Marker For Renal Cell Carcinoma Research Articles

Review of Prognostic Expression Markers for Clear Cell Renal Cell Carcinoma.

Context: The number of prognostic markers for clear cell renal cell carcinoma (ccRCC) has been increasing regularly over the last 15 years, without being integrated and compared.Objective: Our goal was to perform a review of prognostic markers for ccRCC to lay the ground for their use in the clinics.Evidence Acquisition: PubMed database was searched to identify RNA and protein markers whose expression level was reported as associated with survival of ccRCC patients. Relevant studies were selected through cross-reading by two readers.Evidence Synthesis: We selected 249 studies reporting an association with prognostic of either single markers or multiple-marker models. Altogether, these studies were based on a total of 341 distinct markers and 13 multiple-marker models. Twenty percent of these markers were involved in four biological pathways altered in ccRCC: cell cycle, angiogenesis, hypoxia, and immune response. The main genes (VHL, PBRM1, BAP1, and SETD2) involved in ccRCC carcinogenesis are not the most relevant for assessing survival.Conclusion: Among single markers, the most validated markers were KI67, BIRC5, TP53, CXCR4, and CA9. Of the multiple-marker models, the most famous model, ClearCode34, has been highly validated on several independent datasets, but its clinical utility has not yet been investigated.Patient Summary: Over the years, the prognosis studies have evolved from single markers to multiple-marker models. Our review highlights the highly validated prognostic markers and multiple-marker models and discusses their clinical utility for better therapeutic care.

PAX8 EXPRESSION AND ITS ASSOCIATIONS IN PRIMARY RENAL CELL CARCINOMA: A CROSS SECTIONAL STUDY

Objective: To determine the frequency of PAX8 expression in cases of primary renal cell carcinoma (RCC) and its association with patient demographics and tumor type.
 Study Design: Cross sectional study.
 Place and Duration of Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from Jun 2016 to Jun 2017.
 Methodology: After ethics approval, 57 cases were selected by non probability consecutive sampling. Inclusion criteria was diagnosis of primary renal cell carcinoma of all histological types, in both genders, among adults aged >18 years. Exclusion criteria were poorly fixed specimens and metastatic renal cell carcinoma. The main outcome measure was PAX8 frequency in renal cell carcinoma. The secondary outcome measure was correlation of PAX8 expression with age, gender, tumor type and grade. Data was entered and analyzed on Statistical Package for the Social Sciences.
 Results: Out of 57 cases, majority were males 37, (64.9%). The mean age was 55.35 ± 12.60 years. Clear cell carcinoma was the most frequent histopathologic variant in 47 (81%) cases followed by papillary carcinoma in 6 (10.2%), chromophobe cell carcinoma 2 (3.5%), sarcomatoid renal carcinoma 1 (1.75%) and mucinous tubular and spindle cell carcinoma 1 (1.75%). PAX8 expression was positive in 52 (91.2%). No significant difference was found in the frequency of PAX8 expression across age (p=0.321), gender (p=1.00) and tumor type (p=1.00). There was significant difference seen across tumor grade p=0.03.
 Conclusion: PAX8 is an important additional diagnostic marker for renal cell carcinoma. It can be recommended for inclusion in immunohistochemical panel for diagnosis..............

Overexpression of Capns1 Predicts Poor Prognosis and Correlates with Tumor Progression in Renal Cell Carcinoma

Introduction: Calpain small subunit 1 (Capns1) has shown its correlation with the metastasis and invasion of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, the expression and function of Capns1 in human renal cell carcinoma (RCC) have not been clarified. This study aimed to examine the expression of Capns1 in RCC tissues and cell lines and to assess its role performed in RCC. Methods: Capns1 expression was evaluated in 75 pairs of RCC and matched adjacent non-tumor tissues by immunohistochemistry. The prognostic value of Capns1 in RCC was assessed by Kaplan-Meier and Cox regression analyses. The action of Capns1 in the proliferation, adhesion, migration, and invasion of RCC cells and the effects on matrix metalloproteinase (MMP) 2 and 9 expression were evaluated after Capns1 silence. Results: Capns1 expression was significantly higher in RCC tissues compared with the adjacent non-tumor tissues. Multivariate analysis showed that Capns1 overexpression was an independent poor prognostic marker in RCC. The silencing of Capns1 prohibited cell adhesion and impaired the migration and invasion ability of 786-O cells in vitro. Furthermore, Capns1 silence reduced MMP2 and MMP9 expression. Conclusion: Capns1 overexpression predicts poor prognosis and correlates with tumor progression in RCC. Capns1 expression might serve a prognostic marker and therapeutic target for RCC.

Single institutional experience on primary neuroendocrine neoplasms of the kidney: a rare distinct entity

Primary pure renal neuroendocrine neoplasms (R-NENs) are a distinct and rare entity. Not much is known about the histopathology and biologic behavior of these tumors. We attempted to review the clinicopathologic aspects of these neoplasms encountered at our institution. We performed a retrospective chart review to identify primary pure (not admixed with any other tumor component) R-NENs from institutional Cancer Registry database. Pathologic review of the diagnostic archival slides was done for detailed assessment of the histologic features. R-NENs were classified according to the current WHO system for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Eight pure R-NEN cases were identified, all unifocal, and most (6/8) involved the right kidney. Three patients had poorly differentiated neuroendocrine carcinoma (NEC), and five had well-differentiated neuroendocrine tumor (NET). All tumors were located near the renal hilum, stained diffusely with synaptophysin, variably with chromogranin, and were negative for renal site-specific marker PAX8 or for markers of renal cell carcinoma. We identified two distinct patterns of growth: one of sheets with interspersed rosettesand the other of large nests with low proliferative crowded centers and peripheral cells with higher proliferation and prominent palisading. Based on Ki-67 proliferative index, the tumors were classifiable into WHO grade 1 or grade 2 (based on GEP-NEN). All three NECs characteristically showed cytologic features intermediate between classic large and small cell type. This is the first comprehensive clinicopathologic study involving the rare group of R-NEN. Classifying and grading them according to the GEP-NEN system is of prognostic significance.

Clinicopathological comparison of VHL expression as a prognostic tumor marker in renal cell carcinoma: A single center experience.

To assess the VHL gene expression as a prognostic marker in Renal Cell Carcinoma (RCC) and compare it with clinicopathologic features. This retrospective observational study was conducted in the department of Urology and Renal Transplantation in Sri Ramachandra Institute of Higher Education and Research, Chennai from August 2016 to August 2018. Thirty patients who have undergone a radical/partial nephrectomy with biopsy proven histological diagnosis of RCC during the study period were included in the study. Data was analyzed using Statistical package for Social Sciences version 17. A complete loss and retained VHL expression were noted in 60% and 40% of the RCC specimens. Association between smoking and VHL expression was found to be statistically significant. There was no statistical significance found between age group, sex, chief complaints, BMI. ECOG score, hypertension, family history, location of tumor, calcification, venous system or lymphnode involvement. However, rT staging, nature of lesion and cut surface, HPE type, pT staging, HPE grade, necrosis and lympho-vascular invasion were also found to be statistically significant. Complete loss of VHL expression was noted in majority of the specimens that leads to the development of RCC. Smoking has been found to be statistically significant in tumors that retain VHL expression which may contributes to more aggressive form of tumor. Association between rT staging, nature of lesion and cut surface, HPE type, pT staging, HPE grade, necrosis and lympho-vascular invasion were also found to be statistically significant.

IFI16 Can Be Used as a Biomarker for Diagnosis of Renal Cell Carcinoma and Prediction of Patient Survival.

The incidences of renal cell carcinoma (RCC) increase in number each year and account for about 2–3% of all malignant tumors. Many patients have metastasis by the time of diagnosis, and their prognosis is poor. Therefore, it is essential that new diagnostic and prognostic markers for kidney cancer are identified. In this study, we assessed the potential of IFI16 as a diagnostic and prognostic marker for RCC. We analyzed the TCGA and UALCAN databases and found IFI16 to be highly expressed in ccRCC. In addition, high IFI16 levels positively correlated with lymphatic metastasis, tumor stage, and histopathological grade. Kaplan-Meier curve analysis showed that IFI16 expression was related to the prognosis of patients, and high IFI16 expression indicated a worse overall survival (p = 5.1E–0.7). Receiver operating characteristic curve analysis showed that a combination of IFI16 expression and histopathological grade improved predictive accuracy (AUC = 0.697; 95%CI: 0.628–0.765, P < 0.001). Finally, the relative levels of IFI16 in ACHN and Caki-1 cells were higher than that of HK-2 cells by western blotting analysis and RT-PCR. Functional tests showed that knocking down IFI16 expression inhibited migration and invasion in vitro. Therefore, IFI16 is a potential biomarker for the diagnosis and prognosis of RCC patients.

Autophagy as a Vital Therapy Target for Renal Cell Carcinoma.

Autophagy is a process that degrades and recycles superfluous organelles or damaged cellular contents. It has been found to have dual functions in renal cell carcinoma (RCC). Many autophagy-related proteins are regarded as prognostic markers of RCC. Researchers have attempted to explore synthetic and phytochemical drugs for RCC therapy that target autophagy. In this review, we highlight the importance of autophagy in RCC and potential treatments related to autophagy.

Overlapping Immunohistochemical Features of Adenocarcinoma of the Nonpigmented Ciliary Body Epithelium and Renal Cell Carcinoma

To find immunohistochemical markers that distinguish adenocarcinoma of the nonpigmented ciliary epithelium (NPCE) from metastatic carcinoma, especially metastatic renal cell carcinoma. Retrospective case series. Three cases of adenocarcinoma of the NPCE were examined histologically with hematoxylin-eosin stain and immunohistochemical stains including vimentin, AE1/AE3, Cam 5.2, CK7, PAX2, PAX8, AMACR, and CAIX. We also reviewed previously reported cases of this tumor. We found that the immunohistochemical profile of adenocarcinoma of the NPCE can overlap with renal cell carcinoma. Both tumors can express vimentin, cytokeratin AE1/AE3, Cam 5.2, PAX2, PAX8, and AMACR. One of the adenocarcinomas of the NPCE in our series also expressed CD10 and the renal cell carcinoma marker (RCC Ma). Carbonic anhydrase IX (CAIX) was not detected in any of the 3 tumors. Adenocarcinomas arising in phthisic eyes can be diagnostically challenging. We have found it particularly difficult to distinguish adenocarcinoma of the NPCE from metastatic carcinoma, especially metastatic clear cell renal cell carcinoma and papillary renal cell carcinoma. Because of the immunophenotypic overlap, most patients will require systemic workup including imaging of the kidneys to be certain of the diagnosis.

Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining.

The dysregulation of caspase 4 (CASP4) expression is related to the occurrence, development, and outcome of many malignant tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Herein, we investigated the expression of CASP4 in tumor tissues and its relationship with clinical prognosis, immune infiltration, and drug sensitivity status of ccRCC patients. Oncomine and The Cancer Genome Atlas (TCGA) databases were used to determine CASP4 mRNA expression in ccRCC patients. The correlation between CASP4 expression and disease prognosis was evaluated using Kaplan–Meier analysis. Related pathways were obtained from TCGA database via gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). Meanwhile, genes co-expressing with CASP4 in ccRCC were investigated. Finally, we analyzed the proportion of tumor-infiltrating immune cells (TICs) using the CIBERSORT computational method and assessed CASP4 methylation and its relationship with drug sensitivity. Immunohistochemical analysis of 30 paired ccRCC and adjacent normal tissues confirmed the in silico results. CASP4 mRNA expression in ccRCC was significantly higher than that in the normal tissues, positively correlated with clinicopathological features (clinical stage and pathological grade), and negatively correlated with patient overall survival (OS). GSEA and GSVA showed that the genes in the CASP4-high expression group were primarily enriched in immune-related activities. Moreover, CIBERSORT analysis of TIC proportions revealed that activated CD4 memory T cells were positively correlated with CASP4 expression. Notably, methylation analysis revealed that the abnormal upregulation of CASP4 might be caused by hypomethylation. Finally, we found that the abnormal expression of CASP4 may be related to tumor drug resistance. Overall, our study shows that CASP4 is overexpressed in ccRCC and is an important factor affecting disease prognosis. Hence, CASP4 may serve as a potential prognostic biomarker and therapeutic target in ccRCC.

Profiling of Serum Extracellular Vesicles Reveals miRNA-4525 as a Potential Biomarker for Advanced Renal Cell Carcinoma.

To identify novel diagnostic markers for renal cell carcinoma (RCC), we analyzed miRNAs in serum extracellular vesicles (EVs). EVs were purified from serum of healthy controls and patients with localized and advanced RCC using T-cell immunoglobulin domain and mucin domain-containing protein 4 conjugated to magnetic beads. miRNA profiling of EVs was conducted by microarray analysis. miRNA expression was examined by quantitative reverse transcription-polymerase chain reaction. Lastly, proteomic analysis of RCC cells transfected with a miRNA inhibitor was performed to identify its potential targets. Microarray analysis revealed that nine miRNAs were increased by more than 1.5-fold in EVs from patients with RCC. Among them, miRNA-4525 was significantly elevated; miRNA-4525 expression was higher in RCC tissue than in the adjacent normal tissue. Proteomic analysis identified alpha fetoprotein and albumin as its potential targets. These findings suggest the potential of miRNA-4525 in serum EVs as a novel biomarker for advanced RCC.

Immunohistochemical analysis of beta-catenin expression: a probable prognostic marker and potential therapeutic target in renal cell carcinoma

Background and aimsRenal cell carcinoma (RCC) seems to be the most aggressive type of genitourinary neoplasm. Down regulation of normal beta-catenin expression contributes to development of RCC, reflecting the role of beta-catenin/Wnt signaling pathway in pathogenesis. This study aims to evaluate the significance of beta-catenin expression and its correlation with the prognostic parameters.MethodsA cross-sectional observational study was carried out in a tertiary care center on 58 RCC cases using variables like histological grade and type, tumor stage, necrosis. Formalin fixed, paraffin-embedded blocks were evaluated for beta-catenin expression by immunohistochemistry using scoring system. Data were analyzed by mean ± SD, χ2 test, Pearson’s correlation test.ResultsMembranous score (MS) had a strong negative correlation with tumor stage (r=−0.407, p=0.044) and grade (r=−0.787, p=<0.001). Mean membranous score difference between low (Stage 1 and 2) vs. high stage (Stage 3 and 4) and low (Grade 1 and 2) vs. high grade (Grade 3 and 4) was statistically significant (p<0.001). Cytoplasmic score (CS) had positive correlation with tumor stage (r=0.586; p=0.002). No significant correlation was evident between cytoplasmic scores and tumor grade, however the mean cytoplasmic score difference between low grade vs. high grade was statistically significant (p < 0.001).ConclusionBeta-catenin may play a crucial role in the pathogenesis of RCC and has a positive correlation with the biological behavior of this tumor. The important role of beta-catenin as a prognostic parameter and probably a critical evaluator of targeted chemotherapy cannot be overemphasized.

High MCM6 Expression as a Potential Prognostic Marker in Clear-cell Renal Cell Carcinoma.

Minichromosome maintenance (MCM) proteins are involved in initiation of DNA replication and cell-cycle progression. Loss of MCM function results in genomic instability and causes carcinogenesis. Among MCM genes, the role and prognostic value of MCM6 expression in clear-cell renal cell carcinoma (ccRCC) has not been elucidated. We assessed the mRNA expression level of MCM6 using the Gene Expression Profiling Interactive Analysis database and investigated MCM6 protein expression by immunohistochemistry in 238 ccRCC cases. High MCM6 expression was significantly associated with increasing tumor size, pT, stage, tumor necrosis, and metastasis. Furthermore, high MCM6 expression was significantly associated with shorter overall and disease-free survival, and was an independent unfavorable prognostic marker. Regarding patients with metastasis, high MCM6-expressing ccRCC conferred significantly shorter survival than for those with low expression. A high MCM6 expression level may be a promising biomarker to predict tumor progression, metastasis, and survival in patients with ccRCC.

Neutrophil to lymphocyte ratio as a prognostic marker for non-metastatic renal cell carcinoma - does it add to what we already know?

To study the correlation of pre-operative neutrophil to lymphocyte ratio (NLR) with pathological stage, Fuhrman grade, sarcomatoid differentiation, tumor necrosis and lymph node positivity and its prognostic role in non-metastatic renal cell carcinoma (non-mRCC). This retro-prospective, observational study was done at a tertiary care center in Mumbai, India. All patients with non-mRCC from July 2015to April 2018were included. Patients with co-existing systemic infection, prior immunotherapy, and long-term steroids were excluded. NLR closest to surgery, but within one month prior to surgery was used. Patients were stratified as NLR ≥ 3.0or<3. NLR was correlated with known prognostic factors by Pearson's correlation. 113patients, aged 18-81years (83males and 30females) were included. 75% had clear cell RCC. 62% had stage 1disease. 58% patients had Fuhrman Grade 2. 10patients had lymph node metastasis, 6had sarcomatoid differentiation, 40had tumor necrosis. The NLR was<3in 72patients. Statistically significant correlation between NLR and tumor stage (p= 0.0054) as well as NLR and tumor necrosis (p= 0.0128) was shown. NLR correlates significantly with higher T stage and tumor necrosis. NLR may be integrated with well-established prognostic markers to improve the accuracy of prognostic scores.

Quantitative proteomic analysis reveals sophisticated metabolic alteration and identifies FMNL1 as a prognostic marker in clear cell renal cell carcinoma.

Purpose: In this study, we have undertaken the whole proteomic analysis and got a better understanding of biological processes involved in the development and progression of ccRCC. We hope promising biomarkers can be uncovered to facilitate early diagnosis, predict the prognosis and progression, more importantly, to be applied as potential therapeutic targets.Experimental design: Fresh frozen tissue samples were surgically resected from patients with local or locally advanced ccRCC. Trypsin digested proteins were analyzed using TMT-based LC-MS/MS proteomic approach, followed by bioinformatic analysis. A potential prognostic marker FMNL1 was chosen to be validated in TCGA_KIRC datasets (n=525 and 72), further validation sets (n=10 and 10) and expanded validation sets (n=81 and 16). The effects of FMNL1 on proliferation, migration and invasion were determined by colony formation, wound healing, and transwell assays in 786-O and Caki-1 cells in vitro study.Results: A total of 657 differentially expressed proteins were identified and quantified between ccRCC and adjacent normal tissues (p-value<0.05, FC>2 or<1/2), of which 186 proteins were up-regulated and 471 proteins were down-regulated. Bioinformatic analysis showed enriched metabolic biological processes and pathways. Univariate and multivariate analysis defined FMNL1 as an independent negative prognostic marker in the TCGA datasets. High expression of FMNL1 correlated significantly with tumor stage and distant metastasis (P<0.05) both in the TCGA-KIRC datasets and expanded validation sets. Kaplan-Meier survival curve illustrated that the patients with high FMNL1 protein level had shorter OS time in the expanded validation sets (p=0.0273). In vitro experiments presented the functional effects of FMNL1 knockdown on the inhibition of proliferation, migration and invasion in cancer cell lines.Conclusion and clinical relevance: The proteomic results uncovered sophisticated metabolic reprogramming of ccRCC and indicated that the upregulation of rate-limiting enzymes in glycolysis and mitochondrial impairment may be the cause of metabolic reprogramming in ccRCC. Moreover, FMNL1 has been identified as a promising prognostic marker, and knockdown of FMNL1 could inhibit ccRCC cell proliferation, migration and invasion, which might be used as a new effective therapeutic strategy to inhibit the progression of ccRCC.

Autofagija i karcinom bubrežnih ćelija - šta znamo do sada?

Renal cell carcinoma (RCC) is the most common type of kidney tumor in adults, accounting for approximately 90% of kidney malignances, occurring usually between the ages of 60 and 70. The 5-year overall survival rate for all RCC types is 49%. Since RCCs are resistant to numeorus different radio and chemotherapeutics that act via apoptosis induction, the development of new approaches to RCC treatment is still in the focus of modern urology. In particular, in recent years, autophagy in RCC has been widely studied as a mechanism of cell extinction through which tumor cells can overcome resistance to apoptosis activation therapy. Autophagy is often referred to as a double-edged sword because it can be a process that allows cells of cancer to survive and, on the other hand and under other conditions, it can be a cell dying mechanism, independent or closely related to other cell death modalities, like apoptosis and necrosis. The central role in the tempering of the process of autophagy, in general, belongs to the mTOR complex (mammalian target of rapamycin), which integrates numerous signals that affect autophagy, such as growth factors, nutrients, various stressors and the energy status of the cell. In RCC, the most important is PI3K/AKT/mTOR signaling pathway, since activation of this signaling leads to survival of tumor cells through mTOR activation and thus, autophagy inhibition. Up to now, it was found that autophagy markers such as Beclin-1 and LC3-II can be considered as prognostic markers for RCC since the high level of Beclin-1 was detected in tissues and cells of RCC (A498 and ACHN cell lines) and that tumor cell mobility is promoted by the up-regulated expression of LC3. Therefore, a progress in RCC therapy can be expected from the development and synthesis of specific compounds targeting autophagy, as well as the therapy based on their combination.

Significance of CXC chemokine receptor 4 (CXCR4) in Renal Cell Carcinoma

Background: Cancer stem cells (CSCs) represent a population with tumour initiating, self-renewal, and differentiation potential. The aim of the work is to evaluate the expression patterns and clinical significance of chemokine receptor type 4 (CXCR4) as a novel CSC marker in renal cell carcinoma (RCC). Material and Methods: the expression of CXCR4 was examined in 50 well-defined renal tumour tissues, including 28 clear cell renal cell carcinomas (ccRCCs), 11 papillary renal cell carcinomas (pRCCs), and 11 chromophobe renal cell carcinomas (ChRCCs) with immunohistochemistry staining, the association between expression of this marker and clinicopathologic parameters, was then analyzed. Results: CXCR4 expression & intensity was significantly correlated with RCC clinicopathological features as grade, stage, size of the tumor and microvascular invasion (MVI) but there was insignificant correlation between histopathological types and the pattern of CXCR4 expression and its intensity . Conclusion: increased CXCR4 expression was associated with more aggressive tumour behaviour in RCC patients, especially in pRCC and ccRCC subtypes due to their more metastatic behaviour. These findings suggest that CXCR4 can be considered as a novel prognostic and therapeutic marker for targeted therapy of renal carcinoma.

KIM-1 (kidney injury molecule 1) in the urine of renal cell carcinoma patients

Objective: to assess the potential clinical significance of KIM-1 (kidney injury molecule 1) as a urinological marker for kidney cancer.Materials and methods. An enzyme-linked immunosorbent assay was used to assess urinary KIM-1 (uKIM-1 — kidney injury molecule 1) levels in 67 patients with renal cell carcinoma (RCC) and 36 healthy volunteers (a control group).Results. Both in patients and in healthy individuals, uKIM-1 levels were age independent. A difference between mean uKIM-1 values in RCC patients (2.4 ± 0.2 ng/ml) and the control group (0.7 ± 0.1 ng/ml) was statistically significant (p &lt;0.0001). In RCC patients the higher uKIM-1 level was observed at more advanced clinical disease stages: the values increasedfrom 2.0 ± 0.2 ng/ml at the stage I and 3.0 ± 0.5 ng/ml at the stage II—III to 4.4 ± 1.2 ng/ml at the stage IV. In the group of patients with stage IRCC, most representative by the number of cases (n = 44) the uKIM-1 levels correlated with the tumor size and were increased in patients with different histological subtypes of the tumor, including clear cell, papillary and chromophobe RCC. After nephrectomy, a monotonous decrease in uKIM-1 level was observed, and after 6 days its values approached the mean value in the control group. Two days after kidney resection, uKIM-1 increased and then decreased, remaining elevated after 6 days.Conclusion. This study demonstrates that uKIM-1 can be attributed to potentially significant urine tumor-associated markers of RCC.

Sinonasal renal cell-like adenocarcinoma: a clinicopathological analysis of five cases

Objective: To investigate the clinicopathological features, immunophenotype, differential diagnosis and prognosis of sinonasal renal cell-like adenocarcinoma. Methods: Retrospective analysis was performed on the cases of sinonasal carcinoma from August 2014 to December 2018 at Eye, Ear, Nose and Throat Hospital, Fudan University. Renal cell-like adenocarcinoma was screened for clinicopathologic feature analysis, and relevant literatures were reviewed. Results: There were 460 cases of sinonasal carcinoma, among which 70 cases (15.2%) were adenocarcinoma, with five (1.1%) being renal cell-like adenocarcinomas. Four patients were male and one was female, with a mean age of 46.5 years (range 29-52 years). The main clinical manifestations were nasal obstruction and epistasis. A red polypoid mass was found under nasal endoscopy. Imaging showed nasal cavity and ethmoid sinus mass with invasion into surrounding structures and bone destruction. Microscopically, the tumor cells were arranged in nests, alveoli and microcapsules with abundant intervening capillaries, accompanied by hemorrhage. The cytoplasm of the cells was clear with low nuclear grade, and the nucleoli were inconspicuous. In some areas, the tumor invaded bone tissue. Immunohistochemical markers CKpan, CK7, CAⅨ, S-100 and vimentin were positive, with low Ki-67 proliferation index. RCC, CD10, PAX8, p63, SMA, HHF35, Calponin, CD117, TTF-1 and neuroendocrine markers Syn and CHG were all negative. EWSR1 and ETV6 gene rearrangements were not detected by FISH. All five patients underwent surgical resection after initial diagnosis. One patient underwent surgical resection after second recurrence and adjuvant radiotherapy, one patient received postoperative radiotherapy, one patient underwent surgical resection after recurrence, one patient had no recurrence and one patient received radiotherapy after recurrence. All five patients had no distant metastasis and survived without tumor up to December 2019. Conclusions: Primary sinonasal renal cell-like adenocarcinoma is a special subtype of low-grade non intestinal adenocarcinoma, with low incidence and inert biologic behavior. At present, most of the literatures are case reports. Before a diagnosis is made, other primary and metastatic clear cell tumors need to be excluded. Immunohistochemistry is helpful for diagnosis and differential diagnosis. Surgical resection is the mainstay of treatment, and may be supplemented by radiotherapy.

Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma.

Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population (p = 0.013 and p < 0.0001, respectively), as well as at paired analysis (p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months (p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population (p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively (p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.

Multiple Pulmonary Pleomorphic Adenomas of Unknown Primary

Abstract Introduction/Objective The most common site of pleomorphic adenomas (PAs) is salivary glands, which behave as benign tumors and rarely metastasize. Primary PAs in lungs are exceedingly rare. We report a case of multiple PAs in lungs with an inconclusive origin. Methods A 65-year-old woman had a two-year history of numerous scattered bilateral well-circumscribed pulmonary nodules measuring up to 2.1 cm. She had no prior history of smoking, asbestos exposure and salivary gland diseases, and denied any symptoms. The latest chest computed tomography (CT) scan showed the two largest lower lobe nodules had mildly increased in size compared to two years before. The patient then underwent wedge resections. Results Grossly, the wedge resection specimens showed multiple well-circumscribed, pale tan, firm nodules. Microscopically, the nodules comprised cytologically bland nests of polygonal to plasmacytoid cells with eosinophilic cytoplasm, variably set in a myxoid matrix. Immunohistochemical stains demonstrated that the cells were positive for AE-1/AE-3, S-100, bcl-2 and SOX-10, and negative for chromogranin, smooth muscle actin, p63, calponin, PAX-8, CD34, CD31, HMB-45, melan-A, HHF-35, GATA-3, GFAP and RCC marker; TTF-1 highlighted entrapped pulmonary epithelium but the tumor cells were negative. These findings might suggest metastatic low grade PA from salivary glands. However, the patient’s follow-up examination by an otolaryngologist was normal; the CT scan of her chest and abdomen did not show any remarkable findings other than her lung nodules. Conclusion To our knowledge, this is the first reported case of multiple pulmonary PAs without a preceding primary. It has raised questions about the pathogenesis of multiple PAs in lungs. Could PA present as multiple primary nodules in lungs? Could one primary pulmonary PA generate multiple satellite nodules in lungs? Do multiple primary pulmonary PAs have a different IHC profile than that of a single primary pulmonary PA? More research is needed.