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![Nuclear imaging studies of a 55-year old male with metastatic pheochromocytoma who tested negative for succinate dehydrogenase B, C, and D mutation. Primary tumor was found in the urinary bladder and was removed with en bloc cystectomy, prostatectomy, with lymphatic node dissection and creation of ileal neobladder in 2005. In 2009, he was diagnosed with metastatic disease with false-negative iodine-123 metaiodobenzylguanidine single photon emission computed tomography( 123 I-MIBG SPECT/CT). At NIH, 123 I-MIBG SPECT/CT (A) was also negative but other nuclear imaging such as 18 F-fluorodopamine ( 18 F-FDA) (B), 18 F-dihydroxyphenylalanine ( 18 F-FDOPA) (C), and especially 2-[ 18 F]- fluoro-2-deoxy-D-glucose positron emission tomography ( 18 F-FDG PET) (D) showed multiple metastatic foci in lymph nodes, lungs, and liver. He underwent radiofrequency ablation of liver lesions. A repeat 18 F-FDG PET/CT after 3 months showed evidence of progression.](profile/James-Reynolds-2/publication/51876188/figure/fig1/AS:339680236195863@1457997487738/Nuclear-imaging-studies-of-a-55-year-old-male-with-metastatic-pheochromocytoma-who-tested.png)
Nuclear imaging studies of a 55-year old male with metastatic pheochromocytoma who tested negative for succinate dehydrogenase B, C, and D mutation. Primary tumor was found in the urinary bladder and was removed with en bloc cystectomy, prostatectomy, with lymphatic node dissection and creation of ileal neobladder in 2005. In 2009, he was diagnosed with metastatic disease with false-negative iodine-123 metaiodobenzylguanidine single photon emission computed tomography( 123 I-MIBG SPECT/CT). At NIH, 123 I-MIBG SPECT/CT (A) was also negative but other nuclear imaging such as 18 F-fluorodopamine ( 18 F-FDA) (B), 18 F-dihydroxyphenylalanine ( 18 F-FDOPA) (C), and especially 2-[ 18 F]- fluoro-2-deoxy-D-glucose positron emission tomography ( 18 F-FDG PET) (D) showed multiple metastatic foci in lymph nodes, lungs, and liver. He underwent radiofrequency ablation of liver lesions. A repeat 18 F-FDG PET/CT after 3 months showed evidence of progression.
Source publication
The purpose of this study was to present the characteristics and outcome of patients with proven pheochromocytoma or paraganglioma who had false-negative iodine-123 metaiodobenzylguanidine single photon emission computed tomography ((123)I-MIBG SPECT). Twenty-one patients with false-negative (123)I-MIBG SPECT (7 males, 14 females), aged 13-55 years...
Context in source publication
Context 1
... multiple tumor sites found per patient, none showed avid 123 I-MIBG uptake. Patient no. 10 with metastatic disease was concomitantly found to have another primary tumor in the right adrenal gland while patient no. 9 developed another primary tumor in bilateral carotid bodies with metastatic disease to the liver, lungs, lymph nodes and bones as shown in Figure 1 after removal of a urinary bladder PGL. In these patients, both primary and metastatic tumors had no uptake of 123 I-MIBG. ...
Citations
... The three clusters are aligned in their approach to radionuclide therapy, utilizing 131 I-MIBG radionuclide therapy in cases where a positive MIBG scan has been obtained, and employing PRRT in cases where a positive gallium DOTATAE scan has been obtained [2,89,103]. 131 I-MIBG, including the novel high specific activity (HSA) 131 I-MIBG, is the best-studied first-line therapeutic option for patients with PPGLs showing slow to moderate progression [2,[131][132][133][134][135][136][137]. ...
Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors.
... Specifically, in ACTH-producing PPGL cases that were MIBG-negative, the average tumor size was significantly smaller (mean 3.6 cm with a SD of 1.01, n = 11) compared with MIBG-positive cases (mean 6.0 cm with a SD of 2.4, n = 15; p = 0.006, t-test). False-negative results are common in SDHB-related pheochromocytoma with high metastatic potential [79] and in cases with RET gene mutations [80]. Other factors leading to false-negative results include hemorrhage or necrosis in cystic lesions [81,82], a lack of VMAT-1 expression [83], and certain medications, including ß-blockers [84]. ...
Pheochromocytoma or paraganglioma (PPGL) originating from chromaffin cells can produce diverse hormones in addition to catecholamines, including adrenocorticotropic hormone (ACTH). In pheochromocytoma, high levels of ACTH might not result in pigmentation as typically observed in Addison’s disease, and patients might not exhibit the symptoms of Cushing’s syndrome, despite ACTH-dependent hypercortisolism. A 63-year-old male patient with hypertension was admitted to our facility, and computed tomography (CT) revealed a large right adrenal tumor. Despite high plasma ACTH (700-1300 pg/mL) and serum cortisol (90-100 µg/dL) levels, no physical pigmentation or Cushingoid symptoms were observed. Urinary metanephrine and normetanephrine levels reached as high as 16.0 mg and 3.2 mg, respectively. ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy was negative. Low-dose dexamethasone paradoxically increased ACTH and cortisol levels, indicating the potential positive feedback regulation of both hormones by glucocorticoids. The patient was diagnosed with an ACTH-producing pheochromocytoma and underwent successful laparoscopic surgery to remove the adrenal tumor under the intravenous administration of a high-dose α-blocker and hydrocortisone. The levels of ACTH, cortisol, and urinary metanephrine/normetanephrine returned close to normal after tumor removal. We report a rare case of pheochromocytoma with extremely high ACTH/cortisol production but without pigmentation or Cushingoid symptoms. We also reviewed previous reports of ACTH-producing PPGL regarding the paradoxical regulation of ACTH/cortisol by glucocorticoids, pigmentation, Cushingoid symptoms, and negativity of ¹²³I-MIBG scintigraphy.
... 123 I-MIBG scintigraphy has a sensitivity of about 83% to 100% and a very high specificity of about 98% to 100% in detecting PCC. However, its sensitivity has been revised downwards in comparative studies with PET imaging, especially for small tumors, SDHx PPGL (particularly SDHB), metastatic PPGLs, and HNPGLs (37)(38)(39)(40). In more aggressive (eg, fast growing tumors) or metastatic lesions, this is most likely due to lower expression of tumor cell membrane transporter systems. ...
Pheochromocytomas/paragangliomas are unique in their highly variable molecular landscape driven by genetic alterations, either germline or somatic. These mutations translate into different clusters with distinct tumor locations, biochemical/metabolomic features, tumor cell characteristics (eg, receptors, transporters), and disease course. Such tumor heterogeneity calls for different imaging strategies in order to provide proper diagnosis and follow-up. This also warrants selection of the most appropriate and locally available imaging modalities tailored to an individual patient based on consideration of many relevant factors including age, (anticipated) tumor location(s), size, and multifocality, underlying genotype, biochemical phenotype, chance of metastases, as well as the patient's personal preference and treatment goals. Anatomical imaging using computed tomography and magnetic resonance imaging and functional imaging using positron emission tomography and single photon emission computed tomography are currently a cornerstone in the evaluation of patients with pheochromocytomas/paragangliomas. In modern nuclear medicine practice, a multitude of radionuclides with relevance to diagnostic work-up and treatment planning (theranostics) is available, including radiolabeled metaiodobenzylguanidine, fluorodeoxyglucose, fluorodihydroxyphenylalanine, and somatostatin analogues. This review amalgamates up-to-date imaging guidelines, expert opinions, and recent discoveries. Based on the rich toolbox for anatomical and functional imaging that is currently available, we aim to define a customized approach in patients with (suspected) pheochromocytomas/paragangliomas from a practical clinical perspective. We provide imaging algorithms for different starting points for initial diagnostic work-up and course of the disease, including adrenal incidentaloma, established biochemical diagnosis, postsurgical follow-up, tumor screening in pathogenic variant carriers, staging and restaging of metastatic disease, theranostics, and response monitoring.
... Tumor differentiation, tumor size, and genetic abnormalities are considered to be the cause of the negative 123 I-MIBG accumulation in malignant PPGLs. Although it has been reported that 60% to 70% of PPGLs express noradrenergic transporters at the cell membrane, independent of hormonal activity (12), decreased expression of specific transporters due to dedifferentiation or other factors is reportedly involved in decreased 123 I-MIBG accumulation, especially in metastatic or recurrent PGs (13)(14)(15). In this case also, 123 I-MIBG was accumulated only in a part of the lesion, indicating that differences in transporter expression may have occurred within the lesion. ...
... Although 123 I-MIBG accumulation is generally low in dedifferentiated tumor cells, high 18 F-FDG uptake in tumor cells suggests the high proliferative potential due to the activated cellular energy metabolism. In cases where the diagnostic performance of 123 I-MIBG is low, such as in malignant PPGL and SDH mutation, 18 F-FDG PET has a high diagnostic value and can be used to evaluate metastases (2,13,14,16). ...
A 50-year-old woman was diagnosed with iron deficiency anemia on general medical examination. Further, contrast-enhanced abdominal CT and magnetic resonance imaging revealed a large hypervascular mass with internal degeneration and necrosis in the retroperitoneal space. She was referred to our hospital for further evaluation and treatment. Because the paraganglioma was most likely as the imaging diagnosis, ¹²³I-MIBG scintigraphy was performed. It revealed the marked abnormal accumulation in the retroperitoneal lesion indicating the paraganglioma and no other abnormal accumulation was noted. Several plasma catecholamines and their urinary metabolites were normal. On the subsequent ¹⁸F-FDG PET/CT, high FDG uptake was found in the retroperitoneal lesion (SUVmax=38). FDG uptake was also found in a small nodule at the base of the lower lobe of the right lung (SUVmax= 9.8). Contrast-enhanced imaging revealed a hypervascular nodule at the base of the right lung, suggesting pulmonary metastasis of a paraganglioma. The abdominal lesion and right lung nodule were excised, and retroperitoneal paraganglioma and pulmonary metastasis were diagnosed based on the pathology findings. In this case, ¹⁸F-FDG PET/CT was useful in the search for paraganglioma metastasis. We report a relationship between ¹²³I-MIBG accumulation and ¹⁸F-FDG uptake in paraganglioma and review the relevant literature.
... It is critical to determine the [ 123 I]MIBG uptake pattern before considering its administration as it has low sensitivity for metastatic paragangliomas, particularly those with SDHB pathogenic variants [147][148][149][150][151] . ...
Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
... However, studies have shown that metastatic cluster 1-, particularly SDHB-related, PPGLs may be less frequently positive on [ 123 I]-MIBG imaging [53]. Therefore, other radionuclide therapies, such as PRRT, may be particularly interesting for cluster 1-related PPGLs, which often show strong SSTR2 expression and positivity on [ 68 Ga]-DOTA-SSA imaging [38 54 55]. ...
Molecular targeted therapy plays an increasingly important role in the treatment of metastatic pheochromocytomas and paragangliomas (PPGLs), which are rare tumors but remain difficult to treat.
This mini-review provides an overview of established molecular targeted therapies in present use, and perspectives on those currently under development and evaluation in clinical trials. Recently published research articles, guidelines and expert views on molecular targeted therapies in PPGLs are systematically reviewed and summarized.
Some tyrosine kinase inhibitors (sunitinib, cabozantinib) are already in clinical use with some promising results, but without formal approval for the treatment of PPGLs. Sunitinib is the only therapeutic option which has been investigated in a randomized placebo-controlled clinical trial. It is clinically used as a first-, second-, or third-line therapeutic option for the treatment of progressive metastatic PPGLs. Some other promising molecular targeted therapies (HIF2α inhibitors, tumor vaccination together with check-point inhibitors, anti-angiogenic therapies, kinase signaling inhibitors) are currently under evaluation in clinical trials. The HIF2α inhibitor belzutifan may prove to be particularly interesting for cluster 1B-/VHL/EPAS1-related PPGLs, while anti-angiogenic therapies seem to be primarily effective in cluster 1A-/SDHx-related PPGLs. Some combination therapies currently being evaluated in clinical trials, such as temozolomide/olaparib, temozolomide/talazoparib or cabozantinib/atezolizumab, will provide data for novel therapy for metastatic PPGLs.
It is likely that advances in such molecular targeted therapies will play an essential role in the future treatment of these tumors, with more personalized therapy options paving the way towards improved therapeutic outcomes.
... These reports suggest that poor differentiation or an increased risk of metastasis may be associated with MIBG scintigraphy-negative PCCs. Additionally, MIBG scintigraphy-negative PCC exhibits a higher frequency of the SDHB mutation, suggesting aggressive disease behavior, than MIBG scintigraphy-positive PCC [15,[19][20][21]. To support this, it is suggested that the differences in VMAT expression may signify a difference in cellular dedifferentiation and tumor aggressiveness [11]. ...
Pheochromocytoma (PCC) is rare catecholamine-producing endocrine tumor that metastasizes in approximately 10% of cases. As a functional imaging of PCC, 123I-metaiodobenzylguanidine (MIBG) scintigraphy was established, and some cases of PCC exhibit negative accumulation on MIBG scintigraphy, indicating a high risk of metastasis. Additionally, germline genetic variants of PCC are evident in approximately 30% of cases, although the genotype-phenotype correlation in PCC, especially the association between genetic mutations and MIBG scintigraphy, remains unclear. A 33-year-old man was admitted to our hospital for further examination for hypertension. He was diagnosed with sporadic PCC, and left adrenalectomy was performed. The adrenal tumor was negative on MIBG scintigraphy. Histology of the tumor revealed a moderately differentiated PCC. Target gene testing revealed a mutation in RET (c.2071G > A). This mutation has been reported to be a tumor-developing gene involved in the pathogenesis of PCC. Moreover, the RET mutation is the only gene mutation reported in a previous study of PCC with negative results on MIBG scintigraphy, except for the SDHB gene mutation, which is a common mutation in metastatic PCC. Correctively, the present RET gene mutation may be associated to MIBG-scintigraphy negative PCC and its pathophysiology. Clinicians should follow such cases more cautiously in clinical practice.
... In a prospective series of 17 patients with SDH-B mutated metastatic PPGLs, SSTR PET imaging with 68 Ga-DOTATATE had a lesionbased detection rate of 98.6%, higher than that of 18 F-FDG PET/CT (85.8%), and 18 F-DOPA PET/CT (61.4%) [46]. The patients with germline SDH-B mutation (~ 40% of all patients with metastatic PPGLs) frequently have a negative 123 I-MIBG scan and thus are not amenable to 131 I-MIBG therapy (Fig. 7) [47,48]. MIBG, however, remains a relevant target in the detection and treatment of metastatic pheochromocytomas [49,50]. ...
Neuroendocrine neoplasia (NEN) is an umbrella term that includes a widely heterogeneous disease group including well-differentiated neuroendocrine tumours (NETs), and aggressive neuroendocrine carcinomas (NECs). The site of origin of the NENs is linked to the intrinsic tumour biology and is predictive of the disease course. It is understood that NENs demonstrate significant biologic heterogeneity which ultimately translates to widely varying clinical presentations, disease course and prognosis. Thus, significant emphasis is laid on the pre-therapy evaluation of markers that can help predict tumour behavior and dynamically monitors the response during and after treatment. Most well-differentiated NENs express somatostatin receptors (SSTRs) which make them appropriate for peptide receptor radionuclide therapy (PRRT). However, the treatment outcomes of PRRT depend heavily on the adequacy of patient selection by molecular imaging phenotyping not only utilizing pre-treatment SSTR PET but ¹⁸ F-Fluorodeoxyglucose ( ¹⁸ F-FDG) PET to provide insights into the intra- or inter-tumoural heterogeneity of the metastatic disease. Molecular imaging phenotyping may go beyond patient selection and provide useful information during and post-treatment for monitoring of temporal heterogeneity of the disease and dynamically risk-stratify patients. In addition, advances in the understanding of genomic-phenotypic classifications of pheochromocytomas and paragangliomas led to an archetypical example in precision medicine by utilizing molecular imaging phenotyping to guide radioligand therapy. Novel non-SSTR based peptide receptors have also been explored diagnostically and therapeutically to overcome the tumour heterogeneity. In this paper, we review the current molecular imaging modalities that are being utilized for the characterization of the NENs with special emphasis on their role in patient selection for radioligand therapy.
... Of note is that patients in this study were not prospectively stratified by genetic mutations. Especially succinate dehydrogenase complex iron sulfur subunit B (SDHB) mutations are associated with an unfavorable prognosis, and false negative 123 I-mIBG scans have been reported [112]. Patient preparation for 131 I-mIBG diagnostic and treatment includes discontinuation of medication that interfere with norepinephrine transporters for at least five half-lives before and seven days after treatment (i.e., blood pressure medication such as combined alpha/beta blocker labetalol and calcium channel blockers, antidepressants, tramadol and pseudoephedrine) to avoid any false negative scans or transporter saturation a priori. ...
'See what you treat and treat what you see, at a molecular level', could be the motto of theranostics. The concept implies diagnosis (imaging) and treatment of cells (usually cancer) using the same molecule, thus guaranteeing a targeted cytotoxic approach of the imaged tumor cells while sparing healthy tissues. As the brilliant late Sam Gambhir would say, the imaging agent acts like a 'molecular spy' and reveals where the tumoral cells are located and the extent of disease burden (diagnosis). For treatment, the same 'molecular spy' docks to the same tumor cells, this time delivering cytotoxic doses of radiation (treatment). This duality represents the concept of a 'theranostic pair', which follows the scope and fundamental principles of targeted precision and personalized medicine. Although the term theranostic was noted in medical literature in the early 2000s, the principle is not at all new to nuclear medicine. The first example of theranostic dates back to 1941 when Dr. Saul Hertz first applied radioiodine for radionuclide treatment of thyroid cells in patients with hyperthyroidism. Ever since, theranostics has been an integral element of nuclear medicine and molecular imaging. The more we understand tumor biology and molecular pathology of carcinogenesis, including specific mutations and receptor expression profiles, the more specific these 'molecular spies' can be developed for diagnostic molecular imaging and subsequent radionuclide targeted therapy (radiotheranostics). The appropriate selection of the diagnostic and therapeutic radionuclide for the 'theranostic pair' is critical and takes into account not only the type of cytotoxic radiation emission, but also the linear energy transfer (LET), and the physical half-lives. Advances in radiochemistry and radiopharmacy with new radiolabeling techniques and chelators are revolutionizing the field. The landscape of cytotoxic systemic radionuclide treatments has dramatically expanded through the past decades thanks to all these advancements. This article discusses present and promising future theranostic applications for various types of diseases such as thyroid disorders, neuroendocrine tumors (NET), pediatric malignancies, and prostate cancer (PC), and provides an outlook for future perspectives.
... 68 Ga-DOTATATE binds to somatostatin receptor type 2 which has a high level of expression in well-differentiated paragangliomas and pheochromocytomas and most SDHB-deficient tumors 17,23,24 , while decreased 123 I-MIBG uptake may be related to an underlying genetic mutation, usually associated with SDHB 23 . In one study, up to 50% of patients with metastatic PPGL, especially those with pathogenic variants in SDHB , reportedly lacked norepinephrine transporter expression and derived no benefit from 131 I-MIBG therapy 25 , emphasizing the importance of establishing tumor MIBG avidity when considering 131 I-MIBG therapy. It is also important to note that non-MIBG-avid PPGL are more aggressive than their 123 I-MIBG avid counterparts, and are associated with increased malignancy rates and increased rates of metastasis 17,23-28 . ...
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Cancer predisposition syndromes (CPS) are increasingly recognized as the underlying cause for a number of pediatric malignancies and up to 40% of PPGL are currently thought to be associated with a hereditary predisposition1,2. With the increasingly widespread availability of functional molecular imaging techniques, nuclear medicine imaging modalities such as 18F-FDG-PET/CT, 123I-MIBG SPECT/CT, and 68Ga-DOTATATE PET/CT now play an essential role in the staging, response assessment and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these imaging modalities targets a different cellular characteristic, such as glucose metabolism (FDG), norepinephrine transporter expression (MIBG), or somatostatin receptor expression (DOTATATE), and therefore can be complementary to anatomic imaging and to each other. Given the recent FDA approval3 and increasing use of 68Ga-DOTATATE for imaging in children4, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it compares to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, and to offer a decision algorithm for the use of functional imaging that can be applied to PPGL, as well as other neuroendocrine malignancies.
