Eosinophilic Solid and Cystic (ESC) Renal Cell Carcinomas Harbor TSC Mutations

Abstract

Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC) has recently been described as a potentially new subtype of RCC based upon morphologic and immunohistochemical features. These neoplasms typically demonstrate solid and cystic architecture, and the neoplastic cells contain voluminous eosinophilic cytoplasm with granular cytoplasmic stippling. There is frequently focal immunoreactivity for cytokeratin 20. Although the initial cases all occurred in adult females and had benign outcome, we recently expanded the proposed spectrum of this neoplasm to include pediatric cases, multifocal neoplasms, and a case with hematogenous metastasis. ESC has been postulated to be analogous to a subtype of RCC consistently identified in tuberous sclerosis complex patients, and while previous work has demonstrated loss of heterozygosity at the TSC1 locus and copy number gains at TSC2 in ESC RCC, these genes have not been sequenced in ESC RCC. Using capture-based and amplicon-based next-generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases). These included a metastatic ESC RCC which had a complete response to mTOR targeted therapy. We also found these mutations in some neoplasms with variant morphology and thus potentially expand the spectrum of ESC RCC. These include one of our adult cases which demonstrated dominant "type 2" papillary RCC morphology and 2 of 3 previously unclassified pediatric RCC with features of ESC RCC minus granular cytoplasmic stippling. We also demonstrate TSC mutations in a case of so-called "oncocytoid RCC after neuroblastoma" with identical morphology and immunoprofile, providing a molecular link between the latter and ESC RCC. In summary, ESC RCC consistently harbors actionable TSC1 or TSC2 mutations, which are infrequently seen in established subtypes of RCC. These findings support TSC1/2 mutation as a molecular marker of ESC RCC, and suggest expansion of the clinicopathologic spectrum to include neoplasms with papillary architecture, occasional cases lacking well-developed granular cytoplasmic stippling, and a subset of RCC with oncocytic features in patients who have survived neuroblastoma.

ESC, ALK, HOT and LOT: Three Letter Acronyms of Emerging Renal Entities Knocking on the Door of the WHO Classification

“…Other positive stains also include PAX8, AE1/AE3, CK8/18 and vimentin; rare cases can be negative or only focally positive for cytokeratin AE1/AE3 [1,2]. Cathepsin K is also reactive in great majority of ESC RCC, either as diffuse or focal positivity (personal unpublished observations), in line with some of the reported observations of cathepsin K reactivity in ESC RCC [10,12]. Negative stains include CD117, CA9, HMB45 and melan A [1,2].…”

“…Great majority of ESC RCC are sporadic and are found in non-syndromic setting, although a subset of identical tumors have been documented in patients with a tuberous sclerosis complex (TSC) [5,6]. The great majority of ESC RCC are small, solitary tumors of low stage that are found in female patients, and generally exhibit indolent behaviour, although rare cases have been documented with metastatic disease [1,2,[7][8][9][10]. The most salient features of ESC RCC and the other emerging entities included in this review are summarized in Table 1.…”

“…Palsgrove and al have also confirmed a consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases). These included a metastatic ESC RCC which had a complete response to mTOR targeted therapy [10]. Molecular karyotype profiling of ESC RCC has also shown common and recurring genomic changes, including copy number (CN) gains at 16p13-16q23, 7p21-7q36, 13q14, and 19p12 and CN losses at Xp11.21 and 22q11 [2].…”

“…Loss of heterozygosity (LOH) alterations were identified at 16p11.2-11.1, Xq11-13, Xq13-21, 11p11, 9q21-22, and 9q33 [2]. Many of the genes and gene sets in the affected regions are involved in the regulation of MTOR signaling pathway and indicate that ESC RCC genomic alterations are different from those found in the currently recognized renal neoplasms [2,9,10]. Although these molecular alterations are neither pathognomonic nor specific for ESC RCC, taken together with the morphologic and immunohistochemical features seen in ESC RCC, signify a relatively compact and distinct morpho-molecular entity.…”

Molecular Genetics of Renal Cell Tumors: A Practical Diagnostic Approach

“…They are frequently positive for cytokeratin 20, which is highly unusual for any RCCs [132]. Both familiar and sporadic tumors have molecular alterations of TSC1 or TSC2 [133][134][135][136][137].…”