Familial Paraganglioma Syndrome Research Articles

Newly Recognized Genetic Tumor Syndromes of the CNS in the 5th WHO Classification: Imaging Overview with Genetic Updates.

The nervous system is commonly involved in a wide range of genetic tumor-predisposition syndromes. The classification of genetic tumor syndromes has evolved during the past years; however, it has now become clear that these syndromes can be categorized into a relatively small number of major mechanisms, which form the basis of the new 5th edition of the World Health Organization book (beta online version) on genetic tumor syndromes. For the first time, the World Health Organization has also included a separate chapter on genetic tumor syndromes in the latest edition of all the multisystem tumor series, including the 5th edition of CNS tumors. Our understanding of these syndromes has evolved rapidly since the previous edition (4th edition, 2016) with recognition of 8 new syndromes, including the following: Elongator protein complex-medulloblastoma syndrome, BRCA1-associated protein 1 tumor-predisposition syndrome, DICER1 syndrome, familial paraganglioma syndrome, melanoma-astrocytoma syndrome, Carney complex, Fanconi anemia, and familial retinoblastoma. This review provides a description of these new CNS tumor syndromes with a focus on imaging and genetic characteristics.

FRI367 An Unusual Presentation Of A Thyroid Nodule: A Thyroid Paraganglioma

Abstract Disclosure: M. Owrangi: None. F. Hasan: None. Introduction: Thyroid paraganglioma (PGL) is a rare thyroid tumor that originates from inferior laryngeal paraganglia. We present a case of a patient initially believed to have a thyroid nodule which turned out to be a PGL. Case Presentation: A 49 year-old white female with history of GERD and mild dysphagia who was found to have a left parathyroid adenoma vs. a left exophytic thyroid nodule. Previous ultrasounds had all showed slow but progressive enlargement of the lesion. Her labs had showed iPTH, Ca, TSH, and free T4 all within reference range and she was clinically euthyroid. She had 2 fine needle aspirations (FNA) which were both non diagnostic. She ultimately underwent surgical excision of the mass. The pathological examination showed cells that were positive for synaptophysin, chromogranin, GATA-3, S100, and neuron-specific enolase. They were negative for Ki-67, PTH, thyroglobulin, TTF-1, CK AE1/AE3, and CD 138. The overall findings were consistent with thyroid PGL. Discussion: In this case Thyroid PGL was diagnosed after pathological examination, including immunohistochemistry, was performed on a surgically excised sample, after 2 FNAs were non-diagnostic. Thyroid PGLs are elusive tumors. One study suggested that since they were first described in 1964, until 2015, there have only been 54 reported cases of thyroid PGLs, with a strong female predominance (88.9%). They often present as asymptomatic thyroid nodules and their diagnosis can be difficult by FNA alone as they can morphologically mimic medullary thyroid carcinoma, intrathyroidal parathyroid proliferation, metastatic neuroendocrine tumor, or calcitonin-negative neuroendocrine tumor of the thyroid gland (CNNETT). Thyroid PGLs are often benign, slow growing tumors and account for only 0.012% of all head and neck tumors with a malignancy rate of 4-16%. They usually present as single nodules averaging 3.5 cm and are often diagnosed with routine ultrasound assessment of the neck. Since they are associated with the parasympathetic nervous system, signs and symptoms including tachycardia, palpitations, and weight loss due to hormonal activity are classically absent from thyroid PGLs. In about 30% of cases, thyroid PGLs have a genetic predisposition and are more than one and associate with other tumors such as pheochromocytoma. Major hereditary disorders associated with paraganglioma include von Hippel-Lindau disease, multiple endocrine neoplasia, familial paraganglioma syndromes 1 to 4, and neurofibromatosis. Therefore, it is highly recommended that patients with a diagnosis of thyroid PGL undergo additional investigations with imaging, hormonal activity assessment, and genetic testing. Given the difference in management of thyroid PGLs compared to its cytology mimics, and their association with some familial cancer syndromes, use of immunohistochemical staining is crucial in making the correct diagnosis. Presentation: Friday, June 16, 2023

SAT547 Hereditary Paraganglioma: The Rare Co-Existence Of Two Genetic Syndromes Associated With PPGL-pheochromocytoma

Abstract Disclosure: K. Samuel: None. Hereditary Paraganglioma: the rare co-existence of two genetic syndromes associated with PPGL-Pheochromocytoma Kelara Samuel MD, Bryan McIver MD, Colleen Veloski MD, Julie Hallanger-Johnson MD, Valentina D. Tarasova, John Tourtelot MD, George Q. Yang MD, Sarimar Agosto-Salgado MD Background: Paragangliomas are neuroendocrine tumors arising from neural crest chromaffin cells of the autonomic ganglia and can be parasympathetic or sympathetic in nature. Approximately 30 percent of all paragangliomas are hereditary either associated with familial paraganglioma syndromes and other autosomal dominant syndromes, such as multiple neuroendocrine neoplasia 2A and 2B, neurofibromatosis type 1, and von Hippel Lindau disease.Case: A 73-year-old Hispanic female with a past medical history of hypothyroidism, hypertension, hyperlipidemia, and Lupus presented with a large neck mass of 11 years of evolution. An evaluation revealed a large near 12cm hypervascular, hyperenhancing left neck mass that encased the distal common carotid artery, carotid bifurcation, and internal and external carotid arteries and their branches. The multidisciplinary team recommended, given the tumor's extent, a non-surgical localized treatment consisting of radiation. Clinically, the patient had compressive symptoms, including tenderness over the tumor region, hoarseness, dysphagia, and changes in phonation. The patient also had a positive family history of paraganglioma in her grandson and nephew, but specific genetic alteration data from relatives was unavailable. Plasma normetanephrines were 0.68 (normal range 0-0.89), and plasma metanephrines were 0.23 (normal range 0-0.49). Genetic testing was positive for germline alterations in both SDHB p.Q214 and NF1 c.2970_2972delAAT. At this time, there is no evidence of metastatic disease and no clinical manifestations of NF1, suggesting a mild neurofibromatosis phenotype. Restaging imaging revealed an ongoing partial response to radiation and clinically patient has noted a significant improvement in the prior compressive symptoms. Conclusion: We present a case where we see an uncommon presentation of a non-secretory, hereditary paraganglioma with two concomitant rare genetic syndromes. This case highlights the importance of genetic testing for patient-appropriate tumor surveillance and family counseling implications. Presentation Date: Saturday, June 17, 2023

OR08-04 Paradigm Shift In SDHAF2-Related Familial Paraganglioma Syndrome

Abstract Disclosure: A. Fernandez-Pombo: None. G. Rodriguez-Carnero: None. N. Otero Mato: None. J. Cameselle Teijeiro: None. L. Loidi: None. Z. Nogareda Seoane: None. V. Pubul Nunez: None. M. Martinez Olmos: None. J. Cabezas Agricola: None. Introduction: The recommendations of the clinical practice guidelines regarding the management of SDHAF2-related familial paraganglioma syndrome are based on what is described in the literature in relation to two carrier families of the p.Gly78Arg variant in this gene. To date, among other characteristics, paragangliomas (PGLs) have been thought to occur exclusively in the head and neck, with no metastatic disease observed. Objective: To describe the clinical profile of SDHAF2-related familial paraganglioma syndrome in order to increase knowledge of this disorder. Subjects and Methods: A total of 64 individuals were evaluated after the detection of 7 index cases with the same pathogenic variant (p.Gly78Arg) in the SDHAF2 gene. The clinical data of the 46 patients found to be carrying this variant were collected. In addition to the molecular study, these patients underwent a biochemical evaluation, as well as anatomical imaging. PET with 68Ga-DOTA- TOC and 18F-DOPA were also carried out. The surgical specimens were analyzed. Results: A total of 27 patients developed the disease, with a mean age of 37.0 ± 17.2 years at diagnosis (59.2% women). Inheritance in affected patients was of paternal origin in all known cases. All patients manifested PGLs in the head and neck (96.3% carotid bifurcation, 25.9% jugulotympanic and 14.8% glomus vagale), with a high frequency of multifocality (85.2%). Six patients also manifested mediastinal PGLs (retrocardiac, paraaortic, epicardial, paratracheal, phrenic nerve) and two normetanephrine-secreting pheochromocytomas. All extraadrenal PGLs were non-functioning, with the exception of one case with hypersecretion of 3-methoxytyramine. Throughout the follow-up, three patients manifested distant metastasis (bone and lung metastases). Surgical treatment occurred in 85.1% of cases, radiotherapy in 29.6%, radiosurgery in 14.8% and sunitinib in one case, and 58.3% patients reported some type of complication. 68Ga-DOTA-TOC PET was superior to 18F-DOPA PET in identifying extraadrenal PGLs and metastatic involvement, with an overall detection rate of 100% in the case of 68Ga-DOTA-TOC PET (SUVmax 87.6 ± 60.3 g/ml) and 61.0% in the case of 18F-DOPA PET (SUVmax 19.0 ± 16.2 g/ml), p <0.0001. Regarding the immunohistochemical analysis, no positivity for SDHB was observed and Ki-67 index was <3% in all cases. Conclusions: Certain phenotypic variations have been observed in the current study regarding SDHAF2-related familial paraganglioma syndrome, which have not previously been described and which will contribute to modifying the management of this disease. Presentation: Friday, June 16, 2023

Pheochromocytoma and paraganglioma in children and adolescents.

Pheochromocytoma (PPC) and paraganglioma (PGL) are the tumors that rarely occur in the pediatric population (PPGL). Both originate from chromaffin cells, pheochromocytoma is localized in the adrenal gland, whereas paragangliomas are regarded as the tumors present in other localizations, from head to the pelvis. The clinical image is characterized by the presence of the sustained hypertension, headaches, sweating, palpitations. The symptoms are caused by the catecholamine secretion or are related to tumor mass pressure on different organs. The catecholamines and their metabolites levels in urine collection or plasma are necessary for further evaluation of the diagnosis. In pediatric population the tumors occur in multiple familial syndromes such as Multiple Endocrine type 2, Neurofibromatosis type 1, Von Hippel-Lindau syndrome, Familial Paraganglioma syndrome are related to specific mutations (SDHx, RET, VHL, NF1) leading to the characteristic phenotype. The radiological and nuclear imaging are an important part of the examination. Although CT and MR are reported to have overall good sensitivity for the tumor detection, further analysis with nuclear imaging is recommended for the specified diagnosis. Right now 68GA-DOTATATE is regarded as the tracer of choice, leading to the complex evaluation of patients with different mutations and metastatic disease. The treatment of choice is the tumor excision. Also, lately new therapeutic approaches including genetically targeted therapies are under investigation for more complex treatment of tumors with underlying genetic cause or metastatic disease. Long term follow-up after treatment to avoid recurrence or to detect it in early stadium must be performed.

Adrenal pheochromocytoma: Keys to radiologic diagnosis

Pheochromocytomas are adrenal paragangliomas. Potentially malignant, these tumors have a low incidence but clear importance. They can appear in various hereditary syndromes, especially in von Hippel-Lindau syndrome, multiple endocrine neoplasia-2 (MEN2), and familial paraganglioma syndromes. In sporadic cases, underlying genetic alterations are often found, and these findings are changing our understanding of the disease.Although these tumors can manifest with a characteristic clinical presentation, in 13.1%–57.6% of cases, it is the radiologist who first suggests the diagnosis, indicating analyses for catecholamines or nuclear medicine examinations.Radiologists should suspect a pheochromocytoma on detection of a well-delimited adrenal mass with rapid, intense enhancement that typically shows cystic and hemorrhagic phenomena, high T2 signal intensity, and the absence of macroscopic or microscopic lipids. The behavior in diffusion-weighted imaging usually does not provide very useful information. Approximately one-third of lesions show late washout similar to that seen with adenomas on CT. Percutaneous puncture should be avoided to avoid the risk of unleashing a severe hypertensive crisis.

Feocromocitoma adrenal. Claves para el diagnóstico radiológico

Pheochromocytomas are adrenal paragangliomas. Potentially malignant, these tumors have a low incidence but clear importance. They can appear in various hereditary syndromes, especially in von Hippel-Lindau syndrome, multiple endocrine neoplasia-2 (MEN2), and familial paraganglioma syndromes. In sporadic cases, underlying genetic alterations are often found, and these findings are changing our understanding of the disease.Although these tumors can manifest with a characteristic clinical presentation, in 13.1% to 57.6% of cases, it is the radiologist who first suggests the diagnosis, indicating analyses for catecholamines or nuclear medicine examinations.Radiologists should suspect a pheochromocytoma on detection of a well-delimited adrenal mass with rapid, intense enhancement that typically shows cystic and hemorrhagic phenomena, high T2 signal intensity, and the absence of macroscopic or microscopic lipids. The behavior in diffusion-weighted imaging usually does not provide very useful information. Approximately one-third of lesions show late washout similar to that seen with adenomas on CT. Percutaneous puncture should be avoided to avoid the risk of unleashing a severe hypertensive crisis.

Sunitinib Treatment for Advanced Paraganglioma: Case Report of a Novel SDHD Gene Mutation Variant and Systematic Review of the Literature

BackgroundParagangliomas (PGLs) are neuroendocrine neoplasms arising from chromaffin cells of sympathetic or parasympathetic paraganglia. Systemic therapies have been used only in metastatic PGLs. Antiangiogenic agents, such as sunitinib, could be a viable therapeutic choice in the subgroup of patients with SDH-positive PGLs. We describe the case of a man with Familial Paraganglioma Syndrome type 1 (FPGL) related to a novel mutation in SDHD gene treated with sunitinib. Furthermore, we performed a systematic review of the literature aimed to address the following question: is sunitinib treatment effective in patients with advanced/progressive/metastatic PGL?MethodsWe performed a data search using MEDLINE, Cochrane Library, and Scopus between April 2019 and September 2020. We included studies reporting data on clinical or biological characteristics, or clinical outcomes of patients with PGLs treated with sunitinib.ResultsThe search leaded to the selection of 25 publications. Data from case reports and case series showed that disease control rate (DCR = stable disease + partial response + complete response) was achieved in 34.7% of cases under sunitinib treatment. In 39% of patients DCR was followed by progressive disease (PD) or tumor relapse, 26.1% patients showed PD. Data from clinical trials showed that DCR was 83%, and the median progression free survival was 13.4 months.DiscussionData from the present literature review suggested that sunitinib could be a viable therapeutic option in advanced/progressive/metastatic inoperable PGLs. However, further trials on the efficacy of sunitinib in FPGL and sporadic PGL are needed.

An aggressive and expanded phenotype in a kindred with a c.57delG SDHD mutation

SummaryFamilial paraganglioma syndrome type 1 (PGL-1) is maternally imprinted, caused by SDHD mutations on the paternally inherited allele, and presents with paragangliomas and pheochromocytomas that are usually benign. We describe a kindred with a germline c.57delG SDHD mutation that demonstrates an aggressive and possibly expanded phenotype. Eight individuals across four generations were heterozygous for the c.57delG SDHD mutation. The three with known paternal inheritance were clinically affected. The aggressive phenotype was manifested by a neck paraganglioma with distant metastases, and to a lesser degree a neck paraganglioma infiltrating into local connective tissue and a pheochromocytoma presenting at age 8 y. A pulmonary capillary hemangioma may expand the SDHD phenotype. We conclude that the c.57delG SDHD mutation may confer a more aggressive and possibly expanded phenotype than other SDHD mutations.Learning points The c.57delG SDHD mutation may confer a more aggressive phenotype than other mutations associated with familial paraganglioma syndrome type 1. A capillary hemangioma, a component of other pseudohypoxia states, was observed in the lung of a single member of the c.57delG SDHD kindred. This report supports the hypothesis of others that mutations found near the beginning of the SDHD open reading frame are more likely to demonstrate an aggressive phenotype.

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.

SAT-140 Determining the Undetermined: The Role of Tumor Tissue Staining for Interpretation of Inconclusive Genetic Testing Results in Patients with Pheochromocytomas and Paragangliomas

Background:Paragangliomas and pheochromocytomas are neuroendocrine tumors that can occur in several hereditary tumor syndromes. While these are generally rare, individuals with germline loss of function mutations in the succinate dehydrogenase (SDH) genes are at high risk of developing these tumours, with a penetrance of 70% by age 50. Functional SDHB acts as a tumor suppressor. Consequently, pathogenic mutations in the SDHB gene predispose to familial paraganglioma syndrome type 4, with high incidence of extra adrenal paragangliomas and high rates of metastasis. SDHB mutation carriers are also predisposed to developing tumors in other sites such as renal cell cancer, gastrointestinal stromal tumors and pituitary adenomas. Genetic testing for hereditary syndromes is recommended in patients who present with paragangliomas and pheochromocytomas, especially in those with aggressive tumours or who present at a young age. It is recommended that mutation carriers are monitored with routine clinical and imaging surveillance, and effort is made to identify and screen at-risk family members. In some cases, genetic testing can identify variants that are not clearly pathogenic or benign. In such “variants of undetermined significance”, immunohistochemistry or family history can be a helpful tool in discriminating between SDHB related and non-SDH-related pheochromocytomas and paragangliomas.Clinical case:We report on three families who presented with manifestations of paraganglioma syndrome and were found to have Variants of Uncertain Significance (VUSs) in the SDHB gene. Absence of SDHB staining was seen on tumour histopathology in two of the families; staining was not performed in the third. The proband in the third case initially presented at the age of 22 with a cardiac pheochromocytoma. Subsequently, her son was diagnosed with metastatic renal cancer at the age of 37. Genetic test results from both these patients identified a heterozygous VUS in SDHB. The son passed away from complications of his aggressive cancer shortly after diagnosis. Had familial screening and surveillance been initiated sooner in this family, this poor outcome may have been prevented.Conclusion:Our case highlights the important diagnostic dilemma that can arise in patients with VUSs in risk genes for hereditary pheochromocytomas and paragangliomas. While universally treating these VUSs as pathogenic would be costly, low-yield and potentially harmful, the incorporation of family history and tumour tissue staining for SDHB should be considered in all individuals with pheochromocytomas and paragangliomas to help guide interpretation of inconclusive genetic testing results, inform subsequent management and help predict risk for inheritance and recurrence.

Natural History and Management of Familial Paraganglioma Syndrome Type 1: Long-Term Data from a Large Family.

Head and neck paragangliomas are the most common clinical features of familial paraganglioma syndrome type 1 caused by succinate dehydrogenase complex subunit D (SDHD) mutation. The clinical management of this syndrome is still unclear. In this study we propose a diagnostic algorithm for SDHD mutation carriers based on our family case series and literature review. After genetic diagnosis, first evaluation should include biochemical examination and whole-body imaging. In case of lesion detection, nuclear medicine examination is required for staging and tumor characterization. The study summarizes the diagnostic accuracy of different functional imaging techniques in SDHD mutation carriers. 18F-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)-computed tomography (CT) is considered the gold standard. If it is not available, 123I-Metaiodobenzylguanidine (MIBG) could be used also for predicting response to radiometabolic therapy. 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET-CT has a prognostic role since high uptake identifies more aggressive cases. Finally, 68Ga-peptides PET-CT is a promising diagnostic technique, demonstrating the best diagnostic accuracy in our and in other published case series, even if this finding still needs to be confirmed in larger studies. Periodic follow-up should consist of annual biochemical and ultrasonographic screening and biannual magnetic resonance examination to identify biochemical silent tumors early.

Can subunit-specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has come the recognition that mutations in the individual subunits have their own distinct natural histories. Increased genetic screening is leading to the identification of increasing numbers of, mostly asymptomatic, gene mutation carriers and the implementation of screening strategies for these individuals. Yet there is, to date, no international consensus regarding screening strategies for asymptomatic carriers. A comprehensive PubMed search from 1/1/2000 to 28/2/2018 was undertaken using multiple search terms and subsequently a manual review of references in identified papers to identify all clinically relevant cases and cohorts. In this review, the accumulated, published experience of phenotype and malignancy risks of individual SDH subunits is analysed. Where possible screening results for asymptomatic SDH mutation carriers have been analysed separately to define the penetrance in asymptomatic carriers (asymptomatic penetrance). The combined data confirms that "asymptomatic penetrance" is highest for SDHD and when there is penetrance, the most likely site to develop a PGL is head and neck (SDHD) and extra-adrenal abdominal (SDHB). However, the risk in SDHB carriers of developing HNPGL is also high (35.5%) and a PCC is low (15.1%), and in SDHD carriers there is a high risk of developing a PCC (35.8%) or abdominal PGL (9.4%) and a small, but significant risk at other sympathetic sites. The data suggest that the risk of malignant transformation is the same for both PCC and extra-adrenal abdominal PGLs (30%-35%) in SDHB carriers. In SDHD carriers, the risk of malignant transformation was highest in HNPGLs (7.5%) and similar for sympathetic sites (3.8%-5.2%). Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes.

Familial Cancers of Head and Neck Region.

Cancers that occur in families more often than would be expected by chance are termed as familial cancers. They occur due to an inherited genetic mutation and account for 5%-10% of all cancers. This review article presents some of the common Familial Cancer Syndromes (FCS) such as MEN 2B, hyperparathyroidism-jaw tumour syndrome, familial oral squamous cell carcinoma, melanoma, nasopharyngeal carcinoma, paraganglioma, neurofibroma and other syndromes associated with head and neck region.

Four generations of SDHB-related disease: complexities in management

SDHB mutations are linked to the familial paraganglioma syndrome type 4 (PGL4), which is associated with predominantly extra-adrenal disease and has high metastatic rates. Despite the lower penetrance rates in carriers of SDHB mutations compared to mutations in other paraganglioma susceptibility genes, the aggressive behavior of SDHB-linked disease warrants intensive surveillance to identify and resect tumors early. Patients with similar SDHB genotypes in whom the PGL syndrome manifests often exhibit very heterogeneous phenotypes. Tumors can arise in various locations, and management can be considerably different, depending on tumor site and pathology. We present a case series of five SDHB mutation carriers over four generations from the same family to illustrate the complexities in management.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma

Succinate dehydrogenase (SDH) represents a type II mitochondrial complex related to the respiratory chain and Krebs cycle. The complex is composed of four major subunits, SDHA, SDHB, SDHC and SDHD. The oncogenic role of this enzyme complex has only recently been recognized and the complex is currently considered an important oncogenic signaling pathway with tumor suppressor properties. In addition to the familial paraganglioma syndromes (types 1-5) as prototypical SDH-related diseases, many other tumors have been defined as SDH-deficient, in particular a subset of gastrointestinal stromal tumors (GIST), rare hypophyseal adenomas, a subset of pancreatic neuroendocrine neoplasms (recently added) and a variety of other tumor entities, the latter mainly described as rare case reports. As a central core subunit responsible for the integrity of the SDH complex, the expression of SDHB is lost in all SDH-deficient neoplasms irrespective of the specific SDH subunit affected by a genetic mutation in addition to concurrent loss of the subunit specifically affected by genetic alteration. Accordingly, all SDH-deficient neoplasms are by definition SDHB-deficient. The SDH-deficient renal cell carcinoma (RCC) has only recently been well-characterized and it is included as a specific subtype of RCC in the new World Health Organization (WHO) classification published in 2016. In this review, the major clinicopathological, immunohistochemical and genetic features of this rare disease entity are presented and discussed in the context of the broad differential diagnosis.

Discrepancy between radiologic and pathologic measuraments in pancreatic neuroendocrine tumors: A retrospective study on 199 patients

While the vast majority of pancreatic neuroendocrine tumours (pNETs) are sporadic, the recognition of an inherited pNET represents an evolving clinical responsibility of practising pathologists in the era of personalized medicine. The initially well-defined inherited pNET syndromes includes multiple endocrine neoplasia type 1 (MEN-1), von Hippel Lindau disease (VHL), neurofibromatosis type 1 (NF) and tuberous sclerosis (TS). Over the past decade, the spectrum of inherited pNETs has been expanded by the inclusion of new presentations such as multiple endocrine neoplasia type 4 (MEN-4), glucagon cell adenomatosis (Mahvash disease) along with germline mutations in DNA repair genes (MUTYH, BRCA2, and CHEK2) in a subset of seemingly sporadic looking pNETs as well as isolated case reports of succinate dehydrogenase deficient (SDH)- and mismatch repair deficient-pNETs occurring in the setting of SDH-related familial paraganglioma syndrome and Lynch syndrome, respectively. The findings have pointed out that the spectrum of inherited pNETs is indeed larger than what most physicians generally anticipate, likely reaching a rate greater than 15% of the overall presentations. From a morphological perspective, the identification of multifocal pNET should prompt the attention of pathologists to the possibility of an underlying genetic susceptibility. Since not all inherited pNETs manifest with multifocal disease, careful morphological assessment of the tumour and the non-tumorous pancreas, and application of immunohistochemical biomarkers are essential in the prediction of inherited pNETs. In order to facilitate the recognition of inherited pNETs, this review is aimed to provide a practical overview of pancreatic endocrine manifestations of MEN-1, MEN-4, VHL, NF-1, TS and glucagon cell adenomatosis.

Recent advances in management of phaeochromocytoma

Pheochromocytoma (PCC) and paraganglioma (PGL) are the neuroendocrine tumours that arise in adrenal medulla or extra adrenal sympathetic and parasympathetic paraganglia. Paraganglia are small organs that mainly consist of neuroendocrine cells derived from the embryonic neural crest that have the ability to synthesize and secrete catecholamines. Sympathetic PGLs are usually located in the chest, abdomen, or pelvis while parasympathetic PGLs are distributed along parasympathetic nerves in the head, neck, and upper mediastinum, also referred to as head and neck PGL (HNP). PCC/PGLs can be either functional (sympathetic) or non-functional (parasympathetic) based on catecholamine synthesis and secretion. In children diagnosed with hypertension, up to 1.7% have a catecholamine-secreting neoplasm. The majority of these tumours in childhood are PCC/PGLs. Incidence rates of PCC/PGLs are estimated at 0.3 cases per million per year or less. Approximately 10 –20% of these cases are diagnosed during childhood. Approximately half of the apparently sporadic PCC/PGLs that present in patients younger than 18 years are due to an identifiable germline mutation and this increases up to 70% in children less than 10 years of age. Hereditary tumor syndromes associated with PCC include Von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia 2 (MEN-2), the familial PGL syndromes and rarely, neurofibromatosis (NF) type 1. Recently, many other genes are found to be involved in pathogenesis of PCC/PGLs. Hereditary PCC/PGLs are often multifocal and, in the case of PCC, frequently bilateral. Children usually present becauseof symptomatic catecholamine hypersecretion or, less often, due to tumor mass effects (e.g. pain), or as an incidental radiographic finding, or because of family screening. At present, the diagnostic test of choice is the measurement of fractionated plasma and/or urine metanephrines (metanephrines and normetanephrines). A four-fold increase above the reference range is associated with an almost 100% probability of the presence of a catecholamine-secreting tumor. 123I-metaiodobenzylguanidine(MIBG) is a highly specific test that can confirm the catecholamine-secreting nature of a tumor, localize tumors not seen with cross-sectional imaging, and identify other sites of disease as well as metastasis. Because MIBG testingis not 100% sensitive, particularly in some genetic mutations, recently other functional scans have been studied in the evaluation of PCC/PGL: 18F fluorodihydroxyphenylalanine (DOPA) positron emission tomography (PET), 18F fluorodopamine (FDA) PET,18F fluorodeoxyglucose (FDG) PET. Surgical resection is the mainstay in the treatment of PCC/PGLs. It should be done after adequate alfa and beta adrenergic blockade to minimize the hemodynamic fluctuation during surgery. Laparoscopic adrenalectomy is the preferred procedure for most PCC. Laparotomy should be considered in patients with large PCC and/or a concern for underlying malignancy based upon the clinical presentation or radiographic appearance of the tumor. In the setting of bilateral PCC, cortical-sparing procedures should be considered for the adrenal with the least tumor bulk. The cortical-sparing approach is particularly attractive in young children and children at risk for noncompliance with lifelong glucocorticoid and mineralocorticoid replacement. The surgical approach for removal of a PGL depends upon the location of the tumor but in selected cases can also be performed laparoscopically. Patients with unresectable malignant tumors or distant metastatic disease can usually be treated symptomatically with adrenergic blockade. Radiation therapy or radiofrequency ablation can help with symptomatic metastatic disease, and IV bisphosphonates can be considered bony metastases, particularly in patients with bone pain or lesions that increase the risk of pathological fracture. Systemic treatment modalities are only palliative in nature and include 123I-MIBG therapy, peptide receptor radiotherapy (PRRT) and chemotherapy. PCC/PGLs can have unpredictable behavior and metastasize late in the clinical course. In addition, children in particular are at risk for the development of metachronous tumors. This makes long-term follow-up mandatory in children with PCC/PGL.

Counseling patients with succinate dehydrogenase subunit defects: genetics, preventive guidelines, and dealing with uncertainty.

The discovery that mutations in the succinate dehydrogenase (SDH) complex subunit (SDHA, B/C/D/AF2) genes predispose patients to the development of tumors has led to the identification of a large population of patients and relatives at risk for developing malignancies. The most frequent conditions associated with these mutations are the familial paraganglioma syndromes. Other tumors that are frequently associated with SDH mutations (SDHx) are gastrointestinal stromal tumors and renal cell carcinomas. A number of other rare associations have also been described. SDHx mutations are often clinically silent and metastatic, but they may also be aggressive in their presentation. The penetrance of these mutations is beginning to be understood, and the characteristics of the phenotype are being elucidated. However, the inability to accurately predict the appearance, nature, and location of tumors as well as their tendency to recur or metastasize pose challenges to those who counsel and manage patients with SDHx mutations. In this work, we present our approach for counseling these families in the context of the current uncertainties, while striving to maintain patient autonomy.

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

Paragangliomas are rare, slow-growing tumors that frequently arise in the head and neck, with the carotid bodies and temporal bone of the skull base being the most common sites. These neoplasms are histologically similar to pheochromocytomas that form in the adrenal medulla and are divided into sympathetic and parasympathetic subtypes based on functionality. Skull base and head and neck region paragangliomas (SHN-PGs) are almost always derived from parasympathetic tissue and rarely secrete catecholamines. However, they can cause significant morbidity by mass effect on various cranial nerves and major blood vessels. While surgery for SHN-PG can be curative, postoperative deficits and recurrences make these lesions challenging to manage. Multiple familial syndromes predisposing individuals to development of paragangliomas have been identified, all involving mutations in the succinate dehydrogenase complex of mitochondria. Mutations in this enzyme lead to a state of "pseudohypoxia" that upregulates various angiogenic, survival, and proliferation factors. Moreover, familial paraganglioma syndromes are among the rare inherited diseases in which genomic imprinting occurs. Recent advances in gene arrays and transcriptome/exome sequencing have identified an alternate mutation in sporadic SHN-PG, which regulates proto-oncogenic pathways independent of pseudohypoxia-induced factors. Collectively these findings demonstrate that paragangliomas of the skull base and head and neck region have a distinct genetic signature from sympathetic-based paragangliomas occurring below the neck, such as pheochromocytomas. Paragangliomas serve as a unique model of primarily surgically treated neoplasms whose future will be altered by the elucidation of their genomic complexities. In this review, the authors present an analysis of the molecular genetics of SHN-PG and provide future directions in patient care and the development of novel therapies.