Renal cell carcinoma with angioleiomyoma-like stroma and clear cell papillary renal cell carcinoma: exploring SDHB protein immunohistochemistry and the relationship to tuberous sclerosis complex

Abstract

Renal cell carcinoma (RCC) with angioleiomyoma-like stroma appears to be molecularly distinct from clear cell RCC; however, its relationship to clear cell papillary RCC remains debated. Recent studies have found that similar tumors sometimes occur in patients with tuberous sclerosis complex (TSC), of which 1 study found unexpectedly negative succinate dehydrogenase B (SDHB) immunostaining. We evaluated immunohistochemistry for SDHB in 12 apparently sporadic RCCs with angioleiomyoma-like stroma and correlated with clinical information for stigmata of TSC. Tumors were compared with a group of 16 clear cell papillary RCCs and 6 unclassified tumors with prominent stroma. With the exception of 1 unclassified tumor, all exhibited at least focal cytoplasmic staining for SDHB protein, often requiring high magnification and better appreciated with increased antibody concentration. Detailed history information was available for 9 of 11 patients with smooth muscle-rich tumors, revealing no stigmata of undiagnosed TSC. Electron microscopy performed on 1 of these tumors revealed mitochondria to be very sparse, potentially accounting for the weak immunohistochemical labeling for SDHB protein. Weak SDHB immunostaining may represent another shared feature of RCC with angioleiomyoma-like stroma and clear cell papillary RCC, likely due to sparse mitochondria, strengthening the possible relationship of these entities. Although smooth muscle-rich tumors have been recently reported in patients with TSC, absence of staining in tumors with this pattern may not be specific for TSC. In tumors with pale or clear cytoplasm, immunohistochemical staining for SDHB should be interpreted with caution as evidence of abnormality in the SDH pathway.

Atypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma

“…Of note, this same RCCLS subtype has been documented to display aberrant Succinate Dehydrogenase B (SDHB) negativity on immunohistochemistry, similarly to the succinate dehydrogenase‐deficient RCC subtype, although in the absence of detectable deleterious SDHB genetic alterations that portend the development of SDHB‐deficient RCCs . Indeed, a recent study linked SDHB IHC signal rarefaction in RCCLS to decreased mitochondrial density as assessed by electron microscopy . As expected, no likely pathogenic or clearly pathogenic SDHB alterations were detected among our RCC samples studied via massive parallel sequencing.…”

New and emerging renal entities: a perspective post‐WHO 2016 classification

“…Rare cases may show variant morphologies, reminiscent of clear cell or papillary RCC, and these were mostly detected in a tissue microarray (TMA) setting . It remains speculative whether these cases represent true SDH‐deficient RCCs due to germline or somatic SDH subunit gene alterations, or whether they show false‐negative SDHB staining, as documented in cases with clear cytoplasm and a paucity of mitochondria …”

“…To follow up and further investigate this observation, Williamson et al . evaluated 12 apparently sporadic ‘RCCs with angioleiomyoma‐like stroma’ for SDHB expression by using immunohistochemistry . They showed that the great majority of such cases actually showed at least focal and weak cytoplasmic staining for SDHB, and clarified that the apparent negative SDHB staining may be due to their clear or pale cytoplasm and decreased mitochondrial density.…”

“…Moreover, they concluded that the negative SDHB IHC staining in any tumour showing pale or clear cytoplasm, e.g. some renal tumours in TSC patients, should be interpreted with caution, because it may not reflect an abnormality in SDH …”

“…6,24 It remains speculative whether these cases represent true SDH-deficient RCCs due to germline or somatic SDH subunit gene alterations, or whether they show false-negative SDHB staining, as documented in cases with clear cytoplasm and a paucity of mitochondria. 25 In addition to being negative for SDHB on immunohistochemistry ( Figure 1F), SDH-deficient RCCs are typically negative for CD117, and many cases are negative for broad-spectrum keratins, such as AE1/AE3, and are often completely negative for cytokeratin (CK) 7. [6][7][8] Most reported cases with the classic morphology of SDH-deficient RCCs have been associated with germline mutations in SDHB and SDHC.…”