Paraaortic Extra-Adrenal Paraganglioma: Challenging Robotic Resection.

BACKGROUND: Up to 41% of intra- and extra-adrenal paragangliomas are linked to germline mutations with autosomal dominant transmission, which necessitates genetic testing for patients and their relatives.1-4 Certain alterations, such as the succinate dehydrogenase (SDH) subunit B gene mutation, are associated with a significant risk of extra-adrenal, malignant, and metastatic disease forms.4-7 This highlights the need for routine genetic counseling and diligent surveillance, as well as surgeon awareness of hereditary paraganglioma-pheochromocytoma syndrome (HPPS). METHODS: We present a multimedia article featuring a step-by-step video of a complex retroperitoneal resection, enriched with perioperative management insights. RESULTS: A 17-year-old female presented with episodes of hypertension, tachycardia, and diffuse diaphoresis. CT revealed a paraaortic mass adjacent to the left renal hilum later confirmed by a SPECT/CT with iodine-123 meta-iodobenzylguanidine.8 Additional imaging with gallium-68 DOTATATE was not performed then due to unknown mutation status. The patient underwent robotic removal of the tumor and adjacent lymph nodes. Pathology confirmed a poorly differentiated paraganglioma with 0/6 lymph node metastases. Genetic tests revealed SDHB gene mutation, indicative of HPPS.9,10 At 12 months, the patient remained disease-free on CT with normalized metanephrines levels and no detectable circulating tumor DNA. Familial screening detected her mother, maternal uncle, and maternal grandfather to be SDHB mutation carriers, although phenotypically silent. CONCLUSIONS: Robotic-assisted resection can be safe and effective for retroperitoneal malignant paragangliomas. However, management extends beyond surgery and requires cascade genetic testing to address familial risks. Because of the high probability of cancer associated with SDHB mutation, lifelong patient surveillance is imperative.

Hereditary head and neck paraganglioma: from basics to practical consequences.

PURPOSE OF REVIEW: This review summarizes practical recommendations for screening, work-up, and management of hereditary head and neck paragangliomas based on the growing molecular and empirical understanding of this disease. RECENT FINDINGS: The proportion of hereditary cases among head and neck paragangliomas is significant (∼33 to 50%), and specific genetic alterations may increase the risk of malignancy. Genotyping should be performed for each case, and patients carrying a pathological mutation should be regularly screened for new tumors. Computed tomography (CT), magnetic resonance imaging (MRI), digital subtraction angiography (DSA), and functional positron emission tomography (PET) can provide a reliable preoperative diagnosis in the absence of histology. Comparative data on therapeutic outcome and morbidity now render radiation, stereotactic radiosurgery, and active surveillance preferable over surgery in highly advanced cases of jugulotympanic and vagal paragangliomas, whereas surgery remains the first choice for most carotid body paragangliomas. SUMMARY: Complete paraganglioma removal continues to be the primary therapeutic goal; however, this is sometimes impossible to accomplish with acceptable morbidity. In these cases, therapy selection should focus on preserving cranial nerve function and minimizing both tumor-associated and therapy-associated complications, particularly in genetically predisposed patients. An interdisciplinary approach to the management of hereditary head and neck paragangliomas is strongly recommended.

Isolated Cardiac Paraganglioma Encasing Right Coronary Artery With Evidence of Succinyl Dehydrogenase Gene Mutation: Successful Management Using Multimodality Imaging.

This report involves a young woman with isolated cardiac paraganglioma that was diagnosed using 68Gallium-labeled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide positron emission tomographic scintigraphy. For the preoperative evaluation, multimodality imaging accurately described the anatomic location of the tumor and its relationship with the surrounding tissues. The patient underwent successful surgical resection of the tumor along with right coronary artery bypass grafting. The 2-month follow-up scintigraphy was normal. Next-generation sequencing evaluation revealed a novel germline mutation for the succinate dehydrogenase subunit B gene.

Paraganglioma of the Head and Neck: A Review.

OBJECTIVE: To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas. METHODS: A literature review of english language papers with focus on most current literature. RESULTS: Paragangliomas (PGLs) are a group of neuroendocrine tumors that arise in the parasympathetic or sympathetic ganglia. Head and neck PGLs (HNPGLs) comprise 65% to 70% of all PGLs and account for 0.6% of all head and neck cancers. The majority of HNPGLs are benign, and 6% to 19% of all HNPGLs develop metastasis outside the tumor site and significantly compromise survival. PGLs can have a familial etiology with germline sequence variations in different susceptibility genes, with the gene encoding succinate dehydrogenase being the most common sequence variation, or they can arise from somatic sequence variations or fusion genes. Workup includes biochemical testing to rule out secretory components, although it is rare in HNPGLs. In addition, imaging modalities, such as computed tomography and magnetic resonance imaging, help in monitoring in surgical planning. Functional imaging with DOTATATE-positron emission tomography, 18F-fluorodeoxyglucose, or 18F-fluorohydroxyphenylalanine may be necessary to rule out sites of metastases. The management of HNPGLs is complex depending on pathology, location, and aggressiveness of the tumor. Treatment ranges from observation to resection to systemic treatment. Similarly, the prognosis ranges from a normal life expectancy to a 5-year survival of 11.8% in patients with distant metastasis. CONCLUSION: Our review is a comprehensive summary of the incidence, mortality, pathogenesis, presentation, workup and management of HNPGLs.

Paragangliomas da Cabeça e Pescoço: A Experiência de um Centro Oncológico do Sul da Europa.

INTRODUCTION: Paragangliomas are usually benign slow-growing tumors, but they are locally invasive and can cause significant morbidity. The aim of this study was to characterize the presenting symptoms, secretory status, genetics, imaging features, treatment modalities, post-treatment complications and survival of patients with head and neck paragangliomas treated at a single institution. MATERIAL AND METHODS: We retrospectively reviewed the clinical records of patients managed at our center between 1997 and 2020. RESULTS: Seventy-three patients were included in the study, encompassing 89 head and neck paragangliomas. Forty-eight patients (65.8%) were female and 15 (20.5%) had multiple tumor sites (including 10 patients with multicentric benign paragangliomas and five with disseminated malignant disease). Regarding location, our series encompassed 40 temporal bone paragangliomas (44.9%), 24 carotid body paragangliomas (27%), 22 vagal paragangliomas (24.7%), two laryngeal paragangliomas (2.2%) and one sinonasal paraganglioma (1.1%). Excessive catecholamine secretion was detected in 11 patients (15.1%). Sixty-four patients (87.7%) underwent genetic testing. Of those, 24 (37.5%) exhibited pathogenic succinate dehydrogenase complex germline mutations. Regarding patients who presented with untreated disease, 45 patients (66.2%), encompassing 55 tumors, underwent surgery as primary treatment modality, 20 (29.4%; 23 tumors) were initially treated with radiotherapy and three patients (4.4%, encompassing three solitary tumors) were kept solely under watchful waiting. Five-year overall survival was 94.9% and disease-free survival was 31.9%. CONCLUSION: Head and neck paragangliomas are rare, slow-growing but locally aggressive tumors resulting in high morbidity but low mortality rates.

Introdução: Os paragangliomas apresentam frequentemente um comportamento benigno e um crescimento indolente. Apesar disso, são localmente invasivos, podendo causar morbilidade significativa. O objetivo deste trabalho foi descrever as manifestações clínicas, atividade secretora, estudos genéticos e imagiológicos, modalidades terapêuticas, complicações e sobrevivência dos doentes com paragangliomas da cabeça e pescoço. Material e Métodos: Estudo retrospetivo dos doentes com paragangliomas da cabeça e pescoço observados num centro hospitalar terciário entre 1997 e 2020. Resultados: Foram incluídos no estudo 73 doentes, englobando 89 paragangliomas. Quarenta e oito doentes (65,8%) eram do sexo feminino e 15 (20,5%) apresentavam múltiplos focos tumorais (10 por multicentricidade e cinco por doença maligna disseminada). Foram incluídos 40 paragangliomas do osso temporal (44,9%), 24 tumores do corpo carotídeo (27%), 22 vagais (24,7%), dois laríngeos (2,2%) e um nasossinusal (1,1%). A secreção excessiva de catecolaminas foi detetada em 11 doentes (15,1%). Sessenta e quatro doentes (87,7%) foram alvo de teste genético. Desses, 24 (37,5%) exibiram mutações patogénicas do complexo succinato desidrogenase. Dos doentes com doença primária, 45 (66,2%; 55 tumores) foram submetidos a tratamento cirúrgico, 20 (29,4%; 23 tumores) a radioterapia e três (4,4%) ficaram sob vigilância. Aos cinco anos, a sobrevida global foi de 94,9% e a sobrevida livre de doença foi de 31,9%. Conclusão: Os paragangliomas da cabeça e pescoço são tumores raros, de crescimento lento, mas localmente agressivos que resultam em elevadas taxas de morbilidade, mas baixas taxas de mortalidade.

Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas.

This review summarizes the classification of tumors of the adrenal medulla and extra-adrenal paraganglia as outlined in the 5th series of the WHO Classification of Endocrine and Neuroendocrine Tumors. The non-epithelial neuroendocrine neoplasms (NENs) known as paragangliomas produce predominantly catecholamines and secrete them into the bloodstream like hormones, and they represent a group of NENs that have exceptionally high genetic predisposition. This classification discusses the embryologic derivation of the cells that give rise to these lesions and the historical evolution of the terminology used to classify their tumors; paragangliomas can be sympathetic or parasympathetic and the term pheochromocytoma is used specifically for intra-adrenal paragangliomas that represent the classical sympathetic form. In addition to the general neuroendocrine cell biomarkers INSM1, synaptophysin, and chromogranins, these tumors are typically negative for keratins and instead have highly specific biomarkers, including the GATA3 transcription factor and enzymes involved in catecholamine biosynthesis: tyrosine hydroxylase that converts L-tyrosine to L-DOPA as the rate-limiting step in catecholamine biosynthesis, dopamine beta-hydroxylase that is present in cells expressing norepinephrine, and phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine and therefore can be used to distinguish tumors that make epinephrine. In addition to these important tools that can be used to confirm the diagnosis of a paraganglioma, new tools are recommended to determine genetic predisposition syndromes; in addition to the identification of precursor lesions, molecular immunohistochemistry can serve to identify associations with SDHx, VHL, FH, MAX, and MEN1 mutations, as well as pseudohypoxia-related pathogenesis. Paragangliomas have a well-formed network of sustentacular cells that express SOX10 and S100, but this is not a distinctive feature, as other epithelial NENs also have sustentacular cells. Indeed, it is the presence of such cells and the association with ganglion cells that led to a misinterpretation of several unusual lesions as paragangliomas; in the 2022 WHO classification, the tumor formerly known as cauda equina paraganglioma is now classified as cauda equina neuroendocrine tumor and the lesion known as gangliocytic paraganglioma has been renamed composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). Since the 4th edition of the WHO, paragangliomas have no longer been classified as benign and malignant, as any lesion can have metastatic potential and there are no clear-cut features that can predict metastatic behavior. Moreover, some tumors are lethal without metastatic spread, by nature of local invasion involving critical structures. Nevertheless, there are features that can be used to identify more aggressive lesions; the WHO does not endorse the various scoring systems that are reviewed but also does not discourage their use. The identification of metastases is also complex, particularly in patients with germline predisposition syndromes, since multiple lesions may represent multifocal primary tumors rather than metastatic spread; the identification of paragangliomas in unusual locations such as lung or liver is not diagnostic of metastasis, since these may be primary sites. The value of sustentacular cells and Ki67 labeling as prognostic features is also discussed in this new classification. A staging system for pheochromocytoma and extra-adrenal sympathetic PGLs, introduced in the 8th Edition AJCC Cancer Staging Manual, is now included. This paper also provides a summary of the criteria for the diagnosis of a composite paragangliomas and summarizes the classification of neuroblastic tumors. This review adopts a practical question-answer framework to provide members of the multidisciplinary endocrine oncology team with a most up-to-date approach to tumors of the adrenal medulla and extra-adrenal paraganglia.

Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency.

Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.

SDHC Methylation Pattern in Patients With Carney Triad.

Carney triad is a multitumor syndrome affecting almost exclusively young women in a nonfamilial setting, which manifests by multifocal gastric gastrointestinal stromal tumors, paragangliomas, and pulmonary chondroma. The Carney triad-associated tumors are characterized by a deficiency of the mitochondrial succinate dehydrogenase enzymatic complex. Recently, it has been observed that the deficiency results from epigenetic silencing of the SDHC gene by its promoter hypermethylation. To elucidate anatomic distribution of SDHC promoter methylation in Carney triad patients and thus to shed some light on the possible natural development of this epigenetic change, both neoplastic and available non-neoplastic tissues of 3 patients with Carney triad were tested for hypermethylation at the SDHC promoter site. SDHC promoter hypermethylation was proven in all tumors studied. Lack of SDHC epigenetic silencing in the non-neoplastic lymphoid and duodenal tissue (ie, tissues not involved in the development of Carney triad-associated tumors) together with the finding of SDHC promoter hypermethylation in the non-neoplastic gastric wall favors the hypothesis of postzygotic somatic mosaicism as the biological background of Carney triad; it also offers an explanation of the multifocality of gastrointestinal stromal tumors of the stomach occurring in this scenario as well. However, the precise mechanism responsible for the peculiar organ-specific distribution of Carney triad-associated tumors is still unknown.

Somatic SDHA mutations in paragangliomas in siblings: Case report of 2 cases.

RATIONALE: Paragangliomas (PGLs) are rare neuroendocrine tumors that are strongly influenced by genetics, and succinate dehydrogenase-deficient PGLs appear to constitute one of the most important categories. Interestingly, somatic PGLs only possess genomic alterations involving the SDHB and SDHD subunits, and no SDHA alterations have been described. Here, we are presenting the clinical and genetic analyses of 2 cases with the first somatic SDHA variant identified in PGLs. PATIENT CONCERNS: Here, we reported 2 family members with the diagnosis of PGL. Patient 1 is a 55-year-old woman with a functionally perigastric PGL that co-occurred with a gastric gastrointestinal stromal tumor (GIST), and patient 2 is a 43-year-old woman with a nonfunctionally pericardial PGL, who was the younger sister of the first patient. DIAGNOSES: Imaging surveys of the 2 cases depicted the presence of a perigastric and a pericardial mass, respectively. A diagnosis of paragangliomas was established by immunohistochemistry (IHC). INTERVENTIONS: Both patients underwent single-stage resection of the lesion after preoperative oral α-adrenoceptor therapy for 2 weeks. We later performed comprehensive genomic profiling on the tumor samples, including PGL and GIST from patient 1 and PGL from patient 2, and searched for novel actionable mutations, including in all succinate dehydrogenase subunits, as the IHC results were negative for SDHB. OUTCOMES: Both patients had an uneventful recovery after surgery and the sequencing showed a novel somatic variant in the SDHA gene on chromosome 5q11 (c.1945_1946delTT). Regular follow-up with biochemical testing and image studies showed no evidence of recurrence after a year for patient 1 and 6 years for patient 2. LESSONS: PGLs often lead to considerable diagnostic difficulty due to their multiple anatomical locations and variable symptoms, as presented by our cases. The comprehensive use of images and plasma/urine catecholamine measurement can aid the diagnosis of PGLs. In addition, our findings also demonstrate the usefulness and importance of genetic analysis of SDHA mutations in patients exhibiting SDHB IHC-negative PGL. Additional studies utilizing comprehensive genomic profiling are needed to identify the group of PGLs harboring this SDHA genomic alteration.

Recent advances in the management of pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors that cause refractory hypertension and hypertensive crisis. Although metastatic disease accounts for 30% of PPGLs, the diagnosis of malignancy is difficult without the presence of metastatic lesions. Here, we review several advancements in the diagnosis and treatment of PPGL. A nationwide epidemiological survey in Japan revealed that the annual number of patients with PPGL was 3000, which was higher than that reported previously. While plasma and urine fractionated metanephrines are recommended for use in specific biochemical testing for diagnosis, creatinine-corrected fractionated metanephrines in spot urine samples that had been widely used in Japan as a convenient screening test were shown to be as useful as 24-h urine fractionated metanephrines. Regarding imaging studies, a more specific functional imaging for PPGLs, 68Ga DOTATATE, was newly developed. 68Ga DOTATATE provides a clear image with high sensitivity and specificity. Currently, PASS or GAPP histological scores and SDHB immunostaining are clinically used to attempt to discriminate benign from malignant tumors. However, since this distinguishing process remains difficult, all cases were classified as malignant with the possibility of metastasis in the WHO classification of endocrine tumors updated in 2017. Approximately 60% of PPGLs have germline mutations in PPGL-related genes. Currently, the genes are classified into two clusters based on their mechanism for the etiology of tumorigenesis. Based on the possible mechanisms of tumor development associated with gene mutations, several molecular target drugs are under evaluation to explore more promising treatments for malignant PPGL.

Synchronous detection of SDHA-related gallbladder paraganglioma and pancreatic neuroendocrine tumor.

Primary gallbladder paragangliomas (PGLs) are exceedingly rare. PGLs are extraadrenal neuroendocrine tumors that are morphologically inseparable from intraadrenal pheochromocytomas. PGLs and pheochromocytomas are some of the most heritable tumor types in the body and are often associated with other tumors or part of a genetic syndrome. We report a case of gallbladder PGL presenting synchronously with pancreatic neuroendocrine tumor (NET) and pulmonary IgG4-related disease in a 74-year old male patient with disseminated prostate adenocarcinoma. Due to the high rate of germline mutations and the possible syndromal manifestation of PGLs as well as pancreatic NETs, this patient was offered genetic testing, and a pathogenic SDHA germline mutation was found. Immunohistochemically, there was loss of SDHA and SDHB in the PGL but neither in the NET nor in the prostate adenocarcinoma. To our knowledge, this case is the first report of gallbladder PGL associated with pancreatic NET. It is likely that the identified SDHA germline mutation played a role in the development of gallbladder PGL in this patient.

Comprehensive review of evaluation and management of cardiac paragangliomas.

Cardiac paraganglioma (PGL) is a rare neuroendocrine tumour causing significant morbidity primarily due to norepinephrine secretion potentially causing severe hypertension, palpitations, lethal tachyarrhythmias, stroke and syncope. Cardiologists are faced with two clinical scenarios. The first is the elevated norepinephrine, whose actions must be properly counteracted by adrenoceptor blockade to avoid catastrophic consequences. The second is to evaluate the precise location of a cardiac PGL and its spread since compression of cardiovascular structures may result in ischaemia, angina, non-noradrenergic-induced arrhythmia, cardiac dysfunction or failure. Thus, appropriate assessment of elevated norepinephrine by its metabolite normetanephrine is a gold biochemical standard at present. Furthermore, dedicated cardiac CT, MRI and transthoracic echocardiogram are necessary for the precise anatomic information of cardiac PGL. Moreover, a cardiologist needs to be aware of advanced functional imaging using 68Ga-DOTA(0)-Tyr(3)-octreotide positron emission tomography/CT, which offers the best cardiac PGL-specific diagnostic accuracy and helps to stage and rule out metastasis, determining the next therapeutic strategies. Patients should also undergo genetic testing, especially for mutations in genes encoding succinate dehydrogenase enzyme subunits that are most commonly present as a genetic cause of these tumours. Curative surgical resection after appropriate α-adrenoceptor and ß-adrenoceptor blockade in norepinephrine-secreting tumours is the primary therapeutic strategy. Therefore, appropriate and up-to-date knowledge about early diagnosis and management of cardiac PGLs is paramount for optimal outcomes in patients where a cardiologist is an essential team member of a multidisciplinary team in its management.

Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine/Head and Neck Disease-Site Work Group. Part 1 of 2: Advances in Pathogenesis and Diagnosis of Pheochromocytoma and Paraganglioma.

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

De novo SDHB gene mutation in a family with extra-adrenal paraganglioma.

A 14-year-old male presented with abdominal pain. Imaging illustrated a left-sided adrenal mass; he underwent a left nephrectomy, confirming an extra-adrenal PGL. Germline genetic testing revealed a heterozygous, likely pathogenic mutation in the SDHB gene. The patient's family subsequently underwent genetic testing; his mother and sister were both positive for the familial SDHB mutation. Cascade testing for the proband's maternal aunt and maternal grandparents was negative for the familial mutation. SNP genotyping was used to confirm relationships. This is the second reported case of a de novo SDHB gene mutation and the first reported case of a confirmed de novo mutation in a patient who was not the initial proband. As SDHB-associated PGLs and PCCs are expected to be more aggressive and malignant, it is imperative to identify patients with SDHB mutations early. Given that many patients with germline mutations have no family history of PGL of PCC, the possibility of de novo mutations must be considered. Further studies are needed to determine the rate of de novo mutation in SDHB and other SDH-complex genes. Up to 41% of patients with paragangliomas (PGL) or pheochromocytomas (PCC) have an identifiable hereditary cancer predisposition syndrome. Mutations in 12 genes are known to increase the risk of PGL and/or PCC; however, the de novo rate is mostly unknown. Only one case report exists of a de novo SDHB mutation. We present the second case of a family with a de novo SDHB mutation.

Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas.

BACKGROUND: Genetic testing to identify succinate dehydrogenase (SDH) mutations in patients with head and neck paraganglioma (HNP) has been in clinical practice for more than a decade. However, the recurrence and metachronous tumor occurrence risks in surgically treated mutation-positive patients are not well studied. METHODS: Clinical and procedural details of consecutive patients who underwent excision for HNP from January 1996 to October 2016 were retrospectively reviewed. End points included recurrence, metachronous tumor detection, and mortality. Germline DNA was tested to identify mutations in SDHx genes. Patients were divided into three groups on the basis of genetic testing: group I, positive; group II, negative; and group III, unknown or offered but not tested. RESULTS: HNP was diagnosed in 268 patients, 214 (147 female; mean age, 47 years) included in this study. Directed genetic testing was performed in 68; mutations were detected in SDH in 47 (69%), a majority SDHD. In group I, 47 patients had 64 procedures for 81 tumors (52 carotid body tumors [CBTs]); 17 (36%) were bilateral, 7 (15%) multiple, 3 (6%) functional, and 7 (15%) malignant. Residual tumor in 10 was significant in 2, managed by radiation therapy and reoperation. Local recurrence was detected in 12 patients (25%) at a median of 8 years; 11 metachronous mediastinal and retroperitoneal paragangliomas were detected in 8 (17%) at a median of 13 years. Systemic metastases occurred in five (10%). Six patients (13%) had more than one recurrence. In group II, 21 patients had 22 procedures for 23 tumors, 17 CBTs. Two (9%) were bilateral and two (9%) malignant. Excision was complete in all with no recurrence or systemic metastasis at last follow-up. For group III, 146 patients underwent 153 procedures for 156 tumors, 95 CBTs; 7 (5%) were bilateral, 2 (1%) multiple, 8 (5%) functional, and 1 (0.6%) malignant. Local recurrence was detected in nine (6%) at a median of 9 years and metachronous HNP in three (2%) at a median of 5 years. Systemic metastases occurred in two (1%). Mortality was 4% in group I and 3% in group III, none procedure or tumor related. Group I (mutation positive) had 10-year overall, recurrence-free, and metachronous tumor-free survival rates of 93%, 69.4%, and 73%, respectively, lower than the other groups (P < .001). CONCLUSIONS: Bilateral, functional, malignant, recurrent, and metachronous tumors are more common in SDH mutation-positive patients with HNP. Overall survival in patients with HNP is high. Metachronous tumors or local recurrences occur late, and long-term follow-up is necessary.

[Wild-type gastroinestinal stromal tumors]. / Les tumeurs stromales gastro-intestinales sauvages.

Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.