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The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7, ATG5, and ATG10. These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs.

Kindlin‑2 is an integrin-interacting, FERM-domain containing protein, which plays a critical role in tumor progression. However, the specific role of Kindlin‑2 in renal cell carcinoma (RCC) progression has not been described. In this study we investigated the role of Kindlin‑2 in progression of clear cell RCC (CCRCC), which is the most common RCC subtype, and its underlying mechanisms. Immunohistochemistry studies show that expression of Kindlin‑2 in CCRCC is positively correlated with tumor grade, and Kindlin‑2 expression in advanced CCRCC with lymph node metastasis was greater than in localized CCRCC. Kindlin‑2 expression in CCRCC tumor specimens is also correlated with short patient survival, but is not an independent prognostic factor. Kindlin‑2 promotes CCRCC cell migration and invasion in vitro, whereas knockdown of Kindlin‑2 inhibited cell migration and invasion. Knockdown of Kindlin‑2 also inhibits ACHN cell proliferation in vitro and tumorigenesis in vivo. Kindlin‑2 may be required for Wnt pathway activation which underlies the mechanisms of Kindlin‑2 promoting CCRCC progression. These findings demonstrate that expression of Kindlin‑2 is associated with tumor grade, lymph node metastasis and poor prognosis in CCRCC patients. Kindlin‑2 may regulate CCRCC progression through the Wnt signaling pathway, promoting CCRCC cell proliferation, migration and invasion.

Objective: To study the morphologic characteristics and prognostic significance of 2 histologic subtypes of papillary renal cell carcinoma (PRCC)., Methods: A series of 48 tumors previously diagnosed as PRCC during the period from 2003 to 2013 were evaluated. All available slides were reviewed and 39 cases were confirmed to be PRCC. The detailed histomorphologic features were evaluated. The tumors were subtyped using the WHO classification and a novel mechanism suggested in recent literature, with prognostic correlation. Type 1 PRCC was assigned for tumors demonstrating simple cuboidal epithelium, irrespective of nuclear grade or other histomorphologic features. Tumors demonstrating cellular pseudostratification and high-grade nuclei were classified as type 2 PRCC., Results: The novel subtyping mechanism was more practical and correlated with the outcome of patients. The scope of type 1 PRCC was expanded. Type 2 PRCC demonstrated high tumor stage and high nuclear grade, and was more likely to have perinephric/renal sinus fat invasion and sarcomatoid differentiation. Follow-up information was available in 32 patients, including 4 deaths in patients haboring type 2 PRCC. The survival rate of patients with type 2 PRCC was significantly lower than that of type 1 PRCC., Conclusions: The novel subtyping mechanism is more practical than WHO classification. Type 1 and type 2 PRCCs share many overlapping histomorphologic features. Type 2 PRCC is notably associated with worse prognosis. Recognizing the histomorphologic diversity of PRCC and classifying subtypes accurately are important in predicting the prognosis of patients with PRCC.

Background: Insulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC., Methods: Caki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array., Results: IMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-кB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients., Conclusion: IMP3 promotes RCC cell migration and invasion by activation of NF-кB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC.

Epithelial-to-mesenchymal transition (EMT) describes a phenotypical change induced in epithelial cells that lose their cell-cell basement membrane contacts and their structural polarity to become spindle-shaped and morphologically similar to mesenchymal/myofibroblast cell. The abnormal induction of EMT has been demonstrated to contribute to cancer dissemination and progression. Renal cell carcinoma (RCC) with sarcomatoid differentiation (sarcomatoid RCC) represents a good example of EMT both morphologically and immunohistochemically. Early spindle cell changes can at times be identified in RCC and likely represent an early step toward EMT. Herein, we present a review of the current understanding of EMT in renal neoplasms including some known signaling regulation, the association of sarcomatoid differentiation in RCC with aggressive behavior and dismal prognosis, and EMT-related tumor biology in sarcomatoid RCC. A better perception of the EMT may contribute toward an improved understanding of the development of sarcomatoid RCC. In addition, a distinct signature for sarcomatoid RCC may have utility in the differential diagnosis for prognostic stratification as well as in identifying novel genes and pathway targets for therapeutic intervention.

Clear cell carcinoma of the female genital tract (CCCa) shares many histologic features with clear cell renal cell carcinoma (CCRCC) and translocation-associated renal cell carcinoma (TA-RCC), the latter in particular. When CCRCC or TA-RCC metastasizes to the female genital tract, or when patients have a history of both CCCa- and RCC-developed metastatic lesions, it is critical to distinguish the 3 lesions. Such a distinction is not always possible based on the morphology alone and often requires immunostains. We therefore investigated the utility of a panel of routinely used immunohistochemical markers including cytokeratin (CK) 7 and 20, CD10, α-methylacyl-CoA racemase, carbonic anhydrase IX (CA IX), TFE3, and WT-1 in the distinction of the 3 lesions on a tissue microarray of 12 CCCa, 5 TA-RCC, and 23 CCRCC cases. CK7 was positive in all CCCa cases, but only in 20% of TA-RCCs and 4.3% of CCRCCs. In contrast, CD10 was positive in all TA-RCCs and 91.3% of CCRCCs, but in only 7.5% of CCCa cases. TFE3 was positive in all TA-RCCs, but negative in all CCCa and CCRCC cases. CA IX was positive in 87% of CCRCCs, but in only 20% of TA-RCCs, and was negative in all CCCa cases. CK20, α-methylacyl-CoA racemase, and WT-1 were not contributory to the distinction. Although morphologically similar, CCCa can be reliably distinguished from TA-RCC and CCRCC. CCCa is mostly CK7/CD10/CA IX/TFE3, TA-RCC is usually CK7/CD10/CA IX/TFE3, whereas CCRCC is mostly CK7/CD10/CA IX/TFE3. To the best of our knowledge, this was the first study to directly compare the immunophenotypes of these 3 lesions.

Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, α-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel-Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for α-methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as "clear cell tubulopapillary renal cell carcinoma," constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features.