Impact of 123 I-MIBG scintigraphy on clinical decision making in pheochromocytoma and paraganglioma

CONTEXT Cross sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is regarded as a first-choice modality for tumor localization in patients with pheochromocytoma and paraganglioma (PPGL). 123I-labeled metaiodobenzylguanidine (123I-MIBG) is widely used for functional imaging but the added diagnostic value is controversial. OBJECTIVE To establish the virtual impact of adding 123I-MIBG scintigraphy to CT or MRI on diagnosis and treatment of PPGL. DESIGN International multicenter retrospective study. INTERVENTION None. PATIENTS 236 unilateral adrenal, 18 bilateral adrenal, 48 unifocal extra-adrenal, 12 multifocal and 26 metastatic PPGL. MAIN OUTCOME MEASURES Patients underwent both anatomical imaging (CT and/or MRI) and 123I-MIBG scintigraphy. Local imaging reports were analyzed centrally by two independent observers who were blinded to the diagnosis. Imaging-based diagnoses determined by CT/MRI only, 123I-MIBG only, and CT/MRI combined with 123I-MIBG scintigraphy were compared with the correct diagnoses. RESULTS The rates of correct imaging-based diagnoses determined by CT/MRI only versus CT/MRI plus 123I-MIBG scintigraphy were similar: 89.4 versus 88.8%, respectively, (P=0.50). Adding 123I-MIBG scintigraphy to CT/MRI resulted in a correct change in the imaging-based diagnosis and ensuing virtual treatment in four cases (1.2%: two metastatic instead of non-metastatic, one multifocal instead of single, one unilateral instead of bilateral adrenal) at the cost of an incorrect change in seven cases (2.1%: four metastatic instead of non-metastatic, two multifocal instead of unifocal and one bilateral instead of unilateral adrenal). CONCLUSIONS For the initial localization of PPGL, the addition of 123I-MIBG scintigraphy to CT/MRI rarely improves the diagnostic accuracy at the cost of incorrect interpretation in others, even when 123I-MIBG scintigraphy is restricted to patients who are at risk for metastatic disease. In this setting, the impact of 123I-MIBG scintigraphy on clinical decision-making appears very limited

A multicenter epidemiological study on second malignancy in non-syndromic pheochromocytoma/paraganglioma patients in Italy

SIMPLE SUMMARY: As no previous studies had assessed the risk of second malignant tumors in patients with pheochromocytomas/paragangliomas (PPGLs), we aimed to evaluate whether these patients could have an increased risk of additional malignancy, comparing them with patients in the general population who had a first malignancy and developed a second malignant tumor. We demonstrated that PPGL patients had higher incidence of additional malignant tumors and the risk of developing a second malignant tumor increased with age at diagnosis. As the main tumors were prostate, colorectal and lung/bronchial cancers in males, and breast cancer, differentiated thyroid cancer and melanoma in females, our findings could have an impact on the surveillance strategy. ABSTRACT: No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. 60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy

Unenhanced CT imaging is highly sensitive to exclude pheochromocytoma: A multicenter study

Background: A substantial proportion of all pheochromocytomas is currently detected during the evaluation of an adrenal incidentaloma. Recently, it has been suggested that biochemical testing to rule out pheochromocytoma is unnecessary in case of an adrenal incidentaloma with an unenhanced attenuation value ≤10Hounsfield Units (HU) at computed tomography (CT). Objectives: We aimed to determine the sensitivity of the 10HU threshold value to exclude a pheochromocytoma. Methods: Retrospective multicenter study with systematic reassessment of preoperative unenhanced CT scans performed in patients in whom a histopathologically proven pheochromocytoma had been diagnosed. Unenhanced attenuation values were determined independently by two experienced radiologists. Sensitivity of the 10HU threshold was calculated, and interobserver consistency was assessed using the intraclass correlation coefficient (ICC). Results: 214 patients were identified harboring a total number of 222 pheochromocytomas. Maximum tumor diameter was 51 (39–74)mm. The mean attenuation value within the region of interest was 36±10HU. Only one pheochromocytoma demonstrated an attenuation value ≤10HU, resulting in a sensitivity of 99.6% (95% CI: 97.5–99.9). ICC was 0.81 (95% CI: 0.75–0.86) with a standard error of measurement of 7.3HU between observers. Conclusion: The likelihood of a pheochromocytoma with an unenhanced attenuation value ≤10HU on CT is very low. The interobserver consistency in attenuation measurement is excellent. Our study supports the recommendation that in patients with an adrenal incidentaloma biochemical testing for ruling out pheochromocytoma is only indicated in adrenal tumors with an unenhanced attenuation value >10HU

Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/ mTOR axis in metastatic pheochromocytoma/ paraganglioma

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients’ liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients’ management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors

Evaluation of the Molecular Pathogenesis of Adrenocortical Tumors by Whole-Genome Sequencing

Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Our aim was to identify novel genetic alterations in adrenocortical adenomas (ACA) without somatic mutations in known driver genes. Whole-genome sequencing was performed on 26 ACA/blood-derived DNA pairs without driver mutations in PRKACA, GNAS and CTNNB1 genes at previous WES (ENSAT study JCEM 2016). These included 12 cortisol-producing adenomas with Cushing syndrome (CS-CPAs), 7 with mild autonomous cortisol secretion (MACS-CPAs), and 7 endocrine-inactive ACAs (EIAs). Seven adrenocortical carcinomas (ACC) were added to the cohort. We developed a bioinformatics pipeline for a comprehensive genome analysis and to reveal differences in variant distribution. Strelka, VarScan2 and ANNOVAR software and an in-house confidence score were used for variant calling and functional annotation. Combined Annotation-Dependent-Depletion (CADD) values were used to prioritize pathogenic variants. Additional focus relied on variants in pathogenically known pathways (Wnt/β-catenin, cAMP/PKA pathway). NovoBreak algorithm was applied to discover structural variations. Two hypermutated CS-CPA samples were excluded from further analysis. Using different filters, we detected variants in driver genes not observed at WES (one p.S45P in CTNNB1 and one p.R206L in PRKACA in two different CS-CPAs). In total, we report 179,830 variations (179,598 SNVs; 232 indels) throughout all samples, being more abundant in ACC (88,954) compared to ACA (CS-CPAs: 31,821; MACS-CPAs: 35,008; EIAs: 29,963). Most alterations were in intergenic (>50%), followed by intronic and ncRNA intronic regions. A total of 32 predicted pathogenic variants were found in both coding (CADD values ≥ 15) and non-coding (CADD values ≥ 5) regions. We found 3,301 possibly damaging and recurrent variants (intergenic mutations removed) (CS-CPAs: 1,463; MACS-CPAs: 1,549; EIAs: 1,268; ACC: 1,660), mostly accumulated in intronic regions. Some of these were detected in members of the Wnt/β-catenin (CS-CPAs: 6; MACS-CPAs: 2; EIA: 1) and cAMP/PKA (CS-CPAs: 6; MACS-CPAs: 7; EIA: 4) pathways (e.g. ADCY1, ADCY2, GNA13, PDE11A). We also found a slightly higher number of structural variations in EIA (3,620) and ACC (3,486) compared to CS-CPAs (977) and MACS-CPAs (2,119). In conclusion, still unrevealed genetic alterations, especially in intronic regions, may accompany early adrenal tumorigenesis and/or autonomous cortisol secretion

Clinical study on 6 cases of urosepsis associated with septic shock

6例のseptic shockを伴うurosepsis症例について全例で糖尿病, 脳血管障害, 癌のいずれかを合併していた.基礎疾患として, 尿路閉塞の他糖尿病に合併する腎乳頭壊死を伴う腎膿瘍, 気腫性腎盂腎炎が重要であった.尿路閉塞のあるseptic shockでは, 抗shock療法や, DICに対する抗凝固療法の効果は疑問であるAt Asama General Hospital, we experienced six cases of urosepsis with septic shock during a period of five years between 1989 and 1993. All six patients, whose average age was 74 years old, recovered. In four patients, the condition was caused by obstructive uropathy. The remaining two cases were caused by renal inflammatory disease, which was complicated by diabetes mellitus. One of them was renal abscess with renal papillary necrosis, and the other was emphysematous pyelonephritis. The patients, who exhibited symptoms such as gram-negative bacteremia, severe hypotension, tachycardia, decrease of urine volume and mental disturbance, were diagnosed with urosepsis with septic shock. In all cases, symptoms such as a high fever of over 39 degrees C, hypoxemia and thrombocytopenia were observed. Renal dysfunction was found in 67%, and both liver dysfunction and disseminated intravascular coagulation (DIC) were found in 50% of the cases. Since no patients suffered from adult respiratory distress syndrome, a high survival rate was apparent. Anti-shock therapy and anti-coagulation therapy were ineffective for the patients who had septic shock due to urinary tract obstruction. Urinary tract drainage was required to treat the latter patients. Nephrectomy could not be avoided in renal parenchymatous inflammatory disease. In the future, what might be essential in therapeutics against urosepsis with septic shock, particularly to avoid nephrectomy, are the treatments such as immunotherapy against endotoxins and their mediators, and hemoperfusion for the removal of endotoxins

High filamin A expression in adrenocortical carcinomas is associated with a favourable tumor behaviour:a European multicentric study

The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton protein filamin A (FLNA) acts as a repressor of IGF2 mitogenic signalling in ACC cells. The aims of this study were to test FLNA expression by immunohistochemistry in 119 ACCs and 26 adrenocortical adenomas (ACAs) and to evaluate its relationship with clinicopathological features and outcome in ACCs. We found that 71.4% of ACCs did not express FLNA, whereas FLNA absence was a rare event in ACAs (15.4%, p &lt; 0.001 vs. ACCs). In addition, the expression of FLNA was associated with a less aggressive tumour behaviour in ACCs. Indeed, the subgroup of ACCs with high FLNA showed a lower ENSAT stage, Weiss score, and S-GRAS score compared to ACCs with low FLNA expression (p &lt; 0.05). Moreover, patients with high FLNA had a longer overall survival than those with low FLNA (p &lt; 0.05). In conclusion, our data suggest that FLNA may represent a “protective” factor in ACCs, and the integration of FLNA immunohistochemical expression in ACC tissues along with other clinical and molecular markers could be helpful to improve diagnostic accuracy and prognosis prediction in ACCs

Unenhanced CT imaging is highly sensitive to exclude pheochromocytoma: a multicenter study

A substantial proportion of all pheochromocytomas is currently detected during the evaluation of an adrenal incidentaloma. Recently it has been suggested that biochemical testing to rule out pheochromocytoma is unnecessary in case of an adrenal incidentaloma with an unenhanced attenuation value ≤10 Hounsfield Units (HU) at computed tomography (CT). We aimed to determine the sensitivity of the 10 HU threshold value to exclude a pheochromocytoma. Retrospective multicenter study with systematic reassessment of preoperative unenhanced CT-scans performed in patients in whom a histopathologically proven pheochromocytoma had been diagnosed. Unenhanced attenuation values were determined independently by two experienced radiologists. Sensitivity of the 10 HU threshold was calculated and interobserver consistency was assessed using the intraclass correlation coefficient (ICC). 214 patients were identified harboring a total number of 222 pheochromocytomas. Maximum tumor diameter was 51 [39-74] mm. The mean attenuation value within the region of interest was 36 ± 10 HU. Only one pheochromocytoma demonstrated an attenuation value ≤10 HU, resulting in a sensitivity of 99.6% (95% CI: 97.5-99.9). ICC was 0.81 (95% CI: 0.75-0.86) with a standard error of measurement of 7.3 HU between observers. The likelihood of a pheochromocytoma with an unenhanced attenuation value ≤10 HU on CT is very low. The interobserver consistency in attenuation measurement is excellent. Our study supports the recommendation that in patients with an adrenal incidentaloma biochemical testing for ruling out pheochromocytoma is only indicated in adrenal tumors with an unenhanced attenuation value >10 H