COW-2021-23

1. d
2. a
3. b

1. Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC)
2. CK20 and Cathepsin K
3. “Stippling”

The lesion is devoid of a well-formed capsule at the periphery and shows a diffuse, compact acinar and nested growth (Figure 1 and 2). It is cytologically made of cells with eosinophilic and voluminous cytoplasm, showing intracytoplasmic vacuolization (micro and macro) and coarse, basophilic to purple, cytoplasmic granules (“stippling”; Figure 3 and 4). The lesion stains for PAX8, CK20 (also focally as in our case; Figure 5), Cathepsin K (Figure 5), and is negative for CK7, CD117, AMACR, CA-IX, HMB45 and TFE3. A lesion such as this one earns the designation of eosinophilic solid and cystic carcinoma renal cell carcinoma (ESC-RCC).

Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) has been recently introduced as an emerging RCC entity with well-defined clinical, pathological, immunohistochemical and molecular features. ESC is usually a sporadic and non-syndromic tumor, although a subset has been documented in the setting of tuberous sclerosis complex (TSC). ESC-RCC is devoid of a well-formed capsule and shows mixed macrocystic (multifocal and varying in size) and solid patterns (rare cases display almost exclusively solid growth with only rare identifiable microscopic cysts; our case is an example with almost exclusively solid growth pattern). ESC-RCC shows a hobnail arrangement of the epithelial component lining of the cysts, intermixed with more cellular trabeculae (nests and compact acini) and solid areas. Scattered aggregates of foamy histiocytes and lymphocytes are usually present and the cells typically have voluminous and eosinophilic cytoplasm, with intracytoplasmic vacuolization (micro and macro) and coarse, basophilic to purple, cytoplasmic granules (‘stippling’), representing aggregates of rough endoplasmic reticulum. ESC-RCC has a characteristic immunohistochemical profile with positivity for CK20 (diffuse or focal, as in our case) PAX8, AE1/AE3, CK8/18, Cathepsin K, vimentin and negative for CK7, CD117, CA-IX, HMB45 and Melan A. The differential diagnosis is wide and encompasses all the renal tumors with eosinophilic cells, including oncocytoma (O), eosinophilic variant of chromophobe renal cell carcinoma (E-Chr-RCC), low-grade oncocytic tumor (LOT), high-grade oncocytic tumor (HOT), hybrid oncocytic/chromophobe tumor (HOCT), succinate dehydrogenase-deficient renal cell carcinoma (SDH-RCC), MiT family translocation renal cell carcinoma (MiTF RCC), epithelioid angiomyolipoma (E-AML), and many others. However, the morphologic features and its unusual immunohistochemical profile [CK20 and Cathepsin K (+)/CK7 and CD117 (-)] are generally sufficient for the diagnosis.

Karyotype profiling of ESC-RCC showed common and recurring genomic changes as copy number (CN) gains at 16p13-16q23, 7p21-7q36, 13q14, 19p12 and CN losses at Xp11.21 and 22q11; loss of heterozygosity (LOH) have been identified at 16p11.2-11.1, Xq11-13, Xq13-21, 11p11, 9q21-22, and 9q33. Many of the genes in these regions are involved in the mTOR pathway and indicate that ESC-RCC has genetically distinct from other RCC and molecularly “linked” to the genetic pathway involved in the TSC. NGS characterization of ESC-RCC supported this hypothesis revealing somatic bi-allelic loss or mutations in TSC gene family (TSC2 and TSC1). Palsgrove et al. found mutations in TSC1 or TSC2 genes in both pediatric ESC-RCC (many of them arising in patients affected by TSC) and adult ESC-RCC. These data about the genetic landscape of ESC-RCC are therapeutically relevant because these patients may be candidates for mTOR pathway targeted therapy.

1. Trpkov K, Hes O, Bonert M, et al. Eosinophilic, solid, and cystic renal cell carcinoma: Clinicopathologic study of 16 unique, sporadic neoplasms occurring in women. Am. J. Surg. Pathol. 2016;40:60-71.

2. Trpkov K, Abou-Ouf H, Hes O, et al. Eosinophilic solid and cystic renal cell carcinoma (ESC RCC): Further morphologic and molecular characterization of ESC RCC as a distinct entity. Am. J. Surg. Pathol. 2017;41:1299-308.

3. Trpkov K, Hes O. New and emerging renal entities: A perspective post-WHO 2016 classification. Histopathology. 2019;74:31-59.

4. Palsgrove DN, Li Y, Pratilas CA, et al. Eosinophilic solid and cystic (ESC) renal cell carcinomas harbor tsc mutations: Molecular analysis supports an expanding clinicopathologic spectrum. Am. J. Surg. Pathol. 2018;42:1166-81.

5. Siadat F, Trpkov K. ESC, ALK, HOT and LOT: Three Letter Acronyms of Emerging Renal Entities Knocking on the Door of the WHO Classification. Cancers (Basel). 2020;12:168.

Costantino Ricci
Michelangelo Fiorentino
University of Bologna
Bologna, Italy

Kidney

kidney, renal cell carcinoma, eosinophilic solid and cystic renal cell carcinoma, CK20, tuberous sclerosis complex