using different radiotracers are crucial in the functional assessment of these tumors. Surgery, chemotherapy, and radiotherapy are currently available treatment options for PPGLs; antiangiogenic drugs are also being used in treating metastatic disease. Evolving knowledge regarding the different genetic abnormalities involved in the pathogenesis of PPGLs has identified potential therapeutic targets that may be utilized in the discovery of novel drugs.

Prognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors.

To describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG.

Retrospective chart and imaging review at a tertiary referral center.

Six hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment.

Median 18 800 MBq 131-I MIBG.

Overall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A).

Median survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3-6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival.

Imaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.

A 52-year-old male who had chronic hypertension for several years presented with abrupt epistaxis. The CT scan revealed a 40 mm × 40 mm mass in the nasal cavity intended to the maxillary sinus and the base of skull. Nasal endoscope biopsy and serum/urinary catecholamine detection conformed an ectopic noradrenaline-secreting pheochromocytoma. The present research was to discuss the clinical characteristics of the rare pheochromocytoma and the palliative interventional embolization for it.

SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed.

This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs.

We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs.

We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion.

Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Cytosolic calcium (_cCa²⁺) entry into mitochondria is facilitated by the mitochondrial membrane potential (ΔΨm), an electrochemical gradient generated by the electron transport chain (ETC). Is has been assumed that as long as mutations that affect the ETC do not affect the ΔΨm, the mitochondrial Ca²⁺ (_mCa²⁺) homeostasis remains normal. We show that knockdown of NDUFAF3 and SDHB reduce ETC activity altering _mCa²⁺ efflux and influx rates while ΔΨm remains intact. Shifting the equilibrium toward lower [Ca²⁺]_m accumulation renders cells resistant to death. Our findings reveal an unexpected relationship between complex I and II with the _mCa²⁺ homeostasis independent of ΔΨm.

In pheochromocytoma/paraganglioma, nontumorous high 18F-fluorodeoxyglucose accumulations are observed in both beige and brown adipose tissues. Recognizing this feature of 18F-fluorodeoxyglucose accumulation can help physicians make precise diagnoses and help them avoid the pitfalls of a false-positive 18F-fluorodeoxyglucose positron emission tomography result, preventing unnecessary interventions.

Genitourinary (GU) malignancies are a diverse group of common and uncommon neoplasms that may be associated with significant mortality. Metastases from GU neoplasms are frequently encountered in the chest, and virtually all thoracic structures can be involved. Although the most common imaging manifestations include hematogenous dissemination manifesting with peripheral predominant bilateral pulmonary nodules and lymphatic metastases manifesting with mediastinal and hilar lymphadenopathy, some GU malignancies exhibit unique features. We review the general patterns, pathways, and thoracic imaging features of renal, adrenal, urothelial, prostatic, and testicular metastatic neoplasms, as well as provide a discussion of treatment-related complications that might manifest in the chest. Detailed reporting of these patterns will allow the imager to assist the referring clinicians and surgeons in accurate determination of the stage, prognosis, and treatment options available for the patient. Awareness of specific treatment-related complications further allows the imager to enhance patient safety through accurate and timely reporting of potentially life-threatening consequences of therapies.

At present there is no clinical guideline or standardised protocol for the treatment of metastatic or invasive phaeochromocytoma and paraganglioma (collectively known as PPGL) due to the rarity of the disease and the lack of prospective studies or extended national databases. Prognosis is mainly determined by genetic predisposition, tumour burden, rate of disease progression, and location of metastases. For patients with progressive or symptomatic disease that is not amenable to surgery, there are various palliative treatment options available. These include localised therapies including radiotherapy, radiofrequency, or cryoablation, as well as liver-directed therapies for those patients with hepatic metastases (e.g., transarterial chemoembolisation) and systemic therapies including chemotherapy or molecular targeted therapies. There is currently intense research interest in the value of radionuclide therapy for neuroendocrine tumours, including phaeochromocytoma and paraganglioma, with either iodine-131 (131I)-radiolabelled metaiodobenzylguanidine or very recently peptide receptor radionuclide therapy (PRRT), and the most important contemporary clinical studies will be highlighted in this review. The studies to date suggest that PRRT may induce major clinical, biochemical, and radiological changes, with 177Lu-DOTATATE being most efficacious and presenting less toxicity than 90Y-DOTATATE. Newer combination therapies with combined radioisotopes, or combinations with chemotherapeutic agents, also look promising. Given the favourable efficacy, logistic, and safety profiles, we believe that PRRT will probably become the standard treatment for inoperable metastatic PPGL in the near future, but we await data from definitive randomised controlled trials to understand its role.

Metastatic pheochromocytoma and paraganglioma (PCs/PGLs) show high germline mutation, and ¹⁸F-FDG and ⁶⁸Ga-DOTA peptide positron emission tomography/computed tomography (PET/CT) imaging are recommended for the diagnosis of metastatic of PCs. However, there has been lack of direct comparison of the two modalities in the diagnosis of metastatic of PCs up to now.

To evaluate and compare the value of localization of ⁶⁸Ga-somatostatin receptor analogs and ¹⁸F-FDG in the diagnosis of metastatic PCs/PGLs.

A comprehensive literature search of PubMed/MEDLINE, ScienceDirect, and Web of Science was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines published in August 2016. We critically reviewed all studies based on the PICOS criteria. QUADAS-2 was used to evaluate the quality of the methodology of the included studies.

This meta-analysis included 17 studies (629 patients, average age [mean ± SD] = 42.7 ± 6.3 years). The pooled sensitivity and specificity of ¹⁸F-FDG and ⁶⁸Ga peptides were 0.85 (95% confidence interval [CI] = 0.78-0.91) and 0.55 (95% CI = 0.37-0.73), and 0.95 (95% CI = 0.92-0.97) and 0.87 (95% CI = 0.63-0.96), respectively. The area under the sROC curves of the ¹⁸F-FDG and ⁶⁸Ga peptides were 0.88 (95% CI = 0.85-0.91) and 0.78 (95% CI = 0.74-0.81), respectively. A subgroup analysis demonstrated that the difference at the per-lesion level and gene mutation level was significant.

Compared to ¹⁸F-FDG PET/CT, the ⁶⁸Ga-somatostatin receptor demonstrated good performance in the localization of metastatic PCs/PGLs, especially those with germline mutations. The use of the ⁶⁸Ga-somatostatin receptor can be a new tool in the diagnosis of metastatic PCs/PGLs.

A 23-year-old man was diagnosed with a giant pelvic paraganglioma in September 2013, and a 6-month chemotherapy course was performed. The chemotherapy resulted in stable disease of the tumor for about 1 year. However, in April 2015, the patient complained of fever and diarrhea of more than ten times a day. Endoscopy showed serpiginous (snake-like) ulcers in the cecum, ascending, descending, and sigmoid colons, with granulomas without caseation histologically. The patient was diagnosed with the active stage of Crohn's disease (CD) in June 2015. Oral mesalazine (3000 mg/day) and an elemental diet (900 kcal/day) led to temporary clinical remission. At the beginning of January in 2016, an abdominal abscess and fistula were detected by computed tomography, which needed surgical treatment. Adalimumab administration was started at the beginning of February, since active lesions were detected endoscopically. A second endoscopy showed improvement of the inflammatory lesions 3 months after induction therapy with adalimumab. Clinical remission has been maintained with adalimumab administration, with stable disease of the tumor and no adverse events. To the best of our knowledge, this is the first report of a patient with a paraganglioma who developed CD after chemotherapy. The patient was successfully treated with adalimumab after surgery for his CD.

Paragangliomas are rare neoplasms that arise from neural crest cells of the autonomous system. Herein, we present a case of a 37-year-old patient with a history of retroperitoneal paraganglioma and tuberculous infection presenting with a paraganglioma of the neck that was initially misdiagnosed as metastatic tumor originating from the lungs. Cytological features from fine needle aspiration and immunocytochemistry pointed to the right diagnosis. However, distinguishing between primary and metastatic site of a paraganglioma can be very challenging due to the overlapping features of these entities. Furthermore, this case underlines the value of a detailed medical history in the era of modern diagnostic modalities. Diagn. Cytopathol. 2017;45:565-568. © 2017 Wiley Periodicals, Inc.

Paragangliomas and pheochromocytomas (PPGLs) exhibit variable malignancy, which is difficult to determine by histopathology, amine measurements or tissue genetic analyses.

To evaluate whether a 51-neuroendocrine gene blood analysis has clinical utility as a diagnostic and prognostic marker.

Prospective cohort study. Well-differentiated PPGLs (n = 32), metastatic (n = 4); SDHx mutation (n = 25); 12 biochemically active, Lanreotide treated (n = 4). Nine patients had multiple sampling. Age- and gender-matched controls and GEP-NETs (comparators).

Circulating neuroendocrine tumor mRNA measured (qPCR) with multianalyte algorithmic analysis. Metabolic, epigenomic and proliferative genes as well as somatostatin receptor expression were assessed (averaged, normalized gene expression: mean ± s.e.m.). Amines were measured by HPLC and chromogranin A by ELISA. Analyses (2-tailed): Fisher's test, non-parametric (Mann-Whitney), receiver-operator curve (ROC) and multivariate analysis (MVA). All data are presented as mean ± s.e.m.

PPGL were NETest positive (100%). All exhibited higher scores than controls (55 ± 5% vs 8 ± 1%, P = 0.0001), similar to GEP-NETs (47 ± 5%). ROC analysis area under curve was 0.98 for differentiating PPGLs/controls (cut-off for normal: 26.7%). Mutation status was not directly linked to NETest. Genetic and molecular clustering was associated (P < 0.04) with NETest scores. Metastatic (80 ± 9%) and multicentric (64 ± 9%) disease had significantly (P < 0.04) higher scores than localized disease (43 ± 7%). Progressive disease (PD) had the highest scores (86 ± 2%) vs stable (SD, 41 ± 2%) (P < 0.0001). The area under the curve for PD from SD was 0.93 (cut-off for PD: 53%). Proliferation, epigenetic and somatostatin receptor gene expression was elevated (P < 0.03) in PD. Metabolic gene expression was decreased in SDHx mutations. Repeat NETest measurements defined clinical status in the 9 patients (6 SD and 3 PD). Amine measurement was non-informative. Multivariate analysis identified NETest >53% as an independent prognostic factor.

Circulating NET transcript analysis is positive (100% diagnostic) in well-differentiated PCC/PGL, scores were elevated in progressive disease irrespective of mutation or biochemical activity and elevated levels were prognostic.

Malignant pheochromocytoma represents 10% of all patients with pheochromocytoma. Of these cases, only 5-9% presents without elevation of metanephrines and catecholamines.

A 43-year-old female patient presented with an abdominal tumor. An exploratory laparotomy was performed and the final report was a pheochromocytoma. After ten years, multiple liver lesions were detected and surgical treatment was performed. Pathological evaluation revealed a malignant pheochromocytoma with negative margins after 5 years of follow-up without evidence of disease.

The recurrence rate of malignant pheochromocytoma is 15-20% at ten years and a 5-year survival rate that ranges from 50% to 80%. The presence of synchronous metastases is rare (10-27%), but have been reported until 20 years later with the most common metastatic sites being the local lymph nodes, bone (50%), liver (50%) and lung (30%). The prognostic factor such as size >6cm, age over 45 years, synchronous metastasis and no tumor excision are related with poor prognosis.

Surgical treatment offers the best survival rate and the only chance of cure so far and the goal is an R0 resection as in our case. So it should be the treatment of choice.