A registry-based study of thyroid paraganglioma: histological and genetic characteristics

Dobschuetz, Ernst von; Leijon, Helena; Schalin‐Jäntti, Camilla; Schiavi, Francesca; Brauckhoff, Michae l; Pęczkowska, Mariola; Spiazzi, Giovanna; Demattè, S.; Cecchini, M.; Sartorato, Paola; Krajewska, Jolanta; Hasse-Lazar, Kornelia; Roszkowska‐Purska, Katarzyna; Taschin, Elisa; Malinoc, Angelica; Akslen, Lars A.; Arola, Johanna; Lange, Dariusz; Fassina, Ambrogio; Pennelli, Gianmaria; Barbareschi, Mattia; Luettges, Jutta; Prejbisz, Aleksander; Januszewicz, Andrzej; Strate, Tim; Bausch, Birke; Castinetti, Frédéric; Jarząb, Barbara; Opocher, Giuseppe; Eng, Charis; Neumann, Hartmut P. H.

doi:10.1530/erc-14-0558

Cited by 30 publications

(34 citation statements)

References 26 publications

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“…Several recent case reports or small cohorts of patients carrying SDHA mutations have been published . To date, the total number of cases reported is 93 with 41 different mutations.…”

Section: Surveillance Programmesmentioning

confidence: 99%

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

Tufton

Sahdev

Drake

et al. 2018

Clinical Endocrinology

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Objective: 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.Design: 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). Results: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%). Conclusions:Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes. K E Y W O R D S imaging, MRI, paraganglioma, phaeochromocytoma, screening, SDH, succinate dehydrogenase, surveillance S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Tufton N, Sahdev A, Drake WM, Akker SA. Can subunit-specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?. Clin Endocrinol. 2019;90:31-46. https://doi.

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“…Several recent case reports or small cohorts of patients carrying SDHA mutations have been published . To date, the total number of cases reported is 93 with 41 different mutations.…”

Section: Surveillance Programmesmentioning

confidence: 99%

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

Tufton

Sahdev

Drake

et al. 2018

Clinical Endocrinology

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“…Diagnosis can be particularly difficult when they develop in unusual locations such as thyroid (von Dobschuetz et al 2015) or ovary (Schuldt et al 2015). Immunohistochemistry is used as an aid to diagnosis in challenging cases, with the immunohistochemical markers tailored to both the anatomic site and the diagnoses under consideration.…”

Section: Differential Diagnosismentioning

confidence: 99%

“…Expression of tyrosine hydroxylase is useful as a more specific paraganglionic marker. In the thyroid, absence of staining for calcitonin is an important site-specific criterion to distinguish paragangliomas from medullary thyroid carcinomas (von Dobschuetz et al 2015).…”

Section: Differential Diagnosismentioning

confidence: 99%

15 YEARS OF PARAGANGLIOMA: Pathology of pheochromocytoma and paraganglioma

Tischler¹,

deKrijger²

2015

Endocrine-Related Cancer

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Pathologists using their routine diagnostic tools can contribute both to the care of patients with pheochromocytoma/paraganglioma and to understanding the pathobiology of the tumors. They can document details of tissue organization and cytology that are accessible only by microscopy and can characterize admixtures of cell types that are morphologically distinct or show differential expression of immunohistochemical markers. Current roles and challenges for pathologists include differential diagnosis, identifying clues to the presence of hereditary disease, and effective communication of pathology information for clinical and research purposes. Future roles will increasingly involve risk stratification, identification of actionable targets for personalized therapies, and aiding the interpretation of molecular tests by helping characterize genetic variants of unknown significance. It remains to be determined to what extent the need for pathology input will be overshadowed by the availability of genetic testing and other molecular analyses at ever-decreasing cost, together with very effective clinical paradigms for risk stratification and patient care.

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“…It has been established that germline SDHD variants and somatic SDHD/B alterations are associated with heritable and sporadic thyroid cancer, respectively (15–17). We have also demonstrated previously that SDHD variants promote apoptosis in follicular thyroid cancer cells (5).…”

Section: Discussionmentioning

confidence: 99%

Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells

Saji

Ringel

et al. 2017

Human Molecular Genetics

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Thyroid cancer is a major component cancer of Cowden syndrome (CS), a disorder typically associated with germline mutations in PTEN. Germline variants in succinate dehydrogenase genes (SDHx) co-occurring with PTEN germline mutations confer a 2-fold increased prevalence (OR 2.7) of thyroid cancer compared to PTEN-associated CS but 50% decreased prevalence (OR 0.54) of thyroid cancer compared to SDHx-associated CS. We have previously shown that CS-associated SDHD variants G12S and H50R induce PTEN oxidation and nuclear accumulation in thyroid cancer. Our current study shows that SDHD-G12S and -H50R variants cause down-regulation of autophagy, demonstrating a role for SDHD in autophagy-associated pathogenesis of differentiated thyroid cancer. These findings could explain the increased prevalence of thyroid cancer in CS patients with SDHx germline mutations compared to those with PTEN mutations alone. Importantly, we demonstrate the dependence of this process on functional wild-type PTEN with reversal of decreased autophagy after PTEN knockdown. The latter could explain the clinically observed decrease in thyroid cancer prevalence in patients with co-existent PTEN mutations and SDHx variants. We also show that SDHD-G12S/H50R promotes mono-ubiquitination of PTEN, causing its translocation into the nucleus, upregulation of AKT and consequent phosphorylation of FOXO3a. Furthermore, SDHD-G12S/H50R-mediated increase in acetylation of FOXO3a further enhances AKT-associated phosphorylation of FOXO3a. This combination of phosphorylation and acetylation of FOXO3a results in its nuclear export for degradation and consequent down-regulation of FOXO3a-target autophagy-related gene (ATG) expression. Overall, our study reveals a novel mechanism of crosstalk amongst SDHD, PTEN and autophagy pathways and their potential roles in thyroid carcinogenesis.

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A registry-based study of thyroid paraganglioma: histological and genetic characteristics

Cited by 30 publications

References 26 publications

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

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

15 YEARS OF PARAGANGLIOMA: Pathology of pheochromocytoma and paraganglioma

Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells

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