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This article is part of the supplement: Familial Aspects of Cancer 2011 Research and Practice

Open Access Meeting abstract

Use of SDHB immunohistochemistry to identify germline mutations of SDH genes

AJ Gill

Author Affiliations

Royal North Shore Hospital, Australia

Hereditary Cancer in Clinical Practice 2012, 10(Suppl 2):A7  doi:10.1186/1897-4287-10-S2-A7

The electronic version of this article is the complete one and can be found online at: http://www.hccpjournal.com/content/10/S2/A7


Published:12 April 2012

© 2012 Gill; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Meeting abstract

Pheochromocytomas and paragangliomas occur sporadically but are commonly associated with the von Hippel Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) and germline mutations of succinate dehydrogenase B (SDHB), C (SDHC) or D (SDHD). It is therefore recommended that genetic testing be considered if not performed in all cases of even apparently sporadic pheochromocytomas or paragangliomas. Recently it has been demonstrated that immunohistochemistry (IHC) for SDHB is negative in all SDH mutated paragangliomas regardless of whether the B,C or D subunit is involved [1,2]. Furthermore some clearly syndromic paragangliomas without known genetic mutation (including but not limited to those which occur in the Carney Triad) are identified by negative staining for SDHB [3].

Although historically the renal tumours occurring in the setting of SDHB mutation were usually classified as conventional clear cell carcinoma or oncocytoma, they actually display a unique morphology (unrecognized until know) and which can be confirmed by immunohistochemistry.

The GISTs occurring in SDH mutation and Carney Triad are also unique and demonstrate quite a different morphology, natural history and molecular pathogenesis compared to other GISTs occurring in adults (but similar to most GISTs occurring in childhood). We call this unique subtype of GIST the type 2 GIST. Briefly type 2 GISTs arise in the stomach, show an epithelioid morphology, are often multifocal, commonly show lymph node metastasis, are wild type for KIT and PDGFR, have a prognosis not predicted by size and mitotic rate, never respond to imatinib but demonstrate an indolent growth despite the presence of frequent metastases [3,5].

We recommend that all paragangliomas, GISTs which potentially display type 2 morphological or clinical features and renal carcinomas which display the unique morphology we described should undergo immunohistochemistry for SDHB. Negative staining for SDHB indicates an abnormality of the mitochondrial complex 2 and is an absolute indication for formal genetic testing. We perform and interpret SDHB immunohistochemistry of archived formalin fixed paraffin embedded tissue in a manner analogous to MSI testing in colon cancer. In the setting of paraganglioma or renal carcinoma negative staining almost always indicates germline SDHB,SDHC or SDHD mutation (greater than 90% chance) but may indicate Carney Triad. In the setting of GIST, Carney Triad is more likely, but SDHB, SDHC or SDHD mutation accounts for at least 25% of type 2 GIST.

Table 1. Syndromes associated with paraganglioma and pheochromocytoma

The mitochondrial complex 2 links the Krebs cycle and the electron transport chain and is illustrated below:

References

  1. van Nederveen FH, Gaal J, Favier J, et al.: An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC or SDHD gene mutations: a retrospective and prospective analysis.

    Lancet Oncol 2009, 10:764-771. PubMed Abstract | Publisher Full Text OpenURL

  2. Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow G, Richardson A-L, Sidhu SB, Robinson BG, Clifton-Bligh RJ: Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC and SDHD in paraganglioma-phaeochromocytoma syndromes.

    Hum Pathol 2010, 41:805-814. PubMed Abstract | Publisher Full Text OpenURL

  3. Gill AJ, Chou A, Vilain R, Clarkson A, Lui M, Jin R, Tobias V, Samra J, Goldstein D, Smith C, Sioson L, Parker N, Smith RC, Sywak M, Sidhu SB, Ma Wyatt J, Robinson BG, Benn DE, Clifton-Bligh RJ: Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into two distinct types.

    Am J Surg Pathol 2010, 34:636-44. PubMed Abstract | Publisher Full Text OpenURL

  4. Gill AJ, Pachter NS, Clarkson A, Tucker KM, Winship I, Benn DE, Robinson BG, Clifton-Bligh R: Renal tumors and hereditary pheochromoytoma-paraganglioma syndrome.

    N Engl J Med 2011, 364(9):885-886. PubMed Abstract | Publisher Full Text OpenURL

  5. Gill AJ, Chou A, Vilain RE, Clifton-Bligh RJ: "Pediatric-type" gastrointestinal stromal tumors are SDHB negative ("type 2") GISTs.

    Am J Surg Pathol 2011, 35:1245-1247. PubMed Abstract | Publisher Full Text OpenURL

  6. Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, Winship IM, Earls P, Benn DE, Robinson BG, Fleming S, Clifton-Bligh RH: Renal tumors associated with germline SDHB mutation show distinctive morphology.

    Am J Surg Pathol 2011, 35:1578-1585. PubMed Abstract | Publisher Full Text OpenURL