Primary Renal Cell Carcinoma Research Articles

99mTc-MIBI SPECT/CT and FDG PET/CT in Isolated Bilateral Renal Metastases From Adenoid Cystic Carcinoma of the Maxilla.

Renal metastasis from adenoid cystic carcinoma of the head and neck is uncommon. We present 99mTc-MIBI SPECT/CT and FDG PET/CT findings in a case with isolated bilateral renal metastases from adenoid cystic carcinoma of the left maxilla. The metastatic adenoid cystic carcinomas of the kidneys showed photopenia on 99mTc-MIBI SPECT/CT and increased FDG uptake on FDG PET/CT mimicking primary renal cell carcinoma.

Adherence to oral therapies among patients with renal cell carcinoma: Post hoc analysis of the ECOG-ACRIN E2805 trial.

BackgroundAs use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence.MethodsECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (<80% of prescribed pills reported as taken).ResultsMean adherence was 90.7% among those assigned to sunitinib (n = 613) and 84.8% among those assigned to sorafenib (n = 616). Among those assigned to placebo, mean adherence was 94.9% and 92.4% to sunitinib and sorafenib placebo, respectively. Non‐adherence was associated with race/ethnicity (non‐Hispanic Black: prevalence ratio [PR] 2.22, 95% CI 1.63, 3.01; Hispanic: PR 1.54, 95% CI 1.05, 2.26), high volume enrollment (≥10 patients: PR 1.30, 95% CI 1.03, 1.64), treatment group (sunitinib: PR 2.24, 95% CI 1.66, 3.02; sorafenib: PR 2.37, 95% CI 1.74, 3.22), and skin rash (PR 1.36, 95% CI 1.03, 1.80).ConclusionAmong patients participating in a randomized clinical trial, adherence to oral cancer therapies was lower compared to placebo. Adherence was also worse in racial/ethnic minorities, those experiencing toxicities, and high volume enrolling sites. Our findings highlight several challenges to address in clinical practice as use of oral therapies continues to increase.Clinical trial registration numberThis trial is registered with ClinicalTrials.gov, number NCT00326898.

PD-0848 Stereotactic body radiotherapy for poor surgical candidates with primary renal cell carcinoma

PD-0848 Stereotactic body radiotherapy for poor surgical candidates with primary renal cell carcinoma

SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth

Renal cell carcinoma (RCC) cells have increased lipogenesis and cholesterol synthesis. Sterol regulatory element-binding protein-1 (SREBP1) is cleaved by site 1 protease (S1P) to release the transcriptionally active amino-terminal domain. PF-429242 is a potent and competitive S1P inhibitor. We here tested its activity in RCC cells. In established and primary human RCC cells, PF-429242 potently inhibited cell proliferation, migration, and invasion. The S1P inhibitor provoked apoptosis activation in RCC cells. Furthermore, shRNA-mediated S1P silencing or CRISPR/Cas9-induced S1P knockout led to RCC cell growth inhibition and apoptosis activation. Conversely, ectopic overexpression of SREBP1 or S1P augmented RCC cell proliferation and migration. Daily i.v. injection of a single dose of PF-429242 robustly inhibited RCC xenograft growth in severe combined immunodeficiency mice. Additionally, intratumoral injection of S1P shRNA lentivirus inhibited RCC xenograft growth in mice. SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo.

Imaging considerations for thermal and radiotherapy ablation of primary and metastatic renal cell carcinoma.

Ablative (percutaneous and stereotactic) thermal and radiotherapy procedures for management of both primary and metastatic renal cell carcinoma are increasing in popularity in clinical practice. Data suggest comparable efficacy with lower cost and morbidity compared to nephrectomy. Ablative therapies may be used alone or in conjunction with surgery or chemotherapy for treatment of primary tumor and metastatic disease. Imaging plays a crucial role in pre-treatment selection and planning of ablation, intra-procedural guidance, evaluation for complications, short- and long-term post-procedural surveillance of disease, and treatment response. Treatment response and disease recurrence may differ considerably after ablation, particularly for stereotactic radiotherapy, when compared to conventional surgical and chemotherapies. This article reviews the current and emerging role of imaging for ablative therapy of renal cell carcinoma.

Prognostic Factors Affecting Survival after Pulmonary Resection of Metastatic Renal Cell Carcinoma: A Multicenter Experience.

Simple SummaryThis multicentric paper aimed at evaluating the role of pulmonary metastasectomy in patients affected by metastatic renal cell carcinoma. The impact of pulmonary metastasectomy was analysed with respect to long-term survival and disease-free survival in a wide population of patients affected by pulmonary metastases from renal cell carcinoma. The prognostic value of factors affecting survival, disease-free interval and disease-free survival was evaluated. Our results aid clinicians in identifying those patients affected by pulmonary metastases from renal cell carcinoma who are more likely to benefit from pulmonary metastasectomy.In this paper we aimed to address the role of pulmonary metastasectomy (PM) in patients affected by Lung Metastases (LM) from Renal Cell Carcinoma (RCC) and to analyse prognostic factors affecting overall survival (OS), disease-free interval (DFI) between primary RCC and first LM, and disease-free survival (DFS) after PM and before lung recurrence. Medical records of 210 patients who underwent PM from RCC in 4 Italian Thoracic Centres, from January 2000 to September 2019, were collected and analysed. All patients underwent RCC resection before lung surgery. The main RCC histology was clear cells (188, 89.5%). The 5- and 10-year OS from the first lung operation were 60% and 34%, respectively. LM synchronous with RCC (p = 0.01) and (Karnofsky Performance Status Scale) KPSS < 80% (p < 0.001) negatively influenced OS. Five- and 10-year DFI were 54% and 28%, respectively. The main factors negatively influencing DFI were: male gender (p = 0.039), KPSS < 80% (p = 0.009) and lactate dehydrogenase > 1.5 times 140 U/L (p = 0.001). Five- and 10-year disease-free survival were 54% and 28%, respectively; multiple LM (p = 0.036), KPSS < 80% (p = 0.001) and histology of RCC other than clear cells negatively influenced disease-free survival. Conclusions: patients with KPSS > 80%, single metachronous LM with a long DFI from RCC diagnosis, and clear cell histology, benefit from pulmonary metastasectomy.

Synchronous breast carcinoma (with Paget’s disease) and renal cell carcinoma with tubercular axillary lymphadenitis: a rare presentation

Synchronous malignancy are defined as two primary malignancy of two different organs occurring concurrently or within 6 months duration. Reports of synchronous breast carcinoma with RCC (renal cell carcinoma) are very limited. We presented here the first case of non-metastatic synchronous RCC with breast carcinoma and Paget’s disease associated with tubercular axillary lymphadenitis in a 62 year old female for which she underwent right MRM and right partial nephrectomy. She received chemotherapy and anti-tubercular therapy post-surgery and currently on oral hormonal therapy. Follow up scans showed stable disease. There have been cases of breast cancer with TB lymphadenitis as well as of double synchronous malignancies involving breast carcinoma and RCC. Most of the multiple malignancies reported in literature are metastatic tumours or metachronous breast malignancy with RCC. A case of synchronous primary ca breast with pages disease coexisting with primary RCC along with tubercular lymphadenopathy is yet to be reported in literature. This might just be the first one.

Stereotactic Body Radiotherapy for Frail Patients with Primary Renal Cell Carcinoma: Preliminary Results after 4 Years of Experience.

Simple SummarySurgical therapy is currently the standard of care for the treatment of primary renal cell carcinoma (RCC). Alternative strategies such as stereotactic body radiotherapy (SBRT) have emerged as potentially curative treatment approaches. In this study, we show a promising short-term local control effect of SBRT in the management of primary RCC. The treatment was well tolerated with no high-grade side effects. The main advantages are the outpatient management without anesthesia and the non-invasive approach. Thus, SBRT appears to be a promising alternative to surgery, or ablative therapy, to treat primary RCC in patients with poor physical health. Future studies are needed to definitively assess the place of SBRT in the RCC treatment portfolio.Introduction: The aim of this study was to report the oncological outcomes and toxicity of stereotactic body radiotherapy (SBRT) to treat primary renal cell carcinoma (RCC) in frail patients unfit for surgery or standard alternative ablative therapies. Methods: We retrospectively enrolled 23 patients who had SBRT for primary, biopsy-proven RCC at our tertiary center between October 2016 and March 2020. Treatment-related toxicities were defined using CTCAE, version 4.0. The primary outcome was local control which was defined using the Response Evaluation Criteria in Solid Tumors. Results: The median age, Charlson score and tumor size were 81 (IQR 79–85) years, 7 (IQR 5–8) and 40 (IQR 28–48) mm, respectively. The most used dose fractionation schedule was 35 Gy (78.3%) in five or seven fractions. The median duration of follow-up for all living patients was 22 (IQR 10–39) months. Local recurrence-free survival, event-free survival, cancer-specific survival and overall survival were 96 (22/23), 74 (18/23), 96 (22/23) and 83% (19/23), respectively. There were no grade 3–4 side effects. No patients required dialysis during the study period. No treatment-related deaths or late complications were reported. Conclusion: SBRT appears to be a promising alternative to surgery or ablative therapy to treat primary RCC in frail patients.

Epigenetic silencing of ZBTB28 promotes renal cell carcinogenesis.

Zinc finger and BTB domain-containing protein 28 (ZBTB28) is a potential tumor suppressor for some cancers. However, its epigenetic regulation and functions in renal cell carcinoma (RCC) remain to be elucidated. The expression of ZBTB28 mRNA was analyzed by semi-quantitative reverse transcription polymerase chain reaction (PCR) in nine RCC cell lines and normal kidney tissues. Methylation status of ZBTB28 promoter was assessed by methylation-specific PCR in RCC cell lines, primary RCC, tumors and adjacent tissues. The involvement of ZBTB28 in cell proliferation and migration was investigated. ZBTB28 promoter was hypermethylated in 88.9% (8/9) of RCC cell lines with reduced ZBTB28 mRNA expression, and could be reversed by DNA methyltransferase inhibitors. The methylation of ZBTB28 promoter was detected in 73.5% (36/49) of primary RCC tissues, compared with 7.1% (1/14) in normal tissues. Overexpression of ZBTB28 significantly inhibited RCC cell proliferation and migration, and induced apoptosis. Further analyses revealed that ZBTB28 upregulation could inhibit multiple oncogenic signaling transduction pathways. ZBTB28 is frequently silenced by promoter methylation in RCC pathogenesis and functions as a novel tumor suppressive gene. ZBTB28 may be a potential target for the development of RCC therapeutic strategies.

Pulmonary metastasectomy in renal cell carcinoma: Predictive and prognostic elements from paired histopathological analysis of primary tumors and respective metastases

Objective: To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC). Methods: We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry. Results: A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p &lt; 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (&gt;70%) ( p = 0.007) and PD-L1 expression &gt;10% on TILs ( p = 0.024). Conclusions: mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.

Clinicopathological Features of Patients Diagnosed with Both Primary Thyroid Cancer and Primary Renal Cell Cancer and Its Comparison with Patients with Thyroid Cancer or Renal Cell Cancer Alone

Background and Objectives: Thyroid cancer (TC) and renal cell carcinoma (RCC) display more frequent co-occurrence than would be expected by chance. We investigated clinicopathological features of patients with both primary TC and primary RCC (TC/RCC) group to facilitate a greater understanding of the relationship between two cancers. Materials and Methods: A total of 53 patients who diagnosed with TC/RCC were enrolled. 13,663 TC-alone and 3279 RCC-alone patients who had undergone surgery at Samsung Medical Center between 1994 and 2014 were included as control groups. The clinicopathological characteristics of these patients were retrospectively reviewed. Results: The median age at the time of TC or RCC diagnosis was 54 years in TC/RCC group and the RCC-alone group, while the patients in TC-alone group were significantly younger (47 years). The TC/RCC group showed a nearly equal sex prevalence (49% male), significantly different than the results of the TC-alone group (80% female) and RCC-alone group (71% male). A higher grade of pathologic stage (56.6% in stage 3) and greater number of patients with multifocality of thyroid tumors (45 vs. 32%), and more family history of cancer (32 vs. 0.4%) were revealed in TC/RCC group than in TC-alone group. In addition, 15.1% of patients in TC/RCC group presented with additional primary cancers such as prostate, colon, stomach, breast, and lung cancers. Conclusion: Patients in the TC/RCC group have a high rate of cancer family history, multifocality of thyroid tumors, and additional cancers. To understand this unique subset group, additional studies for environmental and genetic factors would be helpful for earlier diagnosis of combined cancers.

Prognostic and predictive value of vessels encapsulating tumor clusters (VETC) in renal cell carcinoma (RCC).

e16554 Background: VETC has been described as an epithelial-to-mesenchymal-transition independent process of metastasis in hepatocellular carcinoma (HCC): endothelium covers small clusters of neoplastic cells allowing tumor dissemination. It has also been noted that VETC-positive HCCs benefit more from tyrosine kinase inhibitors (TKI) therapy. Interestingly, this type of angiogenesis was also found in RCC - and other cancers - and associated with poor prognosis. The objectives of the present study are: 1) to investigate the prognostic role of VETC in a cohort of primary consecutive RCC. 2) to model the predictive role VETC to TKI response in a cohort of metastatic RCC patients treated with sunitinib or pazopanib. Methods: The study was observational and retrospective. To evaluate the VETC effect on overall survival (OS) for Cox regression, with power .8, Hazard Ratio 2.35, proportion of subject VETC+ .4, proportion of events .6, correlation among covariates .4 and a type I error rate .5, the estimated sample size was n=89. We included consecutive patients undergoing surgery at our institution for primary RCC from 2005 to 2007, (Surgical Series; n=92 cases). Moreover, to investigate the possible role of VETC in predicting TKIs benefit, we considered all RCC patients treated with first line TKIs at our center (TKI Series; sunitinib, n = 39; pazopanib n = 17), and recorded the progression free survival (PFS). VETC was assessed with CD34 immunohistochemistry and defined as a continuous endothelial lining around tumor clusters. We used Bayesian probabilistic modeling to detect small effects and multilevel hierarchical modeling to reduce overfitting. Models were fit using Stan and R. The study was approved by institutional review board (n. 865/20) and registered on ClinicalTrials.gov. Results: VETC+ RCC had a worse prognosis in the Surgical Series, with a posterior probability density (PPD) of median OS of 88 months (mo) (standard deviation, SD: 16 mo) for VETC positive Vs 136 mo (SD: 26 mo) for VETC-; the expected loss of median OS was 48 mo (SD: 31 mo) for patients having a VETC + RCC. Conversely in the TKI Series, VETC+ RCC showed longer PFS compared to VETC- ones: with sunitinib a PPD of median PFS of 35 mo (SD:11 mo) for VETC+ Vs 19 mo (SD: 5 mo) for VETC-. Under Pazopanib a PPD of median PFS of 20 mo (SD: 8 mo) for VETC+ Vs 11 mo (SD: 7 mo) for VETC-. The expected gain of median PFS for of VETC+ cases, was 17 and 9 mo (SD: 12 and 11 mo), respectively in sunitinib and pazopanib treated cases. Conclusions: Our results confirmed the general adverse prognostic role of VETC in RCC, however this phenotype gave a substantial PFS gain for patients treated with TKI, similarly to what have been observed in HCC. VETC could be a new predictive bio-marker that allows the delivery of a personalized treatment: patients affected by RCC might directly benefit from a better selection of already approved drugs.

Feasibility of multiple immunoexpression assay for immune tumor micrornvironment (I-TME) on matched metastatic and primary renal cell carcinoma (RCC) for patient prognostication and predictiveness to immunotherapy (preliminary analyses of the Meet URO 18 study).

e16545 Background: The Meet-URO 18 study is ongoing to assess the prognostic role of I-TME in advanced RCC patients treated with ≥second line nivolumab divided into two cohorts according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. We primarily assessed the feasibility of multiple antibody testing related to I-TME on matched metastases and primary tumor. Methods: Immunohistochemical analyses were used for the TME assessment of T-lineage (CD3, CD4, CD8), FOXP-3, granulocytes (CD15), macrophage-lineage (CD68), natural killer (NK)-cells (CD56), tumor cells (TCs) (CD56), B-lineage (CD20) and phosphorylated mTOR (phmTOR). TCs were quantitatively assessed for CD15, CD56 and phmTOR positivity. For T-, B- and CD68 cells within TC nests, the number of immunoreactive cells were counted with a microscopic field of x200 (0.933 mm2). Results: Overall, 42 tumor tissue samples (primary tumors, metastases) were available and for 17 patients both metastatic and primary tumor tissues were assessable for matched analyses. Among these patients, 12 had clear cell, 1 papillary and 4 mucinous tubular and spindle cell histotype according to WHO 2016 classification. Intratumoral T/CD8 cells ranged from 32 to &gt;400 spots (mean 240; &gt;400 in 7 samples) and intratumoral T/CD4 cells from 4 to &gt;400 spots (mean 168; &gt;400 in 5 samples). Nine samples showed absence of phmTOR expression, while 8 ranged from 10% to 90% of positive TCs. We did not observe countable NK-cells, whereas CD56 was visible in 5 samples (mean 55% of positive TCs). Intratumoral CD68 cells ranged from 34 to &gt;400 spots (mean 175, &gt;400 in 3 patients). Agreement of CD15 method of reporting granulocytic presence was high, thus only CD15 neoplastic expression was reported and ranged from 12% to 55% (mean 30%) in 15 patients. TME multiple analysis resulted equally clustered in 8 patients (&lt;20% variability of single immuno-test) whereas the remaining 9 patients showed significant differences as percentage of immuno-tissue expression in at least one of the 5 immuno-indicators (T/CD8-CD4, C15, CD68, CD56, phmTOR). The remaining 8 samples of patients without matched analyses were used to test the feasibility of multiple analyses; among all antibodies exclusion of the CD20 and FOXP-3 final evaluation was needed, due to technical standardization. According to the 5 immuno-indicators, double-triple positive or penta-positive TME indicators may be identified and graded. Conclusions: Providing multiple immunoexpression platforms on a single specimen may be used as routine workflow. Profiling I-TME, especially CD56, CD15 on TCs and CD68 cells and phmTOR, deserves investigation with extensive control groups. A validation cohort will be tested at tissue level and in correlation with peripheral blood markers.

Isolated Central Adrenal Insufficiency Due to Nivolumab: A Case Report

Background: Immune checkpoint inhibitors are immunomodulatory antibodies directed against programmed cell death 1 (PD-1), Nivolumab, or cytotoxic T-lymphocyte antigen-4 (CTLA-4) Ipilimumab. They have improved outcomes in patients with advanced cancers including renal cell carcinoma, non-small cell lung cancer and melanoma. Several immune related adverse events (irAEs) have been recognized with use of immune checkpoint inhibitors, including those involving the endocrine system. We present a case of a patient presenting with isolated central adrenal insufficiency in the context of Nivolumab use. Clinical Case: Our patient is a 54-year old man with pre-existing primary hypothyroidism and metastatic renal cell carcinoma treated with Nivolumab. After receiving a total of 14 cycles of Nivolumab, he presented to the Emergency room with his sister, who found him confused and lethargic. On presentation, he was found to be hypoglycemic (random glucose was 2.2 mmol/L). On physical examination, his vital signs were stable and he appeared euvolemic. He was disoriented without focal neurological deficits. Initial blood work revealed sodium 134 mmol/L, (Normal 135-145mmol/L), potassium 4.5 mmol/L (Normal 3.5-5 mmol/L), and TSH being 12.6 mIU/L (Normal 0.4-4 mIU/L). He was resuscitated with IV Dextrose 50% bolus then admitted to hospital and kept on an IV dextrose infusion. While his glucose improved, he was found to have hyponatremia, and confusion persisted. His nadir sodium was 116 mmol/L without seizures or loss of consciousness and required treatment with hypertonic saline. Giving hypoglycemia and hyponatremia, morning cortisol and ACTH were checked and came back 4 nmol/L (Normal 133-537 nmol/L) and undetectable (< 0.7 pmol/L, Normal 1.6-13.9 pmol/L) respectively. The diagnosis of central adrenal insufficiency was made likely secondary to Nivolumab. He was started on Dexamethasone 8 mg daily. Sodium level normalized and glucose level improved with steroids. He was discharged home on prednisone 50 mg and then switched to hydrocortisone. Furtherwork up confirmed preserved other anterior pituitary hormones. MRI of Sella did not show pituitary enlargement or inflammation. Conclusion: Our patient presented with hypoglycemia and hyponatremia; both could be the presenting manifestations of central adrenal insufficiency. Nivolumab has been commonly associated with thyroid dysfunction and thyroiditis. Given lack of expression of PD-1 in the pituitary, PD-1 inhibitors are less likely to be associated with hypopituitarism in general, or central adrenal insufficiency in particular. However, our report adds to the growing body of literature associating it with central adrenal insufficiency, which can be isolated. In so doing, it underscores the need for early recognition this association with Nivolumab, so as to avoid the potentially life threatening consequences of this condition.

APOBEC1 complementation factor facilitates cell migration by promoting nucleus translocation of SMAD3 in renal cell carcinoma cells.

Metastasis is inevitable in about 30% of patients with primary renal cell carcinoma after nephrectomy treatment. APOBEC1 complementation factor (A1CF), an RNA binding protein, participates in tumor progressions such as growth, apoptosis, differentiation, and invasion. Here, we explored biological functions of A1CF and provided a new insight into renal cell carcinoma metastasis. Wound healing assay was conducted to detect migration in A1CF overexpression and knockdown stable cell lines. Quantitative PCR and western blot assays were utilized to test transcriptional and translation levels of A1CF and SMAD3 in A1CF overexpression and knockdown renal carcinoma cells. Nuclear and cytoplasmic protein separation assays were conducted to evaluate the subcellular distribution of A1CF and SMAD3. Immunoprecipitation assay was conducted to detect the interaction between A1CF and SMAD3. Our study demonstrated A1CF overexpression facilitated cell migration in renal carcinoma cells. A1CF deficiency downregulated expression of SMAD3, Snail1, and N-cadherin. In addition, A1CF promoted nucleus translocation of SMAD3 and interacted with SMAD3. SMAD3 knockdown attenuated cell migration induced by A1CF overexpression. Our study suggested A1CF facilitated cell migration by promoting nucleus translocation of SMAD3 in renal cell carcinoma cells.

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.&#x0D; Study Design: Cross sectional study.&#x0D; Place and Duration of Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from Jun 2016 to Jun 2017.&#x0D; 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 &gt;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.&#x0D; 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.&#x0D; Conclusion: PAX8 is an important additional diagnostic marker for renal cell carcinoma. It can be recommended for inclusion in immunohistochemical panel for diagnosis..............

Tuftelin 1 (TUFT1) Promotes the Proliferation and Migration of Renal Cell Carcinoma via PI3K/AKT Signaling Pathway.

Tuftelin 1 (TUFT1), a protein functioning distinctively in different tissues, is reported to be elevated in several types of cancers and the elevation of TUFT1 is correlated with unfavorable clinicopathologic characteristics and poor survival. However, the involvement of TUFT1 in renal cell carcinoma (RCC) remains unknown. In the current study, we investigated the role of TUFT1 in RCC and potential underlying mechanisms. RT-PCR and Western blot analysis showed that both the mRNA and protein levels of TUFT1 were increased in primary RCC tissue and RCC cell lines. TUFT1 overexpression in RCC cells resulted in enhanced cell proliferation and migration while knockdown of TUFT1 by contrast decreased the growth and migration of the RCC cells, indicating TUFT1 expression is involved in RCC cell growth and migration. The involvement of TUFT1 in the epithelial-mesenchymal transition (EMT) of RCC cells was also determined by measuring the expression of EMT-related markers. Our data showed that TUFT1 overexpression promoted RCC cell EMT progression while knockdown of TUFT1 suppressed such process. Further signaling pathway inhibition assay revealed that TUFT1-induced RCC cell growth, migration and EMT was significantly suppressed by PI3K inhibitor, but not JNK or MEK inhibitors. In addition, TUFT1 overexpression enhanced the AKT phosphorylation, a key member of the PI3K signaling pathway, while PI3K inhibitor suppressed such process. Taken together, our study showed that TUFT1 expression was elevated in RCC and such elevation promoted the proliferation, migration and EMT of RCC cells in vitro, through PI3K/AKT signaling pathway. The findings of our current study imply that TUFT1 is involved in RCC tumorigenesis, and it may serve as a biomarker for RCC diagnosis and a potential target for RCC treatment.

Recurrent Cutaneous Metastasis of Clear Cell Type Renal Cell Carcinoma: Case Report

Cutaneous metastases of internal malignancies are rare events occurring rather late in the primary tumors' progression. We are reporting a recurrent case of cutaneous metastatic renal cell carcinoma (RCC) in a 70-year old male present with a nodular lesion on the scalp, who underwent surgical treatment and histopathological diagnosis at the Lady Davis Carmel Medical Center in Haifa, Israel. The patient had consequently twice in his history similar cutaneous lesions on the scalp which were histologically proved to be clear cell type RCC (classic and eosinophilic variant). The currently excised tumor was an oval white dense lobulated, well-demarcated lesion, up to 2 cm in diameter, in the subcutis, without epidermal involvement. The histopathologic findings consisted of atypical cells, arranged in an organoid pattern, with irregularly distributed eosinophilic cytoplasmic granularity. Immunohistochemically, the tumor cells were found positive for CD10, PAX8, EMA, and vimentin, which is consistent with cutaneous metastatic RCC, conventional (clear cell) variant with eosinophilic features. Revision of the histopathologic material from the previous surgeries of the same patient revealed even higher-graded metastatic RCC comparing with the current one. Our reported case and the revised previous one, as well as medical literature data, reflect dissemination of the primary clear sell type RCC and its characteristic metastatic dermatotropism. However, its recurrent metastases, especially to the same body area, are still to be gathered and studied further to make a statistically relevant conclusion about their prognostic value.

Role of positron emission tomography/computed tomography in the evaluation of renal cell carcinoma.

Introduction:Positron emission tomography (PET) is not a standard recommendation in most of the major guidelines for the evaluation of renal cell carcinoma (RCC). Earlier studies evaluating PET scan in patients with RCC have provided discordant results. However, with the advent of newer hybrid PET/computed tomography (CT) scanning systems, this modality has shown increased efficacy in the evaluation of primary renal masses along with the detection of extrarenal metastases, restaging recurrent RCC, and also in monitoring response to targeted therapy. We performed a systematic review of the existing literature on the role of PET scan in the evaluation of RCC.Methodology:We systematically searched the databases of PubMed/Medline, Embase, and Google Scholar to identify studies on the use of PET scan in RCC. Using Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, 94 full-text articles were selected, of which 54 relevant articles were then reviewed, after a consensus by the authors.Results:Several studies have shown similar sensitivity and specificity of fluoro-2-deoxy-2-d-glucose-PET (FDG-PET) scan as compared to conventional CT scan for the initial diagnosis of RCC, and an improved sensitivity and specificity for the detection of metastases and recurrences following curative therapy. The PET scan may also play a role in predicting the initial tumor biology and pathology and predicting the prognosis as well as the response to therapy.Conclusion:The current guidelines do not recommend PET scan in the staging armamentarium of RCCs. However, FDG-PET scan is as efficacious, if not better than conventional imaging alone, in the evaluation of the primary and metastatic RCC, as well as in evaluating the response to therapy, due to its ability to pick up areas of increased metabolic activity early on. Newer tracers such as Ga68 prostate specific membrane antigen-labeled ligands may help in opening up newer avenues of theragnostics.

Single-cell analysis reveals metastatic cell heterogeneity in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the leading causes of cancer‐related death worldwide. Tumour metastasis and heterogeneity lead to poor survival outcomes and drug resistance in patients with metastatic RCC (mRCC). In this study, we aimed to assess intratumoural heterogeneity (ITH) in mRCC cells by performing a combined analysis of bulk data and single‐cell RNA‐sequencing data, and develop novel biomarkers for prognosis prediction on the basis of the potential molecular mechanisms underlying tumorigenesis. Eligible single‐cell cohorts related to mRCC were acquired using the Gene Expression Omnibus (GEO) dataset to identify potential mRCC subpopulations. We then performed gene set variation analysis to understand the differential function in primary RCC and mRCC samples. Subsequently, we applied weighted correlation network analysis to identify coexpressing gene modules that were related to the external trait of metastasis. Protein‐protein interactions were used to screen hub subpopulation‐difference (sub‐dif) markers (ACTG1, IL6, CASP3, ACTB and RAP1B) that might be involved in the regulation of RCC metastasis and progression. Cox regression analysis revealed that ACTG1 was a protective factor (HR < 1), whereas the other four genes (IL6, CASP3, ACTB and RAP1B) were risk factors (HR > 1). Kaplan‐Meier survival analysis suggested the potential prognostic value of these sub‐dif markers. The expression of sub‐dif markers in mRCC was further evaluated in clinical samples by immunohistochemistry (IHC). Additionally, the genetic features of sub‐dif marker expression patterns, such as genetic variation profiles, correlations with tumour‐infiltrating lymphocytes (TILs), and targeted signalling pathway activities, were assessed in bulk RNA‐seq datasets. In conclusion, we established novel subpopulation markers as key prognostic factors affecting EMT‐related signalling pathway activation in mRCC, which could facilitate the implementation of a treatment for mRCC patients.