Schreiner and colleagues, in 2010, first described ESC RCC [10]. It is not a new tumor subtype, it is just recognized recently. The present incidence is estimated at around 0.2% [5], but it is expected to increase as previously unclassified cases of RCC are being reviewed retrospectively. The incidence in our case series was 0.48%. The median age at diagnosis was 48.5 years with an age range of 14–85 years [9]. This is in contrast to the age of diagnosis of renal cell carcinoma which is between 60 and 70 years [11]. ESC RCC mainly affects females with 87% reported cases in females [9]. Initially it was described in patients with tuberous sclerosis (TSC); later, it was found that majority (80%) occur in patients who do not have TSC [9]. In our study, mean age of presentation was 26.7 years with only one out of three patients being male and none of the cases had a syndromic association. Only one study has focused on imaging findings of ESC RCC of two cases in detail [12]. ESC RCC tumors are typically solitary, unifocal tumors, small size and low stage [13]. 90% of tumors were stage T1 or T2 as organ-confined disease, as against 66.6% of all RCC [9]. Median size was 4.15 cm with a range of 0.5–15 cm [9]. Four cases of metastases are described [13] and hence the need for long-term surveillance. Of our patients, two patients had organ-confined disease, and one patient presented with metastasis who later died after surgery and mean size of tumor on presentation was 7.7 cm.
Grossly, as per the name of the tumor, there are multiple solid and cystic areas in the tumor specimen. Tumor is well delineated and circumscribed with a capsule. Cysts are macrocysts, multifocal, variably sized. Tumor surface is yellow/gray/tan [13]. Microscopically, cysts have epithelial lining in hobnail arrangement, cyst trabeculae are variable thickness, and scattered foamy histiocytes and lymphocytes are present. Cells are in acinar pattern, show eosinophilic, voluminous cytoplasm, coarse basophilic cytoplasmic stippling which are the aggregates of rough endoplasmic reticulum and have a low mitotic count. Nuclei are round to oval with prominent nucleoli focally, corresponding to WHO/ISUP grade 2 or 3 [13]. Cells may look like leishmania bodies due to the presence of scattered cells with densely eosinophilic globulles surrounded by delicate rims [5]. Our patients showed multiple solid and cystic areas in the gross specimen and microscopically showed cystic areas with proteinaceous fluid lined by tumor cells with eosinophilic cytoplasm and solid areas showed tumor composed of nests and tubules composed of tumor cells with dense eosinophilic cytoplasm.
Immunohistochemistry (IHC) shows CK 20 positive in 85–90% of ESC RCC, either focally or diffuse and this is usually paired with negative CK7 in 75% of cases. None of the cases show CK20 negative and CK 7 positive immunophenotype [13]. Other positive stains include PAX8, Vimentin, CK8/18, AE1/3, Cathepsin K and AMACR, and negative stains include CA9, HMB45, CD117 and melan A [13]. Negative CK20 staining does not rule out ESC RCC, specially if other positive markers are present.
Molecular analysis by next-generation sequencing (NGS) of ESC RCC showed recurrent and mutually exclusive somatic bi-allelic loss or mutation of TSC gene family, including TSC1 and TSC2 in 85% of the reported cases [13]. Molecular karyotyping of ESC has shown common and recurring genomic changes such as copy number (CN) gains at 16p13-16q23, 7p21-7q36, 13q14 and 19p12 and CN losses at Xp11.21 and 22q11, and loss of heterozygosity (LOH) was seen at 16p11.2-11.1, Xq11-13, Xq13-21, 11p11, 9q21-22 and 9q33 [13]. These genes were involved in regulation of mTOR signaling pathway and these genomic changes are distinct from commonly described RCC subtypes. Although these molecular changes were not specific for ESC RCC, taken together with the histopathological and immunohistopathologic features, they suggest a separate entity of RCC. The histopathological and immunohistochemistry features of ESC RCC are sufficient to distinguish ESC RCC from other renal tumors with eosinophilic cytoplasm such as oncocytoma, eosinophilic chromophobe RCC, epitheloid angiomyolipoma, MiTF RCC and SDH-deficient RCC [5].
In our cases, all three patients were having histopathological features of ESC RCC, with two patients having CK20 positivity and one patient with CK20 negative, but other markers were contributory to making the diagnosis of ESC RCC such as CK7 negative, PAN-CK positive, PAX 8 positive, EMA positive, Vimentin positive, RCC positive, C KIT negative, E cadherin negative, HMB 45 negative, Melan A negative and WT 1 negative.
Surgical therapy is curative in majority of the ESC RCC, and in metastatic disease, therapy with mTOR inhibitors may be more effective [14]. In our patients, surgery in the form of radical nephrectomy was done in all patients, with laparoscopic surgery done in one patient; one patient with metastasis was started on tyrosine kinase inhibitor with a plan to switch to mTOR inhibitor if there is disease progression who later died at 12 months post-surgery; one patient had tumor in contralateral kidney and was advised partial nephrectomy for the same, but patient the was not willing for the same and was undergoing an alternative therapy. Most of the cases are reported in the pathological literature, and even then, the available literature is less. So additional studies are required to determine the clinical significance and the biologic nature of this newly diagnosed subtype of ESC RCC which is more important from the urology point of view.
Limitations of the present study were the small patient population, retrospective study, variable presentation and short follow-up. Thus, the detection of significant differences of variables may not have been possible and definitive conclusions may not be possible.
