Succinate Dehydrogenase B Research Articles

Comprehensive Investigation of Angiogenesis, PASS Score and Immunohistochemical Factors in Risk Assessment of Malignancy for Paraganglioma and Pheochromocytoma.

A challenging task in routine practice is finding the distinction between benign and malignant paragangliomas and pheochromocytomas. The aim of this study is to conduct a comparative analysis of angiogenesis by assessing intratumoral microvascular density (MVD) with immunohistochemical (IHC) markers (CD31, CD34, CD105, ERG), and S100 immunoreactivity, Ki67 proliferative index, succinate dehydrogenase B (SDHB) expressiveness, tumor size with one the most utilized score Pheochromocytoma of Adrenal Gland Scales Score (PASS), using tissue microarray (TMA) with 115 tumor samples, 61 benign (PASS < 4) and 54 potentially malignant (PASS ≥ 4). We found no notable difference between intratumoral MVD and potentially malignant behavior. The group of potentially malignant tumors is significantly larger in size, has lower intratumoral MVD, and a decreased number of S100 labeled sustentacular cells. Both groups have low proliferative activity (mean Ki67 is 1.02 and 1.22, respectively). Most tumors maintain SDHB expression, only 6 cases (5.2%) showed a loss of expression (4 of them in PASS < 4 group and 2 in PASS ≥ 4). PASS score is easily available for assessment and complemented with markers of biological behavior to complete the risk stratification algorithm. Size is directly related to PASS score and malignancy. Intratumoral MVD is extensively developed but it is not crucial in evaluating the malignant potential.

Abstract 1767: Molecular subclassification of gastrointestinal stromal tumors by genomic backgrounds

Abstract Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. While about 10% of GISTs are known to be developed from the KIT or PDGFRA gain-of-function mutations, the rest, which is the majority of GISTs, is so-called as wild-type GISTs. There are attempts to make subclassification of wild-type GISTs in syndromic or non-syndromic group as promising for understanding of heterogeneity or treatment strategy. Genomic states of succinate dehydrogenase B (SDHB) and neurofibromatosis type 1 (NF1) have been raised as candidates for subclassification of wild-type GISTs. In this presentation, we will discuss our recent three cases of wild-type GISTs, carrying germline pathogenic variants in SDHB or NF1. Two cases with SDHB germline pathogenic variants showed stomach GISTs with good clinical course, the maintained performance status and long survival nevertheless of the recurrence. The other case with an NF1 germline pathogenic variant showed multiple GISTs in small intestine which was controlled surgically and the late onset of other clinical symptoms of NF1. These cases might clinically suggest potential prognostic and predictive markers in genomic alterations of SDHB or NF1 for the cases with wild-type GISTs. Citation Format: Hideki Yamamoto, Eiji Nakada, Seiji Kawano, Fumino Kato, Chika Fukano, Mashu Futagawa, Yusaku Urakawa, Risa Ohsumi, Sayaka Ueno, Hiroyuki Yanai, Akira Hirasawa. Molecular subclassification of gastrointestinal stromal tumors by genomic backgrounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1767.

Combination of the cuproptosis inducer disulfiram and anti‑PD‑L1 abolishes NSCLC resistance byATP7B to regulate the HIF‑1 signaling pathway.

Disulfiram (DSF) is used to treat non‑small cell lung cancer (NSCLC). DSF significantly increases expression of programmed death‑ligand 1 (PD‑L1), which may enhance immunosuppression and immune escape of tumors. Therefore, the present study aimed to investigate the role of combined treatment of DSF and anti‑PD‑L1 in NSCLC resistance. The viability and apoptosis of A549 cells were detected by the Cell Counting Kit‑8 assay and flow cytometry, respectively. The expression levels of ATPase copper‑transportingβ (ATP7B) and PD‑L1 in A549 cells were detected by reverse transcription‑quantitative PCR and western blot analysis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) in A549 cells were detected by respective assay kits. The expression levels of cuproptosis‑associated proteins ferredoxin‑1 (FDX1), ATP7B, solute carrier family 31 member 1 (SLC31A1), succinate dehydrogenase B (SDHB), PD‑L1 and hypoxia inducible factor (HIF)‑1A were analyzed by western blotting in A549 cells. DSF inhibited the viability of A549 cells and promoted expression levels of ATP7B and PD‑L1 at both mRNA and protein levels in A549 cells. The viability of cisplatin (DPP)‑treated A549 cells was increased following DSF treatment. JQ‑1 (a PD‑L1 inhibitor) suppressed the viability of DPP‑treated A549 cells pretreated with DSF. DSF increased expression levels of ATP7B and PD‑L1. The combination treatment of DSF and JQ‑1 in A549 cells increased levels of ROS and MDA, as well as expression levels of FDX1 and SLC31A1; however, combination treatment decreased levels of SOD, as well as expression levels of ATP7B, SDHB, PD‑L1, and HIF‑1A. PX478 (an HIF‑1 inhibitor) acted with DSF to enhance the inhibitory effects on the viability and on the induction of apoptosis of A549 cells. PX478 upregulated the levels of ROS and MDA, while it downregulated levels of SOD in DSF‑treated A549 cells. PX478 promoted expression levels of FDX1 and SLC31A1, while it suppressed expression levels of ATP7B, PD‑L1, and HIF‑1A in DSF‑treated A549 cells. In conclusion, the combined treatment of A549 cells with anti‑PD‑L1 and DSF enhanced the effect of cuproptosis on the inhibition of NSCLC cell viability.

Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers

The molecular basis of reduced autofluorescence in oral squamous cell carcinoma (OSCC) cells relative to normal cells has been speculated to be due to lower levels of free flavin adenine dinucleotide (FAD). This speculation, along with differences in the intrinsic optical properties of extracellular collagen, lies at the foundation of the design of currently-used clinical optical detection devices. Here, we report that free FAD levels may not account for differences in autofluorescence of OSCC cells, but that the differences relate to FAD as a co-factor for flavination. Autofluorescence from a 70 kDa flavoprotein, succinate dehydrogenase A (SDHA), was found to be responsible for changes in optical properties within the FAD spectral region, with lower levels of flavinated SDHA in OSCC cells. Since flavinated SDHA is required for functional complexation with succinate dehydrogenase B (SDHB), decreased SDHB levels were observed in human OSCC tissue relative to normal tissues. Accordingly, the metabolism of OSCC cells was found to be significantly altered relative to normal cells, revealing vulnerabilities for both diagnosis and targeted therapy. Optimizing non-invasive tools based on optical and metabolic signatures of cancers will enable more precise and early diagnosis leading to improved outcomes in patients.

Tumour microenvironment in pheochromocytoma and paraganglioma.

Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10-15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.

Low-grade oncocytic tumour (LOT) of the kidney is characterised by GATA3 positivity, FOXI1 negativity and mTOR pathway mutations.

Aims: We present a 5-case series of low-grade oncocytic tumour of the kidney to further discuss their clinicopathological characteristics. Methods and results: Five patients were included in this study. There were three females and two males aged 45-66years, with a median age of 65years. Four tumours were located in the right kidney, and one was located in the left kidney. Most of the tumour sections were yellow-brown in colour. Tumour sizes ranged from 2.5 to 4.5cm, with a median size of 3cm. Microscopically, the tumours were well-circumscribed but lacked a fibrous capsule; the tumours consisted of monomorphous oncocytic cells arranged mainly in solid and nested architectural patterns. The tumour cells had uniformly round to oval nuclei and often had perinuclear halos but lacked significant irregularities. Immunohistochemically, the tumour cells showed a diffuse and strong positivity for CK7 and were negative for CD117. The tumour cells were also positive for GATA3, E-cadherin, Pax-8, Succinate dehydrogenase B (SDHB) and Fumarate hydratase (FH), and negative for vimentin, Carbonic anhydrase 9 (CA9), CD10, P504s, CK20, TFE3, TFEB, HMB45, ALK and Forkhead box protein I1 (FOXI1). Next-generation sequencing identified genetic variations in these tumours, including MTOR gene mutations (4/5) and PIK3CA gene mutation (1/5). All patients were alive without disease progression at a median follow-up of 32months (range 10-57months). Conclusion: LOT is an emerging renal entity of indolent behaviour that has morphologic overlap with some renal tumours with eosinophilic cytoplasm, primarily with oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma. Familiarity with the distinctive morphological features, immunophenotype and molecular genetics of LOT helps avoid misdiagnosis.

Imagenomics. Findings in PET with 68Ga-DOTA-TOC associated with the detection of the mutation of the succinate dehydrogenase B (SDHB) gene in the screening of hereditary pheochromocytoma/paraganglioma

Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are prognostic predictors in patients with diffuse large B-cell lymphoma (DLBCL). The objective of this study is to evaluate the prognostic impact of the baseline volumetric parameters calculated with positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) and its added value to the molecular characteristics in patients with DLBCL not otherwise specified (NOS).This is a retrospective observational study, which included 35 patients who underwent a baseline 18F-FDG PET/CT prior to treatment. A univariate analysis of the volumetric parameters (MTV and TLG), immunohistochemical study and chromosomal translocations were performed. The method for calculating the volumetric parameters was the SUV 2.5 threshold. The comparison between the predictive models was selected based on the information criterion value of Akaike (AIC), bayesian (BIC) and Harrell's C, after performing a Cox proportional hazards regression model. In addition, a univariate analysis of the volumetric parameters was performed according to the data of the immunohistochemical study using the Wilcoxon–Mann–Whitney test.A univariate analysis revealed that VMT and TLG are predictors of progression-free survival (PFS) and overall survival (OS), with a high discrimination capacity. Adding VMT and TLG to the immunohistochemical study and chromosomal translocation provided a better prognostic value for PFS and OS in patients diagnosed with DLBCL-NOS. Likewise, it was evidenced that the values of the volumetric parameters were lower in patients who presented a germinal center B cell phenotype (GCB) compared to patients with an activated B cell phenotype (ABC) who presented higher values.MTV and TLG added to the immunohistochemical study and chromosomal translocation provided a better prognostic value for PFS and OS in patients diagnosed with DLBCL-NOS.El volumen metabólico tumoral (VMT) y la glicólisis total de la lesión (TLG) son predictores pronósticos en los pacientes con linfoma B difuso de células grandes (LBDCG). El objetivo del presente estudio es evaluar el impacto pronóstico de los parámetros volumétricos basales calculados con la tomografía por emisión de positrones/tomografía computarizada con 18F-fluorodesoxiglucosa (18F-FDG PET/TC) y su valor agregado a las características moleculares en pacientes con LBDCG tipo no especificado (NOS).Se trata de un estudio retrospectivo observacional, en el que se incluyeron 35 pacientes sometidos a un 18F-FDG PET/TC basal previo al tratamiento. Se realizó un análisis univariable de los parámetros volumétricos (VMT y TLG), estudio inmunohistoquímico y traslocaciones cromosómicas. El método para el cálculo de los parámetros volumétricos fue el umbral SUV 2,5. La comparación entre los modelos predictivos se seleccionó en función del valor de criterio de información de Akaike (AIC), bayesiano (BIC) y C de Harrell, después de realizar un modelo de regresión de riesgos proporcionales de Cox. Además, se realizó un análisis univariable de los parámetros volumétricos, según los datos del estudio inmunohistoquímico utilizando la prueba de Wilcoxon–Mann–Whitney.Al realizar un análisis univariable se evidenció que el VMT y la TLG son predictores de la supervivencia libre de progresión (SLP) y de la supervivencia global (SG), con una alta capacidad de discriminación. El añadir el VMT y la TLG al estudio inmunohistoquímico y a la traslocación cromosómica proporcionó un mejor valor pronóstico a la SLP y SG en los pacientes diagnosticados con LBDCG tipo NOS. Así mismo, se evidenció que los valores de los parámetros volumétricos eran menores en los pacientes que presentaron un fenotipo células B centro germinal (GCB) frente a los pacientes con fenotipo células B activadas (ABC) que presentaron valores mayores.El VMT y la TLG añadidos al estudio inmunohistoquímico y a la traslocación cromosómica proporcionan un mejor valor pronóstico a la SLP y a la SG en pacientes diagnosticados con LBDCG tipo NOS.

An exploration in pitfalls in interpreting SDHBimmunohistochemistry.

Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumour types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the succinate dehydrogenase B (SDHB) subunit can help to detect SDH-deficiency, which manifests as complete loss of staining in tumour cells. However, a subset of SDH-deficient tumours can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as 'retained', a diagnostic pitfall complicating interpretation. Herein, we characterise in detail aberrant SDHB-IHC staining patterns in SDH-deficient tumours. We identified 23 tumours from patients with known germline SDHx and/or molecularly confirmed SDHx pathogenic/likely-pathogenic variants in their tumour. Of these, eight (35%) showed significant SDHB-IHC staining: one SDHA-, one SDHB-, three SDHC- and three SDHD-mutated cases. In all eight cases, closer inspection revealed differences in intensity and intracellular distribution of SDHB-IHC staining in tumour cells compared to adjacent non-neoplastic cells: non-neoplastic cells showed intense cytoplasmic coarse granular staining; tumour cells in seven of eight cases showed weak to focally strong, cytoplasmic blush to fine granular staining, in > 80% of cells. The remaining case in the initial block showed variably strong non-granular cytoplasmic staining with globular perinuclear accentuation throughout, only subtly distinct from the staining pattern of non-neoplastic cells. SDHB-IHC performed on two additional blocks in this latter case revealed significant intratumoral heterogeneity, including convincing areas of complete loss. When evaluating SDHB-IHC, care should be taken to distinguish true retained expression from aberrant cytoplasmic expression, which may be difficult to appreciate. Sometimes this may require additional molecular testing.

Value of Immunohistochemical Expression of Apelin, Succinate Dehydrogenase B, Chromogranin B, Human Epidermal Growth Factor Receptor-2, Contactin 4, and Succinyl-CoA Synthetase Subunit Beta in Differentiating Metastatic From Non-Metastatic Pheochromocytoma and Paraganglioma.

ObjectiveWe aimed to retrospectively collect pathologically identified pheochromocytoma and paraganglioma (PPGL) tumor tissues from our center and investigate the expression of apelin and succinyl-CoA synthetase subunit beta (SUCLG2), human epidermal growth factor receptor-2 (HER2 or ERBB-2), contactin 4 (CNTN4), chromogranin B (CHGB), and succinate dehydrogenase B (SDHB) in metastatic and non-metastatic PPGLs, for exploring their roles in the diagnosis of metastatic PPGLs.MethodsA total of 369 patients with pathologically and surgically confirmed PPGLs at Xiangya Hospital, Central South University, between June 2010 and June 2020 were retrospectively included. Sixty patients—12 patients with metastatic PPGLs and 48 patients with non-metastatic PPGLs—were selected through propensity score matching (1:4) to reduce the effect of PPGL type, sex, and age. We observed and quantified the expression of apelin, SDHB, CHGB, ERBB-2, CNTN4, and SUCLG2 in paraffin-embedded samples using immunohistochemical staining.ResultsNo significant differences were observed between the metastatic group and non-metastatic group with respect to the expression of CNTN4 and SUCLG2. The expression of apelin, SDHB, CHGB, and ERBB-2 was significantly different between the two groups. The expression of apelin, SDHB, and CHGB was significantly lower in the metastatic group than that in the non-metastatic group (P < 0.001). ERBB-2 expression was significantly higher in the metastatic group than in the non-metastatic group (P = 0.042). Kaplan–Meier analysis revealed that patients with negative expression of apelin, SDHB, and CHGB showed significantly lower metastasis-free survival than those with positive expression. Multivariate Cox analysis revealed that SDHB and CHGB levels were independently associated with metastasis-free survival.ConclusionThe expression levels of apelin, CHGB, SDHB, and ERBB-2 may be predictive biomarkers for the diagnosis of metastatic PPGLs. Patients with negative expression of apelin, CHGB, and SDHB should be subjected to frequent postoperative follow-up procedures

Thyroid hormone resistance with succinate dehydrogenase-B gene mutation.

Thyroid hormone resistance with succinate dehydrogenase-B gene mutation.

PSXII-19 Organ and cellular contributions to heat production in Brahman and Angus steers

Abstract Reductions in basal metabolism and growth rate appear to contribute to decreased heat production of Bos indicus breeds. Lower metabolic rate may be due to smaller organ size and lower metabolic activity. Liver and heart account for high percentage of metabolic activity relative to their weight, and at a cellular level, mitochondria are responsible for producing energy for cellular maintenance. Our objective was to determine liver and heart weight and evaluate expression of key mitochondrial proteins in Bos indicus (80–100% Brahman) and Bos taurus (80–100% Angus) steers. Steers (n = 14 per breed) were harvested at the university meat laboratory. After evisceration, livers and hearts were weighed, and samples were frozen in liquid nitrogen for further analyses. Western blotting was used to determine expression of proteins in mitochondrial energy production: citrate synthase, a marker of mitochondria content; succinate dehydrogenase B (SDH-B), complex II; cytochrome c oxidase subunit IV, complex IV; and ATP synthase subunit 5A (ATP5A), complex V. Data were analyzed using an unpaired t-test in SAS-JMP. Although steers were similar age at slaughter (P = 0.84), Brahman steers weighed less (P &amp;lt; 0.0001) and thus produced lighter carcasses (P &amp;lt; 0.0001) and smaller livers and hearts (P &amp;lt; 0.0001). On a relative basis (kg organ/kg BW), Brahman tended to possess smaller hearts (P = 0.06) and smaller livers (P = 0.03). Expression of mitochondria proteins in heart did not differ between breeds (P &amp;gt; 0.3). However, Brahman exhibited lower expression of SDH-B (P = 0.005) but tended to have higher expression of ATP5A (P = 0.07) in liver. Altogether, this supports that smaller organ size is a contributing factor to lower heat production in heat-tolerant Brahman steers, and shifts in mitochondria protein expression in liver may impact energy metabolism at the cellular level.

Effects of Cold Exposure on Performance and Skeletal Muscle Fiber in Weaned Piglets.

Simple SummaryMuscle fiber is the basic unit of muscle composition. The type of skeletal muscle fiber can be transformed from fast-twitch to slow-switch or vice versa by internal and external factors. Low-temperature is one of the major environmental factors that influences the growth performance of animals. However, the influence of low-temperature on weaned piglets’ skeletal muscle fiber, and whether this influence is related to mitochondrial function and antioxidant capacity, has not been reported. Our results indicated that low temperature could negatively affect growth performance and nutrient digestibility in weaned piglets. Moreover, evidence was provided to show that low-temperature induces a shift toward oxidative muscle fibers, which may occur through mitochondrial function regulation and increased antioxidative capacity.Low-temperature is one of the most significant risks for the animal industry. In light of this, the present study aimed to explore the effects of low-temperature on growth performance, nutrient digestibility, myofiber types and mitochondrial function in weaned piglets. A total of sixteen 21-day-old male Duroc × Landrace × Yorkshire (DLY) piglets were randomly divided into a control group (CON, 26 ± 1 °C) and a low-temperature group (LT, 15 ± 1 °C), with eight duplicate piglets in each group. The trial period lasted for 21 days. We showed that LT not only increased the ADFI (p < 0.05), as well as increasing the diarrhea incidence and diarrhea index of weaned piglets in the early stage of the experiment (p < 0.01), but it also decreased the apparent digestibility of crude protein (CP), organic matter (OM) and dry matter (DM) (p < 0.05). Meanwhile, in the LT group, the mRNA expression of MyHC IIa (p < 0.05) in longissimus dorsi muscle (LM) and MyHC I (p < 0.01) in psoas muscle (PM) were increased, while the mRNA expression of MyHC IIx in PM was decreased (p < 0.05). In addition, LT increased the mRNA expression of mitochondrial function-related genes citrate synthase (CS) and succinate dehydrogenase-b (SDHB) in LM, as well as increased the mRNA expression of CS (p < 0.05) and carnitine palmitoyl transferase-1b (CPT-1b) (p < 0.01) in PM. Furthermore, LT increased the T-AOC activity in serum and LM (p < 0.01), as well as increased the T-SOD activity in PM (p < 0.05). Taken together, these findings showed that low-temperature could negatively affect the growth performance and nutrient digestibility, but resulted in a shift toward oxidative muscle fibers, which may occur through mitochondrial function regulation.

Immunoexpression of SDHB, FH, and CK20 among eosinophilic renal tumors: A tissue microarray study

BackgroundDifferential diagnosis can be a challenge for eosinophilic subtypes of renal cell tumors due to their overlapping histomorphological and immunohistochemical features. We aimed to investigate the frequency of rare variants of renal cell carcinomas (RCCs) such as succinate dehydrogenase-deficient RCC (SDDRCC), hereditary leiomyomatosis and RCC (HLRCC)-associated RCC, and eosinophilic, solid, and cystic RCC (ESCRCC) in our population. Materials and methodsRenal tumors which could be considered in the eosinophilic tumor category were included: 91 conventional clear cell RCCs with eosinophilic cytoplasm, 72 papillary RCCs, 74 chromophobe RCCs, 88 oncocytomas, and 37 other rare subtypes. Using the tissue microarray method, succinate dehydrogenase B (SDHB), fumarate hydratase (FH), and cytokeratin 20 (CK20) antibodies were performed by immunohistochemistry. Immunohistochemistry was repeated on whole block sections for selected cases. The utility of these antibodies in the differential diagnosis was also investigated. ResultsLoss of SDHB expression was detected in three tumors, two of which showed typical morphology for SDDRCC. In additional two tumors, SDHB showed weak cytoplasmic expression without a mitochondrial pattern (possible-SDHB deficient). None of the tumors showed loss of FH expression. Heterogeneous reactions were observed with SDHB and FH antibodies. Only one ESCRCC was detected with diffuse CK20 positivity. ConclusionSDDRCCs, HLRCC-associated RCCs, and ESCRCCs are very rare tumors depending on the population. Possible weak staining and focal loss of SDHB and FH expression should be kept in mind and genetic testing must be included for equivocal results.

Low-grade oncocytic tumour expands the spectrum of renal oncocytic tumours and deserves separate classification: a review of 23 cases from a single tertiary institute

AimsLow-grade oncocytic tumour (LOT) has recently been introduced as a potential distinct entity.MethodsAt the Indiana University department of pathology, primary renal epithelial neoplasms between 2005 and 2020 were searched after...

Malignant pheochromocytoma: A diagnostic and therapeutic dilemma.

IntroductionMalignant pheochromocytomas are rare endocrine tumors that develop within chromaffin tissue. The diagnosis of malignancy is based on neoplastic recurrence or the presence of metastasis in organs that lack chromaffin tissue. We report a series of four cases because of their diagnostic and therapeutic particularities.Presentation of casewe describe four clinical cases of patients with malignant pheochromocytoma whose Menard triad “headache-palpitations-sweating” was present in three out of four patients, the methoxylated derivatives were measured in 4 patients, 3 of which had high values, all of our patients carried out a CT scan which objectified signs of malignancy, MRI was performed on a single patient; presenting with a neoplastic recurrence; looking for a locoregional invasion.DiscussionPheochromocytoma (PC) is a rare neuroendocrine tumor derived from the chromaffin cells of the adrenal medulla. Its annual incidence is 2 to 8 per million adults. A peak frequency is observed between 30 and 40 years of age. Approximately 10% of pheochromocytomas are malignant and in 10% of cases, bilateral localization is observed. Criteria for malignancy include the invasion of neighboring organs, a large tumor, the presence of lymphadenopathy on imaging, or fixation on scintigraphy. Surgery for MAP is not always curative. In the case of multiple liver metastases, treatment is based on adrenalectomy, which can be effectively combined with chemoembolization, cryoablation, or radiofrequency techniques.ConclusionThe main prognostic factors of the malignant pheochromocytomas are a large tumor volume, the existence or number of visceral metastases, and the presence of a mutation in the SDHB (Succinate dehydrogenase B) gene.

Presyncope in a Woman With Incidental Bladder Mass: A Case of De Novo SDHB Mutation Bladder Paraganglioma

Background: Paragangliomas (PGLs) are catecholamine secreting neuroendocrine tumors originating from extra-adrenal neural crest cells. Urinary bladder paragangliomas (UBPGLs) are extremely rare, accounting for only 0.06% of all bladder tumors. Sporadic UBPGLs associated with Succinate Dehydrogenase B (SDHB) mutation have a higher malignant potential versus patients with a positive family history due to a lack of screening. We present a case of sporadic UBPGL detected early due to follow-up of an incidental bladder mass. Clinical Case: A 31 year-old female presented to the ER with presyncope and lower abdominal pain while running. On arrival she was mildly hypertensive with BP 140/88 mmHg, HR was 98 beats/min, other vital signs were stable. Denied headaches, diaphoresis, or weight loss. No known personal or family history of any endocrine disorders or cancer. CT abdomen pelvis performed for the evaluation of her abdominal pain revealed a large fibroid along with an unexpected finding of a 3 cm enhancing lesion in the right bladder wall, suggestive of a PGL. 24 hr urine total catecholamines and plasma total metanephrines were elevated at 284 mcg (normal range 26-121 mcg/24h), and 386 pg/mL (normal <205 pg/ml) respectively, confirming the diagnosis of UBPGL. Chromogranin A was within the normal range. Metastasis was ruled out with metaiodobenzylguanidine (MIBG) whole-body scan and octreotide scan which showed isolated uptake in the bladder. Pan CT scan was negative for other SBHB mutation associated tumors such as RCC (14% incidence), GIST, and thyroid carcinoma. Genetic testing with PGLNest revealed a heterozygous SDHB mutation (5’-3’ UTR_5’-3’ UTR deletion). Her parents were found to be negative for the mutation. During follow up she developed episodic palpitations. She was treated with alpha followed by beta blocker and underwent successful resection of the tumor with partial cystectomy, and of the fibroid with myomectomy on the same day (TAH was avoided to minimize manipulation of the uterus hence decreasing the risk of intra-abdominal HTN crisis). She has been tumor-free in the three years of follow up post-surgery with imaging and biochemical surveillance. Conclusion: This case illustrates the importance of following up on incidental radiographic findings and adds to the limited literature on sporadic UBPGLs, an uncommon, yet potentially life-threatening tumor. The diagnosis of these tumors is especially challenging when patients present with non-specific symptoms. Fortunately, in our case, the imaging study clued us into the possibility of a PGL. SDHB mutation associated PGLs, in particular, are notorious for their late presentation with metastasis and associated tumors. Hence, timely detection with close follow-up of these patients will likely have an impact on their mortality.

Update on Molecular Genetics of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10–15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called “wt-GISTs”. Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.

Large Retroperitoneal Paraganglioma Associated with Germline Mutation of the Succinate Dehydrogenase Gene.

Paragangliomas (PGLs) are rare neural tumors that can be benign or malignant and often associated with familial syndromes. We present a case of a 23-year-old male with a large retroperitoneal PGL found incidentally during the workup of elevated liver enzymes. After surgical excision, the patient was found to have an autosomal dominant mutation in the succinate dehydrogenase B (SDHB) gene, which when compared to sporadic PGLs or other familial syndromes is associated with a higher risk of tumor recurrence, occult metastasis, and development of other cancers. The patient’s first-degree relatives were recommended to undergo screening for the genetic mutation.

Impact of gender on the prognosis of carotid body tumor after surgical resection

BackgroundCarotid body tumors (CBTs) are rare neuroendocrine neoplasms, but the prognosis of patients with resected CBTs has seldom been elucidated. This study was conducted to investigate the association between variables, especially sex, and the prognosis of carotid body tumor resection.MethodsThis was a large-volume single-center retrospective cohort study. Patients who were diagnosed with CBTs between 2009 and 2020 at our center were analyzed retrospectively. Their preoperative, surgical, and follow-up data were collected, and the association between variables and outcomes of CBT resection was assessed by correlation analysis, multivariate logistic regression, and multivariate Cox regression as appropriate.ResultsA total of 326 patients (66.6% were females) were included. Males developed larger CBTs than females (4.3 ± 1.8 cm vs. 3.8 ± 1.4 cm, P = .003). Males were more likely to develop succinate dehydrogenase B (SDHB) mutations (P = .019) and had worse relapse-free survival rates (P = .024). Although tumor size and Shamblin classification had positive relationships with neurological complications and intraoperative blood loss, they did not affect the overall survival rate of patients, which was only influenced by remote metastasis (P = .007) and local recurrence (P = .008).ConclusionsCompared to females, males with CBT resection were found to have more SDHB mutations and worse relapse-free survival rates, which may lead to the deterioration of prognosis. Tumor size and Shamblin classification cannot predict the overall survival rate of patients with excised CBTs.Graphical abstract

SDHB and SDHA Immunohistochemistry in Canine Pheochromocytomas

Simple SummaryPheochromocytomas are adrenal tumors that occur in both dogs and people. One of the more common gene families involved in the development of this tumor in people is succinate dehydrogenase (SDH). In people, immunohistochemistry can be used with biopsy samples to predict gene pathways that may be involved in the development of the tumor. This is faster and cheaper than performing extensive sequencing to determine if genes are involved. We tested 35 dog tumors to determine how likely SDH mutations were. While our data suggest significant numbers of SDH mutations, these mutations do not appear to be associated with tumor aggression.Pheochromocytomas (PCs) are tumors arising from the chromaffin cells of the adrenal glands and are the most common tumors of the adrenal medulla in animals. In people, these are highly correlated to inherited gene mutations in the succinate dehydrogenase (SDH) pathway; however, to date, little work has been done on the genetic basis of these tumors in animals. In humans, immunohistochemistry has proven valuable as a screening technique for SDH mutations. Human PCs that lack succinate dehydrogenase B (SDHB) immunoreactivity have a high rate of mutation in the SDH family of genes, while human PCs lacking succinate dehydrogenase A (SDHA) immunoreactivity have mutations in the SDHA gene. To determine if these results are similar for dogs, we performed SDHA and SDHB immunohistochemistry on 35 canine formalin-fixed, paraffin-embedded (FFPE) PCs. Interestingly, there was a loss of immunoreactivity for both SDHA and SDHB in four samples (11%), suggesting a mutation in SDHx including SDHA. An additional 25 (71%) lacked immunoreactivity for SDHB, while retaining SDHA immunoreactivity. These data suggest that 29 out of the 35 (82%) may have an SDH family mutation other than SDHA. Further work is needed to determine if canine SDH immunohistochemistry on PCs correlates to genetic mutations that are similar to human PCs.