Construction and Validation of a Mutation-Related Model in Papillary Renal Cell Carcinoma and Associated Immune Infiltration.

BACKGROUND: To improve the clinical evaluation of the prognosis of papillary renal cell carcinoma (PRCC), we screened a model to predict the survival of patients with mutations in related genes. METHODS: We downloaded RNA sequencing information from all patients with PRCC in TCGA. We first analyzed the differences in genes and the enrichment of these differences. Then, by selecting mutant genes, constructing a protein-protein interaction network, least absolute shrinkage and selection operator regression, and multivariable Cox regression, a prognosis model was constructed. Additionally, the model was validated using external data sets. We analyzed the immune infiltration of PRCC and the correlation between the model and popular targets. Finally, we performed tissue microarray analysis and immunohistochemistry to verify the expression levels of the three genes. RESULTS: We constructed a three-gene (never in mitosis gene A-related kinase 2 [NEK2], centromere protein A [CENPA], and GINS complex subunit 2 [GINS2]) model. The verification results indicated that the model had a good prediction effect. We also developed a visual nomogram. Enrichment analysis revealed the major pathways involved in muscle system processes. Immunoassays showed that the expression level of CENPA was positively correlated with PD-1 and CTLA4 expression levels. Immunohistochemical and tissue microarray results showed that these three genes were highly expressed in PRCC, which was consistent with the predicted results in the database. CONCLUSION: We constructed and verified a three-gene model to predict the patient survival. The results show that the model has a good prediction effect.

Malignant solitary fibrous tumor of the kidney with IGF2 secretion and without hypoglycemia.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare fibroblastic mesenchymal tumor that mostly involves the pleura and infrequently involves extra-pleural sites. De novo SFT of the kidney is uncommon, and malignant SFT is extremely rare. CASE PRESENTATION: We report a case of a 51-year-old man with a large malignant SFT in the left kidney. Pathological examination confirmed the diagnosis of SFT based on typical morphology, nuclear STAT6 expression, and NAB2-STAT6 gene fusion. The malignant subtype was determined by a large tumor size (≥ 15 cm) and high mitotic counts (8/10 high-power fields). KRAS mutation was identified by DNA sequencing. Insulin-like growth factor 2 (IGF2) was diffusely and strongly expressed in tumor cells, however, hypoglycemia was not observed. Hyperglycemia and high adrenocorticotropic hormone (ACTH) concentration were observed one month after surgery. Hormone measurements revealed normal blood cortisol and aldosterone levels, and increased urinary free cortisol level. A pituitary microadenoma was identified using brain magnetic resonance imaging, which may be responsible for the promotion of hyperglycemia. CONCLUSIONS: We report a case of renal malignant SFT with a KRAS mutation, which was previously unreported in SFT and may be associated with its malignant behavior. Additionally, we emphasize that malignant SFT commonly causes severe hypoglycemia due to the production of IGF2. However, this effect may be masked by the presence of other lesions that promote hyperglycemia. Therefore, when encountering a malignant SFT with diffuse and strong IGF2 expression and without hypoglycemia, other lesions promoting hyperglycemia need to be ruled out.

The zinc finger and BTB domain containing protein ZBTB20 regulates plasma triglyceride metabolism by repressing lipoprotein lipase gene transcription in hepatocytes.

BACKGROUND AND AIMS: Lipoprotein lipase (LPL) is responsible for the lipolytic processing of triglyceride-rich lipoproteins, the deficiency of which causes severe hypertriglyceridemia. Liver LPL expression is high in suckling rodents but relatively low at adulthood. However, the regulatory mechanism and functional significance of liver LPL expression are incompletely understood. We have established the zinc finger protein ZBTB20 as a critical factor for hepatic lipogenesis. Here, we evaluated the role of ZBTB20 in regulating liver Lpl gene transcription and plasma triglyceride metabolism. APPROACH AND RESULTS: Hepatocyte-specific inactivation of ZBTB20 in mice led to a remarkable increase in LPL expression at the mRNA and protein levels in adult liver, in which LPL protein was mainly localized onto sinusoidal epithelial cells and Kupffer cells. As a result, the LPL activity in postheparin plasma was substantially increased, and postprandial plasma triglyceride clearance was significantly enhanced, whereas plasma triglyceride levels were decreased. The dysregulated liver LPL expression and low plasma triglyceride levels in ZBTB20-deficient mice were normalized by inactivating hepatic LPL expression. ZBTB20 deficiency protected the mice against high-fat diet-induced hyperlipidemia without causing excessive triglyceride accumulation in the liver. Chromatin immunoprecipitation and gel-shift assay studies revealed that ZBTB20 binds to the LPL promoter in the liver. A luciferase reporter assay revealed that ZBTB20 inhibits the transcriptional activity of LPL promoter. The regulation of LPL expression by ZBTB20 is liver-specific under physiological conditions. CONCLUSIONS: Liver ZBTB20 serves as a key regulator of LPL expression and plasma triglyceride metabolism and could be a therapeutic target for hypertriglyceridemia.

Long noncoding RNA SNHG6 promotes carcinogenesis by enhancing YBX1-mediated translation of HIF1α in clear cell renal cell carcinoma.

Recent studies have showed that Small nucleolar RNA host genes (SNHGs) acted as a subset of long noncoding RNAs (lncRNAs) have critical roles in human cancer carcinogenesis. However, the biological functions of SNHGs in clear cell renal cell carcinoma (ccRCC) have not been fully investigated. In this study, we screened an oncogenic lncRNA termed SNHG6 using RNA-Seq data of ccRCC from The Cancer Genome Atlas (TCGA). Quantitative real-time PCR was then used to demonstrate the expression of SNHG6 in ccRCC tissues. SNHG6 overexpression is highly associated with malignant features in patients and is a prognostic indicator. SNHG6 significantly promotes ccRCC cell proliferation and metastasis in vitro and in vivo. Mechanistic investigations identified that SNHG6 exerts oncogenic effects by interacting with YBX1, and then, enhancing HIF1α translation. Taken together, SNHG6 promotes ccRCC progression by binding YBX1 and may serve as a novel molecular target for ccRCC therapy.

GATA3 aids in distinguishing fumarate hydratase-deficient renal cell carcinoma from papillary renal cell carcinoma.

GATA3 has been reported to be positive in clear cell papillary renal cell carcinoma and papillary renal neoplasm with reverse polarity. However, its features in high-grade RCC remain unclear. Despite the emergence of novel renal entities, FH-deficient RCC remains one of the most aggressive renal neoplasms. The diagnosis is mainly based on the loss of FH at the protein level. Previous studies have shown that inclusion-like nuclei, multiple architectural patterns, FH loss, and 2SC positivity can differentiate FH-deficient RCC from other RCC. In some FH-deficient RCC cases, FH is normally expressed and is difficult to diagnose. This study included 11 FH-deficient RCC, and GATA3 showed different expression in seven cases. However, 147 papillary renal cell carcinomas were included, and GATA3 expression was negative. A comparison of clinicopathological aspects between 11 FH-deficient RCC and 30 high-grade PRCC showed statistical significance in age, size, multiple architectural patterns, inclusion-like nuclei, and prognosis. However, PRCC exhibited similar characteristics. CK7, GATA3, and FH profiles were also statistically significant. Different chromosomal alterations were found in FH-deficient RCC, and chromosomal alterations were not different between FH-deficient RCC and PRCC. GATA3 was positive in 33 % (7/21) of collecting duct carcinomas and negative in other high-grade renal neoplasms. GATA3 is negative in PRCC, but can be positive in FH-deficient RCC and collecting duct carcinoma. GATA3 expression may indicate a worse outcome in high-grade RCC with papillary architecture. We recommend GATA3 IHC for the differential diagnosis and prognostic assessment of high-grade RCC with papillary architecture.

B cell lymphoma with IRF4 rearrangement: A clinicopathological study of 13 cases.

Interferon regulatory factor 4 (IRF4) rearrangement is commonly detected in patients with a range of lymphoproliferative malignancies, including myelomas, large B cell lymphomas and low-grade B cell neoplasms. However, IRF4 rearrangement is generally a relatively rare finding in these latter two cancer types. In the present article, we describe and summarize the clinicopathological and genetic features of 13 cases of B cell lymphoma with IRF4 rearrangement, including 12 cases of large B cell lymphoma and one case of low-grade lymphoma exhibiting such rearrangement. These cases were detected in six females and seven males between 14 and 71 years of age. From a morphological perspective, large B cell lymphoma tumors included in this analysis exhibited large neoplastic cells in diffuse or follicular patterns, while the case of low-grade lymphoma mainly composed of small lymphocytes. All analyzed cases exhibited a split in the IRF4 gene consistent with IRF4 translocation. Three of six analyzed large B cell lymphoma cases harbored IGLL5 mutations. Mutations in SAMHD1 were detected in the low-grade lymphoma with IRF4 rearrangement case. In summary, our results offer further insight into the morphological and molecular heterogeneity of cases of B cell lymphoma exhibiting IRF4 rearrangements.

Pathologic evaluation of the solid variant of aneurysmal bone cysts with USP6 rearrangement with an emphasis on the frequent diagnostic pitfalls.

The solid variant of aneurysmal bone cyst (SVABC) is very uncommon and frequently misdiagnosed. We reevaluated and summarized the clinicopathologic features of 17 SVABCs and further discussed the use of this nomenclature to differ SVABCs from extragnathic giant cell reparative granuloma (GCRG) in the setting of the USP6 rearrangement era. The immunohistochemical markers included α-SMA, SATB2, AE1/AE3, Ki67, S100, CD68 and P63. USP-6 status was detected by fluorescence in situ hybridization using a break-apart probe. The 17 patients with SVABCs comprised 10 males and 7 females ranging in age from 4 to 70 years. The involved locations included the long bone (n = 11), hand (n = 4), rib (n = 1) and vertebra (n = 1). The lesions were characterized by proliferated spindle cells with scattered giant cells and hemorrhages with variable positive α-SMA, SATB2, CD68 and Ki-67 expression. All patients had USP6 rearrangements without H3F3A glycine 34 mutations. Our study reveals that SVABC shares similar clinical and histologic features with other bone lesions, which may lead to an erroneous diagnosis. The presence of an USP-6 rearrangement contributes to the diagnosis SVABC; SVABC and most of the previously documented extragnathic GCRGs may be considered within the umbrella of primary aneurysmal bone cysts.

Juxtaglomerular cell tumor: Clinicopathologic evaluation in a large series emphasizing its broad histologic spectrum.

The juxtaglomerular cell tumor (JCT) is a rare renal tumor. We re-evaluated the clinicopathologic features of 21 JCTs to summarize their variable morphologies. Immunohistochemical, fluorescent in situ hybridization and periodic acid-Schiff stains were routinely performed, and four JCT cases were detected via transmission electron microscopy. The 21 JCTs involved five males and 16 females, ranging in age from 19 years to 69 years (mean, 36.9 years; median, 34 years). The tumors were composed of large, small, or spindle cells with a round, oval or polygonal shape, arranged in various growth patterns. Both necrosis (1/21) and mitosis (2/21, with 1/50HFP, 8/50HFP) was rarely appreciated. All cases were immunoreactive for renin and CD34 (21/21), and few were positive for α-SMA (13/21;11/21, focally; 2/21, diffusely,), CD117 (9/21, focally) and synaptophysin (3/21, focally). Ultrastructurally, all four cases exhibited secretory granules in varying sizes in the cytoplasm, two of which exhibited cellular junctions. Almost all cases (20/21) had a favorable prognosis, but one succumbed due to bone and hepatic metastases, which corresponds to malignant JCT. Our study demonstrates that JCTs may have atypical clinical presentations and variable histologic appearances. A familiarity with these features may contribute to a correct diagnosis.

Biphasic squamoid alveolar renal carcinoma with positive CD57 expression: A clinicopathologic study of three cases.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a rare and recently characterized form of papillary renal cell carcinoma (PRCC). Herein, we describe three cases of BSARCC that were CD57+. Among a total of 90 cases of PRCC, three cases were found to be consistent with a diagnosis of BSARCC. In addition to reviewing these cases, we reviewed the relevant literature pertaining to this form of cancer and assessed the immunohistochemical staining for CD57 on the available tumor samples. The three BSARCC cases in the present study were composed of two primary populations of cells. Tumors stained positive for CK, PAX8, CK7, CK19, AMACR, EMA, and vimentin. Larger cells expressed detectable levels of cyclin D1, and expression of CD57 was limited to the larger cells. All three patients were alive and free of disease during the most recent follow-up. Our results suggest that the CD57 positivity of at least a subset of cases should necessitate their differentiation from cases of metanephric adenoma.

[Primary neuroendocrine tumor of the testis: clinicopathological study of 7 cases].

OBJECTIVE: To investigate the clinicopathologic characteristics, diagnosis, differential diagnosis and treatment of primary neuroendocrine tumor (NET) of the testis. METHODS: Using light microscopy and immunohistochemistry, we studied 7 cases of primary NET of the testis, reviewed relevant literature, and analyzed the clinical manifestations, histomorphologic and immunohistochemical characteristics, treatment and prognosis of the tumor. RESULTS: The 7 male patients, at the mean age of 40.6 years, all presented with testicular painless masses, none accompanied with carcinoid syndrome. Histologically, the uniform tumor cells were arranged in trabecular, island, solid and/or flake structures and locally in a tubulo glandular pattern, round and polygonal in shape, with a small amount of lipid vacuoles in the eosinophilic cytoplasm. The cells had round nuclei with fine chromatin and rarely identified mitosis. Immunohistochemical staining showed that the tumor cells were positive for Syn, CgA, NSE and CK, with a Ki-67 positive rate of < 2%. CONCLUSION: Primary NET of the testis is a rare and low-grade malignancy. Early diagnosis and surgical resection are essential for good prognosis. Immunohistochemistry helps its diagnosis and differential diagnosis from other metastatic neuroendocrine carcinoma, teratomas with carcinoid, seminoma, and Sertoli cell tumor.

Long non-coding RNA HIF1A-AS2 promotes carcinogenesis by enhancing Gli1-mediated HIF1α expression in clear cell renal cell carcinoma.

BACKGROUND: The most common urologic tumor in humans with the highest incidence rate is clear cell renal cell carcinoma (ccRCC). Long non-coding RNAs (lncRNAs) act as regulatory factors in several tumors. Here, we studied ccRCC regulated by hypoxia-inducible factor 1α (HIF1α)-antisense RNA 2 (AS2) or HIF1A-AS2. METHODS: We performed wound-healing, transwell, and CCK-8 assays by decreasing or increasing the HIF1A-AS2 expression in RCC cell lines. Western blotting and qRT-PCR were used to identify the expression of downstream genes of the HIF1A-AS2 pathway. Gli1 and HIF1A-AS2 relationship was assessed using RIP and RNA pull-down assays. Lastly, transcriptome sequencing was performed on kidney cancer cells that had been knocked down to find possible regulatory mechanisms. RESULTS: Our results suggest that high expression of HIF1A-AS2 may promote RCC cell proliferation and Gli1 expression as a downstream factor. Furthermore, they have physical binding sites and together regulate HIF1α to encourage the development of ccRCC. HIF1A-AS2 lncRNA may offer a new molecular target for ccRCC treatment. CONCLUSION: lncRNA HIF1A-AS2 affects ccRCC development by regulating HIF1a expression through Gli1.

Acquired cystic disease-associated renal cell carcinoma with PTCH1 mutation: a case report.

Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is an extremely rare kidney tumor seen mainly in patients with end-stage renal disease. Currently, there are few reports on this type of tumor. We describe the case of a 58-year-old man who had been receiving peritoneal dialysis for more than nine years due to chronic renal insufficiency and uremia. One year after undergoing left renal clear cell renal cell carcinoma resection, a space-occupying lesion was found in the right kidney for which he underwent right nephrectomy. The histopathology of this tumor showed solid or tubular cell arrangements, with some areas of cyst formation. Vacuoles of varying sizes were present in the cytoplasm, and varying amounts of calcium oxalate crystals were found in the tumor cells or interstitium. The pathological diagnosis was ACD-RCC. Next-generation sequencing detected mutations in the PTCH1, MTOR, FAT1, SOS1, RECQL4, and CDC73 genes in the right renal tumor. This is a rare case of a patient with ACD-RCC in the right kidney and clear cell renal cell carcinoma in the left kidney. The findings suggest that mutations in PTCH1 associated with ACD-RCC may have acted as oncogenic drivers for the development of ACKD-RCC, together with providing insight into mechanisms underlying ACD-RCC development, as well as diagnostic and treatment options.

Clinicopathological, Immunohistochemical, and Molecular Characteristics of Pigmented Microcystic Chromophobe Renal Cell Carcinoma with Favorable Prognosis.

Background. Pigmented microcystic chromophobe renal cell carcinoma (RCC) is a subtype of chromophobe RCC. Its distinct histopathologic features are microcystic and microtubular pattern, pigmentation, and microcalcifications. Pigmented microcystic chromophobe RCC has ultrastructure, immunophenotypic structure, and molecular results similar to chromophobe RCC. Methods. We report five tumors of pigmented microcystic chromophobe RCC. Morphological observation and immunohistochemical examination were performed, and clinical and molecular features were analyzed. Results. Microscopically, all five tumors showed brown pigmentation, microcystic, and tubular cystic structures, one tumor presented microscopic calcifications. All tumors were positive for EMA, AE1/AE3, PAX8, KRT7, KIT (CD117), claudin 7, KRT8, and E-cadherin, and three tumors expressed P504S. All tumors were negative for vimentin, CA9, KRT20, TFE3, TFEB, Melan-A, HMB45, FH, SDHB, and GATA3. Ki-67 index varied from less than 1% to 2%. In three tumors, next-generation sequencing of the 688 gene was performed, the results found gene variants with potential clinical significance such as JMJD1C, MYCL, TP53, PI3KCA, KRAS, APC, GLI1, LRRK2, and gene variants with unclear clinical significance such as NTRK1 and RAD50; All patients remained alive over a follow-up period of 8-46 months without tumor recurrence and sarcomatoid transformation. Conclusions. Pigmented microcystic chromophobe RCC has a relatively benign biological behavior, and distant metastases and sarcomatoid transformation are rare. This overview of five additional tumors of pigmented microcystic chromophobe RCC offers further insight into this special subtype of chromophobe RCC.

Fumarate Hydratase-Deficient Renal Cell Carcinoma With Predominant Tubulocystic Features Mimics Tubulocystic Renal Cell Carcinoma.

CONTEXT.­: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) rarely exhibits a predominant tubulocystic architecture with few other components. RCC with pure tubules and cysts lined by eosinophilic tumor cells with prominent nucleoli would raise the diagnosis of tubulocystic RCC. It is important to differentiate the 2 entities because they lead to different outcomes. OBJECTIVE.­: To address the concern, a multicenter study was implemented to explore useful clinicopathologic features in differentiation between tubulocystic FH-deficient RCC and tubulocystic RCC. DESIGN.­: Clinical factors included age, sex, tumor size, and outcome. Morphologic factors included cell morphology, presence or absence of a nontubulocystic component, and stromal findings. Immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing were performed to explore the protein expression and molecular profiles of the 2 entities. RESULTS.­: We evaluated 6 patients with tubulocystic RCC and 10 patients with tubulocystic FH-deficient RCC. Tubulocystic RCC exhibited a small size (<4.0 cm, pT1a), low Ki-67 index (<5%), retained FH, and negative 2SC expression. Tubulocystic FH-deficient RCC had a relatively large size and a high Ki-67 index. Perinucleolar haloes, loss of FH, and 2SC positivity were always observed. Pure tubulocystic architecture was not observed in FH-deficient RCC, because focal nontubulocystic components can always be seen. CONCLUSIONS.­: We emphasized multiple sectioning to identify a nontubulocystic architecture to exclude tubulocystic RCC. Moreover, tumor size, FH/2SC staining, and the Ki-67 index can differentiate tubulocystic FH-deficient RCC from tubulocystic RCC. The diagnosis of tubulocystic RCC was not recommended in renal mass biopsy because of the limited tissues sampled.

A role for protein inhibitor of activated STAT1 (PIAS1) in lipogenic regulation through SUMOylation-independent suppression of liver X receptors.

Liver X receptors (LXRs) are nuclear receptors that function to modulate lipid metabolism as well as immune and inflammatory responses. Upon activation by their ligands, LXRs up-regulate a spectrum of gene transcription programs involved in cholesterol and fatty acid homeostasis. However, the mechanisms by which LXR-mediated transcriptional activation is regulated remain incompletely understood. Here, we show that PIAS1, a member of the protein inhibitor of the activated STAT family of proteins with small ubiquitin-like modifier (SUMO) E3 ligase activity, acts to suppress LXR ligand-dependent transcriptional activation of the lipogenic program in hepatocytes. We found that liver mRNA expression levels of Pias1 and Pias3 were inversely associated with those of genes involved in lipogenesis in mouse models with diet-induced or genetic obesity. Overexpression of PIAS1 in primary hepatocytes resulted in a reduction of LXR ligand-induced fatty acid synthesis and suppression of the expression of lipogenic genes, including Srebp1c and Fas. Moreover, PIAS1 was able to interact with LXRß and repress its transcriptional activity upon ligand stimulation, which did not require PIAS1-promoted SUMO modification of LXRß. In addition, PIAS1 could also interact with PGC-1ß and attenuate its association with LXRß, blunting the ability of PGC-1ß to co-activate LXRß. Importantly, PIAS1 impaired LXRß binding to its target DNA sequence. Taken together, our results suggest that PIAS1 may serve as a lipogenic regulator by negatively modulating LXRs in a SUMOylation-independent manner.

The zinc finger protein ZBTB20 regulates transcription of fructose-1,6-bisphosphatase 1 and ß cell function in mice.

BACKGROUND & AIMS: Fructose-1,6-bisphosphatase (FBP)-1 is a gluconeogenic enzyme that regulates glucose metabolism and insulin secretion in ß cells, but little is known about how its transcription is controlled. The zinc finger protein ZBTB20 regulates glucose homeostasis, so we investigated its effects on expression of FBP-1. METHODS: We analyzed gene expression using real-time reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry. We generated mice with ß cell-specific disruption of Zbtb20 using Cre/LoxP technology. Expression of Zbtb20 in ß cells was reduced using small interfering RNAs, and promoter occupancy and transcriptional regulation were analyzed by chromatin immunoprecipitation and reporter assays. RESULTS: ZBTB20 was expressed at high levels by ß cells and other endocrine cells in islets of normal mice; expression levels were reduced in islets from diabetic db/db mice. Mice with ß cell-specific knockout of Zbtb20 had normal development of ß cells but had hyperglycemia, hypoinsulinemia, glucose intolerance, and impaired glucose-stimulated insulin secretion. Islets isolated from these mice had impaired glucose metabolism, adenosine triphosphate production, and insulin secretion after glucose stimulation in vitro, although insulin secretion returned to normal levels in the presence of KCl. ZBTB20 knockdown with small interfering RNAs impaired glucose-stimulated insulin secretion in the ß cell line MIN6. Expression of Fbp1 was up-regulated in ß cells with ZBTB20 knockout or knockdown; impairments to glucose-stimulated insulin secretion were restored by inhibition of FBPase activity. ZBTB20 was recruited to the Fbp1 promoter and repressed its transcription in ß cells. CONCLUSIONS: The transcription factor ZBTB20 regulates ß cell function and glucose homeostasis in mice. It might be a therapeutic target for type 2 diabetes mellitus.

Exploration of Morphological Features of Clear Cell Renal Cell Carcinoma With PBRM1, SETD2, BAP1, or KDM5C Mutations.

The last decade has seen great advances in genomic profiling and prognosis-associated factors of clear cell renal cell carcinoma (RCC), the most common entity in kidney cancer. Following VHL, PBRM1, SETD2, BAP1, and KDM5C have been validated as the most common co-occurring gene mutations in clear cell RCC by multicenter studies. However, the morphological features of clear cell RCC with co-occurring gene mutations remain unclear. In this study, we presented 20 clear cell RCCs that underwent next-generation sequencing, of which 1 tumor was reclassified as ELOC-mutated RCC. PBRM1, SETD2, BAP1, and KDM5C were the most common mutations, following VHL. Morphologically, clear cell RCC with PBRM1 or KDM5C mutation usually displayed a low-grade pattern. Cystic changes and hyalinized stroma were often observed. The Ki67 index was <10%. These observations indicated good prognosis. However, mutated SETD2 may increase the malignancy of clear cell RCC with PBRM1 mutation. Two clear cell RCCs with mutated PBRM1 and SETD2 developed local or distant metastases. Clear cell RCC with BAP1 mutations always had high-grade patterns, and rhabdoid differentiation was also observed, indicating that BAP1 mutation was associated with poor outcomes. Papillary architecture was often a feature of BAP1 mutation, which is uncommon in clear cell RCC. PDL1 was positive in only one tumor with BAP1 mutation, and the positivity rate was limited to 5%. B7H3 was negative in all tumors. Morphologic findings in this small cohort may suggest why PBRM1 mutation does not correlate with decreased survival, whereas BAP1 mutation usually predicts poor outcomes.

Mutated ASXL1 upregulates mTOR expression in renal cell carcinoma with fibromyomatous stroma.

Renal cell carcinoma with fibromyomatous stroma (RCC FMS), defined as an "emerging entity" in the 2016 WHO classification and recommended to be a novel entity by GUPS, is represented by tumor cells with clear to mildly eosinophilic cytoplasm displaying elongated and branching tubules and papillae. A fibromyomatous stroma could be observed in these tumors. These tumors are immunopositive for CK7 and featured by ELOC and/or TSC/mTOR gene mutations. In the 2022 WHO classification, ELOC mutated RCC is classified as a molecularly defined RCCs as an individual renal entity. However, there are limited descriptions of TSC/mTOR alterations in RCC FMS. Herein, we reported a case of 28-year-old woman with RCC FMS with intact ELOC and TSC/mTOR genes but ASXL1 mutation. The tumor cells were positive for mTOR expression. This case may indicate that altered mTOR expression, but not limited to mutated TSC/mTOR gene, that participates in the pathogenesis of RCC FMS.

Exploration of clinicopathological features of rearranged renal cell carcinoma and TFE3, TFEB, and ALK staining performance in renal entities.

Rearranged renal cell carcinomas (RCC) are rare types of kidney cancer. The clinicopathological features of rearranged RCC require further validation. The pathological diagnosis usually depends on immunohistochemistry and molecular analysis. This study aimed to explore the expression features of anti-TFE3, TFEB, and ALK in different renal entities. In addition, we collected thirty-six TFE3-rearranged RCC, two TFEB-altered RCC, and one ALK-rearranged RCC to explore their clinicopathological features. We observed that TFE3 can sometimes be weakly expressed in non-TFE3-rearranged RCC. TFE3-rearranged RCC usually exhibited strong TFE3 expression. However, clear cell RCC and FH-deficient RCC also displayed strong TFE3 expression. TFEB also can be weakly expressed in clear cell RCC. However, ALK IHC showed a relatively high specificity and was negative for all non-ALK-rearranged RCC. The ALK-rearranged RCC was analyzed using next generation sequencing to explore gene alterations, and we identified a novel gene partner, SLIT1. ALK-rearranged RCC appears to have eosinophilic cytoplasm. Tumor cells with clear cytoplasm may exclude this diagnosis. Psammomatous bodies (22/38) and pattern multiplicity (35/38) were observed in more than half of the patients. In conclusion, weak TFE3 expression did not indicate TFE3 rearrangement. Strong TFE3 expression had a higher value for indicating TFE3-rearranged RCC, although other entities can also exhibit a strong pattern. Young age combined with morphological features (psammomatous calcification and pattern multiplicity) may indicate the diagnosis of rearranged RCC.