Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients

Fuchs, Talia L; Maclean, Fiona; Turchini, John; Vargas, Ana Cristina; Bhattarai, Selina; Agaimy, Abbas; Hartmann, Arndt; Kao, Chia Sui; Ellis, Carla LaShannon; Bonert, Michael; Leroy, Xavier; Kunju, Lakshmi P.; Schwartz, Lauren E.; Matsika, Admire; Williamson, Sean R.; Rao, Priya; Divatia, Mukul K.; Guarch, Rosa; Algaba, Ferrán; Balancin, Marcelo Luiz; Zhou, Ming; Samaratunga, Hemamali; Cunha, Isabela Werneck da; Brimo, Fadi; Ryan, Andrew; Clouston, David; Aron, Manju; O’Donnell, Marie; Chan, Emily; Hirsch, Michelle S.; Moch, Holger; Pang, Chun-Yin; Cheuk, Wah; Yin, Wenwu; Perry-Keene, Joanna; Yilmaz, Aslı; Chou, Angela; Clarkson, Adele; Westhuizen, Gerhard van der; Morrison, Ella; Zwi, Jonathan; Hes, Ondřej; Trpkov, Kiril; Gill, Anthony J.

doi:10.1038/s41379-021-00998-1

Cited by 25 publications

(30 citation statements)

References 30 publications

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“…The cytoplasm has a more dense eosinophilic quality with a darker and coarser chromatin pattern. Solid sheet‐like growth, irregular anastomosing tubular structures and papillary architectures embedded in desmoplastic stroma were also observed in high‐grade tumours 108 . Tumours develop most commonly in patients with germline mutations in SDHB , less frequently in SDHC and SDHD and only rarely in SDHA 107,109 .…”

Section: Succinate Dehydrogenase Germline Mutationsmentioning

confidence: 96%

“…[104][105][106][107] architectures embedded in desmoplastic stroma were also observed in high-grade tumours. 108 Tumours develop most commonly in patients with germline mutations in SDHB, less frequently in SDHC and SDHD and only rarely in SDHA. 107,109 Therefore, loss of SDHB reaction by immunohistochemistry with retained reaction in the non-neoplastic entrapped tubules serves as a valuable tool in the diagnosis (Figure 7B).…”

Section: Succinate Dehydrogenase Germline Mutationsmentioning

confidence: 99%

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The pathological and molecular genetic landscape of the hereditary renal cancer predisposition syndromes

et al. 2022

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It is estimated that 5–8% of renal tumours are hereditary in nature, with many inherited as autosomal‐dominant. These tumours carry a unique spectrum of pathological and molecular alterations, the knowledge of which has expanded in recent years. Due to this knowledge, many advances in the treatment of these tumours have been achieved. In this review, we summarize the current understanding of the genetic renal neoplasia syndromes, clinical and pathological presentations, molecular pathogenesis, advances in therapeutic implications and targeted therapy.

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Section: Succinate Dehydrogenase Germline Mutationsmentioning

confidence: 96%

Section: Succinate Dehydrogenase Germline Mutationsmentioning

confidence: 99%

The pathological and molecular genetic landscape of the hereditary renal cancer predisposition syndromes

et al. 2022

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“…Interestingly, 1 patient with ISUP grade 2 tumor developed biopsy-proven vertebral metastasis 30 years later. Recently, the study by Fuchs et al 55 on 62 SDH-deficient RCC described variant features (21%) that also showed high-grade features including WHO/ ISUP grade 3 (54%) and grade 4 (46%) nuclei. Interestingly, the OS was significantly shorter in SDH-deficient RCCs with variant morphologies.…”

Section: Renal Cell Carcinoma Subtypes Where World Health Organizatio...mentioning

confidence: 99%

Updates in Grading of Renal Cell Carcinomas Beyond Clear Cell Renal Cell Carcinoma and Papillary Renal Cell Carcinoma

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Chumbalkar

Montironi

et al. 2022

Advances in Anatomic Pathology

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The World Health Organization (WHO) recommends grading of clear cell renal cell carcinoma (RCC) and papillary RCC using the WHO/International Society of Urological Pathology (ISUP) grade, which is primarily based on nuclear features. As the spectrum of RCC continues to evolve, with more recently described subtypes in the past decade, literature evidence on grading these subtypes is limited or not available for some tumor types. Herein, we outline a pragmatic approach to the topic of grading RCC, dividing the contemporarily described RCC subtypes into 7 categories based on the potential clinical applicability of grading as a useful prognostic parameter: (1) RCC subtypes that are reasonably validated and recommended for WHO/ISUP grading; (2) RCC subtypes where WHO/ISUP is not applicable; (3) RCC subtypes where WHO/ISUP grading is potentially clinically useful; (4) inherently aggressive RCC subtypes where histologic classification itself confers an aggressive biologic potential; (5) renal epithelial tumors where WHO/ISUP grading provides potentially misleading prognostic implication; (6) renal epithelial neoplasms where low WHO/ISUP grade features are a prerequisite for accurate histologic classification; and (7) renal epithelial neoplasms with no or limited data on grading or incomplete understanding of the biologic potential. Our aim in outlining this approach is 2-fold: (a) identify the gaps in understanding and application of grading in RCC subtypes so that researchers in the field may perform additional studies on the basis of which the important pathologic function of assignment of grade may be recommended to be performed as a meaningful exercise across a wider spectrum of RCC; and (b) to provide guidance in the interim to surgical pathologists in terms of providing clinically useful grading information in RCC based on currently available clinicopathologic information.

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“…SDHx mutation status and the particular subunit involved have been shown to have distinctive clinicopathological associations for different tumour types. 1,[4][5][6][7][8][9][10][11][12] For example, patients with germline SDHB pathogenic variants have a high propensity for developing intra-abdominal and extra-adrenal PHEO/ PGL and a higher risk of metastatic disease. 13 In addition, compared to usual GIST, SDH-deficient GISTs are resistant to imatinib therapy and show a high rate of distant metastasis even with small tumour size or low mitotic rates.…”

Section: Introductionmentioning

confidence: 99%

“…Patients and their family members with germline SDHx pathogenic variants are prone to developing multiple tumours and require lifelong screening; therefore, identification of an SDH‐deficient tumour should prompt genetic counselling. SDHx mutation status and the particular subunit involved have been shown to have distinctive clinicopathological associations for different tumour types 1,4–12 . For example, patients with germline SDHB pathogenic variants have a high propensity for developing intra‐abdominal and extra‐adrenal PHEO/PGL and a higher risk of metastatic disease 13 .…”

Section: Introductionmentioning

confidence: 99%

An exploration in pitfalls in interpreting SDHB immunohistochemistry

et al. 2022

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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 SDHdeficient 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.

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Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients

Cited by 25 publications

References 30 publications

The pathological and molecular genetic landscape of the hereditary renal cancer predisposition syndromes

The pathological and molecular genetic landscape of the hereditary renal cancer predisposition syndromes

Updates in Grading of Renal Cell Carcinomas Beyond Clear Cell Renal Cell Carcinoma and Papillary Renal Cell Carcinoma

An exploration in pitfalls in interpreting SDHB immunohistochemistry

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