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. 2022 Aug;81(2):264-269.
doi: 10.1111/his.14681. Epub 2022 May 27.

An exploration in pitfalls in interpreting SDHB immunohistochemistry

Chien-Kuang Cornelia Ding  1 , Salina Chan  2 , Julie Mak  2 , Sarah E Umetsu  1 , Jeffry P Simko  1 , Roberto Ruiz-Cordero  1 , Tara Saunders  1 , Emily Chan  1
Affiliations

An exploration in pitfalls in interpreting SDHB immunohistochemistry

Chien-Kuang Cornelia Ding et al. Histopathology. 2022 Aug.

Abstract

Aims: Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumour types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the succinate dehydrogenase B (SDHB) subunit can help to detect SDH-deficiency, which manifests as complete loss of staining in tumour cells. However, a subset of SDH-deficient tumours can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as 'retained', a diagnostic pitfall complicating interpretation. Herein, we characterise in detail aberrant SDHB-IHC staining patterns in SDH-deficient tumours.

Methods and results: We identified 23 tumours from patients with known germline SDHx and/or molecularly confirmed SDHx pathogenic/likely-pathogenic variants in their tumour. Of these, eight (35%) showed significant SDHB-IHC staining: one SDHA-, one SDHB-, three SDHC- and three SDHD-mutated cases. In all eight cases, closer inspection revealed differences in intensity and intracellular distribution of SDHB-IHC staining in tumour cells compared to adjacent non-neoplastic cells: non-neoplastic cells showed intense cytoplasmic coarse granular staining; tumour cells in seven of eight cases showed weak to focally strong, cytoplasmic blush to fine granular staining, in > 80% of cells. The remaining case in the initial block showed variably strong non-granular cytoplasmic staining with globular perinuclear accentuation throughout, only subtly distinct from the staining pattern of non-neoplastic cells. SDHB-IHC performed on two additional blocks in this latter case revealed significant intratumoral heterogeneity, including convincing areas of complete loss.

Conclusions: When evaluating SDHB-IHC, care should be taken to distinguish true retained expression from aberrant cytoplasmic expression, which may be difficult to appreciate. Sometimes this may require additional molecular testing.

Keywords: gastrointestinal stromal tumour (GIST); immunohistochemistry; paraganglioma; renal cell carcinoma; succinate dehydrogenase (SDH).

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References

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