Prevalence of succinate dehydrogenase deficiency in paragangliomas and pheochromocytomas at Tygerberg Hospital: a retrospective review.

Bruce-Brand, Cassandra (2020-12)

Thesis (MMed)--Stellenbosch University, 2020.

Thesis

IntroductionPheochromocytomas (PC) and paragangliomas (PGL) are rare neural crest-derived tumours that occur at adrenal and extra-adrenal sites. These tumours may be sporadic but a significant proportion are caused by familial syndromes due to germline mutations. Mutations of the succinate dehydrogenase (SDH) complex make up the bulk of syndromic cases in the international literature. SDH mutated cases are now known to have higher rates of metastatic disease, a younger age of onset, an association with other SDH mutated tumours as well as implicationsforfirst degree relatives. An immunohistochemical stain for SDHB that has excellent correlation with SDH mutation status has been developed and is routinely used in many centres to infer SDH mutation status. Loss of staining is seen when there is a mutation of any of the SDH subunit complexes. The prevalence of SDHmutated tumoursis not known in the South African setting. MethodsA retrospective laboratory-based study was conducted at Tygerberg Hospital in South Africa to assess the prevalence of SDH deficiency in all PC and PGLs between 2005 and 2015. These tumours were further stratified by other characteristics:tumour site, patient age, sex and presence of metastatic disease. Fifty-two cases met the inclusion criteria and the SDHB immunohistochemical stain was performed on these cases. Germline testing or sequencing of these cases was not performed. ResultsThirty-six percent of cases showed loss of staining of SDHB by immunohistochemistry. Head and neck PGLs made up the bulk of cases (50%) and females were strongly represented, particularly at head and neck sites (73%). Loss of staining was significantly correlated with a younger age at presentation(z= -3.59, p< .001).There was no correlation betweenloss of staining and tumour site or patient sex. The inter-observer agreement in interpretation of the immunohistochemical stain was excellent (Cohen’s kappa= 0.917, p< .001). Conclusion The prevalence of SDH deficiency in our setting, as shown by loss of immunohistochemical staining for SDHB, is comparable to the literature and makes up a significant proportion of our PC/PGL cases. This highlights the need for performance of this stain in our setting in order to recognise these syndromic cases. Many patients in South Africa do not have access to genetic testing upon diagnosis of a PC or PGL as this is costly and not widely available. Many studies have shown excellent correlation of the immunohistochemical stain with underlying SDH mutation status. Immunohistochemistry is widely available in South African pathology laboratories and is relatively affordable. Although interpretation of this stain can be challenging, we report excellent inter-observer agreement in a generalist pathology practice when following published guidelines for interpretation. We therefore advocate for routine use of this stain in all PC/PGL cases diagnosed in our setting.

InleidingFeochromositome (FC) en paragangliome (PGL) is seldsame neurale kruin-afgeleide tumorewat voorkom indiebyniere en buitedie byniererespektiewelik. Hierdie gewasse kommeestal sporadiesvoor, maar 'n beduidendeaantal gevalle word veroorsaak deur familiële sindrome as gevolg van kiemlynmutasies. Mutasies van die suksinaatdehidrogenase (SDH) -kompleks is verantwoordelik virdie meeste familiële sindrome in dieinternasionale literatuur. Ditisbekend dat SDH-gemuteerde gevalle‘nhoër insidensie van metastaseshet, 'n jonger ouderdom van aanvang, geassosieer ismet ander SDH-gemuteerde gewasse, en ook implikasies mag inhou vir eerstegraadse familielede. 'nImmunohistochemiese kleuringvir SDHB wat 'n uitstekende korrelasie met SDH-mutasie-status het, is ontwikkel en word roetinegewysin baie sentrums gebruik om die SDH-mutasie-status af te lei. Verlies van kleuringword gesien as daar 'n mutasie van enige van die SDH-subeenheidskomplekse is. Die prevalensievan SDH-gemuteerde tumour is niebekendin die Suid-Afrikaanse konteks nie.Metodes'nRetrospektiewelaboratoriumgebaseerde studie is in die Tygerberg-hospitaal in Suid-Afrika gedoen om die prevalensievan SDH-gebrek in alle FC en PGLtussen 2005 en 2015 te bepaal. Hierdie tumoreis verder gestratifiseer deur ander eienskappe: anatomiese verspreiding, pasiëntouderdom, geslag en teenwoordigheid van metastatiese siektes. Twee-en-vyftiggevalle het aan die insluitingskriteria voldoen, en die SDHB-immunohistochemiese kleuringis op hierdie gevalle uitgevoer. Daar is nie 'n kiemlyntoetseof nukleotied-volgorde bepalingvan hierdie gevalle gedoen nie.ResultateSes-en-dertig persent van die gevalle het verlies van kleuringvan SDHB deur immunohistochemie getoon. PGvandiekop en nek het die grootste gedeelte van gevalle uitgemaak (50%) en die vroulike geslagwas die meeste verteenwoordig, veral indie kop-en nektumore(73%). Die verlies van kleuringwas beduidend gekorreleer met 'n jonger ouderdom van presentasie (z= -3.59, p<.001).Daar was geen verbandtussen verlies van kleuringen anatomiese verspreiding of geslag nie. Die ooreenkoms in die interpretasie van die immunohistochemiese kleuring tussen waarnemers was uitstekend (Cohen se kappa = 0,917, p<0,001).GevolgtrekkingDie voorkoms van SDH-mutasies in ons konteks, soos aangetoon deur die verlies van immunohistochemiese kleuring vir SDHB, is vergelykbaar metdie literatuur en maak 'n beduidende deel van ons FC / PGL-gevalleuit. Dit beklemtoon die behoefte aan die uitvoering van hierdie kleuringin ons praktyk om hierdie sindroomgevalle te herken. Baie pasiënte in Suid-Afrika het nie toegang tot genetiese toetsing tydensdie diagnose van 'n FCof 'n PGL nie, aangesien dit duurisen nie algemeen beskikbaaris nie. Baie studies hetuitstekende korrelasie van die immunohistochemiese kleuringmet die onderliggende SDH-mutasie-statusgetoon. Immunohistochemie is algemeen beskikbaar in Suid-Afrikaanse patologie laboratoriums en is relatief bekostigbaar. Alhoewel interpretasie van hierdie kleuring. uitdagend kan wees, rapporteerons 'n uitstekende ooreenkoms tussen waarnemers in 'n algemene patologiepraktyk wanneer gepubliseerde riglyne vir interpretasie gevolgword. Ons stel dus voor dat hierdiekleuring roetinegewys gedoen word in alle FC / PGL-gevalle wat in ons praktykgediagnoseer word.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/109067
This item appears in the following collections: