Clear Cell Tumors Research Articles

Clear-cell papillary renal cell tumour: New insights into clinicopathological features and molecular landscape after renaming by 5th WHO classification

ObjectiveClear cell papillary renal cell tumour (CCPRCT) is a kind of renal epithelial cell tumor, and was renamed by the 5th WHO due to its specific epidemiology and clinicopathological characteristics. However, the biological mechanism and molecular basis of CCPRCT still need to be further clarified. This study aims to comprehensively evaluate clinicopathologic and molecular characteristics of CCPRCC, and particularly compare it with other more prevalent subtypes of renal cell carcinoma. Methods12 cases of CCPRCT were collected for analyzing the clinicopathological characteristics. Then, whole-exome sequencing (WES) was employed to reveal the genetic profiles, followed by comparison with the molecular genetic alterations identified in ccRCC (341) and pRCC (200) datasets obtained from the TCGA database. ResultsOf the 12 CCPRCT cases, the male-to-female ratio was 4:1 with a mean age of 49.5 years (48.5 ± 10.5) at diagnosis. All patients were diagnosed accidentally during routine physical examinations. All tumors (12/12, 100%）had a solid-cystic appearance with a well-defined fibrous capsule. The median size of the tumors was 3 cm (2.98 ± 1.2). Histologically, the cystic papillary structures were considered to be prominent, lined with cuboidal tumor cells away from basement membrane. The tumor cells were moderately atypia equivalent to grade 1 or grade 2 according to the ISUP nuclear grading system. Typically, the tumor cell diffusely positive for CK7 and CAIX in a “cup-like” pattern. The results of WES revealed recurrent gene alterations (mainly missense mutation) of TTN and FLT in 4 cases (4/12, 33.3%), respectively, of which, the alteration of FLT was not observed in ccRCC and pRCC of the TCGA database. Other gene alterations including POTEC (1 cases), PRADC1 (1 cases), ZZZ3 (1 case) and PTPRZ1 (1 case), etc. Moreover, all of the CCPRCT cases displayed a lower tumor mutation burden (TMB) compared to ccRCC and pRCC with median TMB of 1.04 (range: 1.94 ± 2.74). None of the patients experienced tumor metastasis, recurrence, or tumor-related deaths. ConclusionCCPRCT is a renal epithelial cell tumor characterized by specific clinical and pathological features. Our study provides additional evidence supporting the favorable prognosis of CCPRCT. Furthermore, the potential molecular alterations were uncovered by this study in CCPRCT such as the FLT family and TTN. However, due to the limited sample size, larger studies are required to validate these findings.

Comprehensive analysis of pain genes in prognosis of kidney renal clear cell carcinoma and tumor immunotherapy: A comprehensive bioinformatic study.

The effect of pain genes (NAV1, EHMT2, SP1, SLC6A4, COMT, OPRM1, OPRD1, CYP2D6, and CYP3A4) have not been reported previously in kidney renal clear cell carcinoma (KIRC) patients and thus we made a comprehensive analysis of pain genes in the prognosis of KIRC and tumor immunotherapy. In this study, TCGA, Kaplan-Meier plotter, Metascape, STRING, Human Protein Atlas, Single Cell Expression Atlas database, LinkedOmics, cBioPortal, MethSurv, CancerSEA, COSMIC database and R package (ggplot2, version 3.3.3) were used for comprehensive analysis of pain genes in KIRC. Pearson and Spearman correlation coefficients were for co-expression analysis. Immunotherapy and TISIDB database were used for tumor Immunotherapy. Representative pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4) were statistically significant (p < 0.0001) in the prognosis of KIRC. Immunotherapy (anti-PD-1 therapy, anti-PD-L1 therapy, and anti-CTLA4 therapy) and immunomodulator (immunoinhibitor, immunostimulator, and MHC molecule) in KIRC were significant associated with pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4), which were the important addition to clinical decision making for patients. Our study uncovered a mechanism for the effect of pain genes on KIRC outcome via the modulation of associated co-expression gene networks, gene variation, and tumor Immunotherapy.

MED15::ATF1-Rearranged Tumor: A Novel Cutaneous Tumor With Melanocytic Differentiation

We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers—Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.

Tumor papilar renal de células claras bifocal no asociado a enfermedad renal terminal

Clinical case description: A 63-year-old man with gastrointestinal symptoms without history of kidney disease. Through an abdominal computed axial tomography study, two lesions were detected in the right kidney that were resected. By morphology both lesions showed papillary pattern with clear cell features, low grade and fibromuscular stroma. By immunohistochemistry cytokeratin 7, cytokeratin 34βE12, carbonic anhydrase IX, PAX8, parafibromin and vimentin were positive, while CD10, AMARC, RCC, TFE3 were negative. Clinical implications: Clear cell papillary renal cell tumor (CCPRCT) is a recognized entity that has a unique morphologic and immunohistochemical features with an indolent clinical behavior with no recurrences, metastases or lymph node involvement. It was initially described in conjunction with end-stage renal disease; however, sporadic cases have been described in patients without kidney disease. It is important to correctly differentiate from other subtypes with worse prognosis. Relevance: CCPRCT previously called carcinoma has changed its name in the latest WHO publication (2022) due to the absence of cases with metastasis or recurrence, it is an indolent neoplasm that must be differentiated from other more aggressive tumors. Conclusions: CCPRCT can occur in patients without history of renal disease, it has an excellent prognosis, partial or total nephrectomy is the treatment of choice. The pathologist must differentiate it from other renal cell tumors with more aggressive behavior.

CLEAR CELL TUMORS OF CNS: HISTOMORPHOLOGIC APPROACH TO DIAGNOSIS

Introduction:Tumors of the central nervous system (CNS) that may assume a clear cell appearance are diverse in nature. Primary conditions in this category include oligodendroglioma, hemangioblastoma, clear cell meningioma, pleomorphic xanthoastrocytoma, and lipid-rich glioblastoma, chordoma, central neurocytoma.They can be correctly identified by giving attention to clinical presentation, location, radiographic findings, and histomorphological features, immunohistochemistry analysis wherever necessary.The literature was reviewed with emphasis on incidence, morphology and precise histopathological assessment of clear cells tumors of CNS. Method: This study was prospective observational study of 33 Cases received from August 2020 to December 2022 for clear cell tumors of CNS. This prospective study was carried out in Department of Pathology of a tertiary care teaching hospital. The ethical permission has been obtained from Institutional Ethics Committee for conducting the study. Result:Total 33 Central nervous system clear cell tumors were observed out of which 6 were benign and 27 were malignant cases. They can be correctly identified by giving attention to clinical presentation, location, radiographic findings, and histomorphological features in most of the instances. Two cases of metastasis identified in which immunohistochemistry in addition to morphological examination was performed to arrive at final diagnosis. Conclusion:Clearing of cytoplasm or clear cell changes are seen in various entities of different locations due to diverse reasons. So whenever clear cell is encountered, algorithmic approach is required to further proceed. In most of the instances morphologic features directs us to reach at diagnosis along with clinical and radiological findings.

Assessment of Ki-67 proliferation index in prognosis prediction in patients with nonmetastatic clear cell renal cell carcinoma and tumor thrombus

PurposeTo determine the optimal cut-off value of Ki-67 for predicting the survival of patients with clear cell renal cell carcinoma (ccRCC) and tumor thrombus and to explore the correlation between Ki-67 expression and pathological features. Patients and MethodsWe retrospectively analyzed Ki-67 immunohistochemical staining of ccRCC and tumor thrombus resected from February 2006 to February 2022. The survival rate was evaluated using the Kaplan-Meier method. The optimal cut-off value of the Ki-67 expression for predicting survival was determined by the minimum P-value method. Clinicopathological data were compared based on Ki-67 status (low versus high expression). Univariate and multivariate Cox regression analysis was used to explore independent predictors. ResultsA total of 202 patients (median age, 58 years [IQR, 52–65 years], 147 men) with ccRCC and tumor thrombus were included in the study. The optimal cut-off value of Ki-67 for predicting survival was 30%. 159 (78.7%) and 43 (21.3%) patients were included in the low-expression and high-expression groups. Patients with Ki-67 high expression had significantly worse recurrence-free survival (P < 0.001) and cancer-specific survival (P < 0.001). Ki-67 high expression was associated with adverse pathological features, including tumor necrosis, ISUP nuclear grade, sarcomatoid differentiation, perirenal fat invasion, renal pelvis invasion, and inferior vena cava wall invasion (all P < 0.050). Ki-67 expression ≥ 30% (P = 0.016), tumor side (P = 0.003), diabetes (P = 0.040), blood loss (P = 0.016), inferior vena cava wall invasion (P = 0.016), and sarcomatoid differentiation (P = 0.014) were independent predictors of cancer-specific survival. ConclusionThe optimal cut-off level of Ki-67 in predicting the prognosis of ccRCC and tumor thrombus was 30%. The high expression of Ki-67 was associated with the aggressive pathological phenotype and poor prognosis.

Anoikis-related genes signature development for clear cell renal cell carcinoma prognosis and tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is one of the most common primary malignancies of the urinary tract, highly heterogeneous, and increasing in incidence worldwide. Anoikis is a specific type of programmed cell death in which solid tumor cells or normal epithelial cells that do not have metastatic properties lose adhesion to the extracellular matrix or undergo inappropriate cell adhesion-induced apoptosis. Anoikis is thought to play a critical role in tumorigenesis, maintenance, and treatment, according to an increasing amount of research. However, there is still some uncertainty regarding the general impact of anoikis-related genes (ARGs) on the prognostic importance, tumor microenvironment characteristics, and treatment reaction of ccRCC patients. For this study, we used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus datasets to access the RNA sequencing results and clinical information from ccRCC patients. 29 ARGs related to survival were found using differential analysis and univariate Cox regression analysis. The samples were then divided into two clusters that had different immune traits via unsupervised cluster analysis using 29 prognosis-associated differently expressed ARGs. Then, to build an ARGs signature, 7 genes (PLAU, EDA2R, AFP, PLG, TUBB3, APOBEC3G, and MALAT1) were found using Least Absolute Shrinkage and Selection Operator regression analysis. The new ARGs signature demonstrated outstanding prognostic capability for ccRCC patients' overall survival. In conclusion, for ccRCC patients, we created an ARGs signature that strongly connects to immunological traits and therapy response. Clinicians may find this ARGs signature helpful in developing more individualized and detailed treatment strategies for ccRCC patients.

Arginase-1 is More Specific Than Hepatocyte Paraffin 1 for Differentiating Hepatocellular Carcinomas With Cytoplasmic Clearing from Nonhepatocellular Clear Cell Tumors in Liver Biopsies.

Arginase-1 (Arg1) and hepatocyte paraffin antigen 1 (HepPar1) are specific and sensitive markers of hepatocellular differentiation. HepPar1 is a granular cytoplasmic immunostain that may be negative in hepatocellular carcinoma (HCC) with cytoplasmic clearing. Arg1 shows uniform cytoplasmic positivity and frequent nuclear positivity. This study was undertaken to determine the staining pattern of Arg1 in HCC with cytoplasmic clearing and compare its use to HepPar1. Fifteen resected HCCs with cytoplasmic clearing and 31 biopsies of clear cell liver tumors (14 HCCs and 17 nonhepatocellular tumors) were identified. Resections were stained with Arg1 to characterize the pattern, intensity, and extent of Arg1 positivity. Biopsies were stained with Arg1 (n=31) and HepPar1 (n=28). In all, 13/15 resected and 11/14 biopsied HCCs with cytoplasmic clearing showed nuclear positivity for Arg1. Both Arg1 and HepPar1 stained significantly more HCCs than nonhepatocellular tumors (13/14 and 11/12, respectively, with P <0.0001 and P =0.0018, respectively). However, HepPar1 stained significantly more nonhepatocellular tumors (5/12) than Arg1 (0/17, P =0.0445). Arg1 frequently displayed nuclear positivity, and interobserver agreement was better for Arg1 ( K =0.93 vs. 0.79). Overall, Arg1 is more specific than HepPar1 for differentiating HCC with cytoplasmic clearing from nonhepatocellular clear cell tumors in the liver. Its staining characteristics, including nuclear positivity, make it easier to interpret in combination with morphology, improving interobserver variability, and it stains significantly fewer mimics than HepPar1.

Clear Cell Squamous Cell Carcinoma of the Maxillary Gingiva Associated with PIK3CA and HRAS Mutations: Report of a Case and Literature Review

BackgroundSquamous cell carcinoma (SCC) is the most common oral malignancy, and somatic mutations in some driver genes have been implicated in SCC development. Clear cell SCC (CCSCC) is a rare histological variant of SCC, and various clear cell neoplasms must be considered in the differential diagnosis of CCSCC in the oral cavity. Based on a limited number of CCSCC cases reported in the oral cavity, CCSCC is considered an aggressive variant of SCC with a poor prognosis; however, its genetic characteristics remain unknown.MethodsA maxillary gingival tumor in an 89-year-old female was described and investigated using immunohistochemical staining, special staining, fluorescence in situ hybridization, and next-generation sequencing (NGS) with a custom panel of driver genes, including those associated with SCC and clear cell neoplasm development.ResultsHistopathological examination revealed a proliferation of atypical epithelial cells with abundant clear cytoplasm and enlarged and centrally placed round nuclei. The tumor was exophytic with deep, penetrating proliferation. The atypical clear cells were continuous with the conventional SCC cells. Immunohistochemical analysis showed that the clear cells were positive for CK AE1/AE3 and CK5/6 and nuclear-positive for p63. In contrast, the clear cells were negative for αSMA, S100, HMB45, Melan-A, CD10, and p16. p53 immunoreactivity exhibited a wild-type expression pattern. Additionally, the clear cells were positive for periodic acid-Schiff (PAS) and negative for diastase-PAS, mucicarmine, and Alcian blue. Based on these results, the diagnosis of CCSCC was confirmed. Molecular analysis of the clear cells identified PIK3CA p.E542K (c.1624G>A) and HRAS p.G12A (c.35 G>C) somatic mutations classified as oncogenic. No pathogenic variants were identified in TP53, EWSR1, AKT1, PTEN, BRAF, KRAS, NRAS, RASA1, or MAML2.ConclusionsWe report a case of CCSCC of the oral cavity with PIK3CA and HRAS mutations. The identification of PIK3CA and/or HRAS mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.

Positive GPNMB Immunostaining Differentiates Renal Cell Carcinoma With Fibromyomatous Stroma Associated With TSC1/2/MTOR Alterations From Others.

Renal cell carcinoma with fibromyomatous stroma (RCCFMS) include ELOC/TCEB1 -mutated renal cell carcinoma (RCC) and those with TSC1/2 / MTOR alterations. Besides morphologic similarity, most of these tumors is known to be diffusely positive for carbonic anhydrase IX and cytokeratin 7 by immunohistochemistry. We previously showed strong and diffuse expression of GPNMB (glycoprotein nonmetastatic B) in translocation RCC and eosinophilic renal neoplasms with known TSC1/2/MTOR alterations. We retrospectively identified molecularly confirmed cases of TCEB1/ELOC -mutated RCC (7 tumors from 7 patients), and RCCFMS with alterations in TSC1/2/MTOR (6 tumors from 5 patients, 1 patient with tuberous sclerosis syndrome). In addition, we included 7 clear cell papillary renal cell tumors (CCPRCTs) and 8 clear cell RCC, as they can also present morphologic overlap with RCCFMS. Morphologically, RCCs with TSC1/2/MTOR alterations and those with TCEB1/ELOC mutations were indistinguishable and characterized by papillary, nested, or tubular architecture, with tumor cells with clear cytoplasm and low nuclear grade. By immunohistochemistry, cytokeratin 7 was positive in 5/7 (71%) of TCEB1/ELOC -mutated RCCs, 6/6 (100%) of RCCs with TSC1/2/mTOR alterations, and 7/7 (100%) of CCPRCTs ( P =not significant). Carbonic anhydrase IX was positive in 7/7 TCEB1/ELOC -mutated RCCs, 6/6 (100%) of RCCs with TSC1/2/MTOR alterations, and 7/7 (100%) of CCPRCTs ( P =NS). GPNMB was strongly and diffusely positive in all tumors with TSC1/2/MTOR alterations (6/6), while negative in all TCEB1/ELOC -mutated RCCs (0/6), or CCPRCTs (0/7) ( P =0.002). Two of 8 clear cell RCC showed focal weak staining, while 6/8 were negative. In conclusion, the results support the use of GPNMB to distinguish RCCFMS with TSC1/2/MTOR alterations from others with similar morphology.

Morphologic and Immunochemical Features of Clear Cell Papillary Renal Cell Tumor May be Seen in Renal Cell Carcinomas

Morphologic and Immunochemical Features of Clear Cell Papillary Renal Cell Tumor May be Seen in Renal Cell Carcinomas

Paracetamol use and risk of epithelial ovarian cancer: A nationwide nested case-control study.

To investigate whether paracetamol use is associated with a reduced risk of epithelial ovarian cancer (EOC). A nationwide nested case-control study. Danish female population. A total of 9589 EOC cases diagnosed from 2000 to 2019 were age-matched with 383 549 randomly selected female controls using risk set sampling. Paracetamol use, reproductive history, history of medication and history of surgery were retrieved from Danish national registers. Paracetamol use was defined as at least two prescriptions for up to 1 year before the index date, and was further classified according to recency, duration, cumulative dose and intensity of dose. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between paracetamol and EOC risk, overall and by histological subtypes. 'Ever' use of paracetamol was associated with a reduced EOC risk after adjusting for potential confounding factors (OR 0.92, 95% CI 0.87-0.97). The association was only significant among recent users (OR 0.89, 95% CI 0.84-0.95). The risk declined further with the increasing level of cumulative dose and intensity; women from the group with a high cumulative dose and a high intensity had a 13% (OR 0.87, 95% CI 0.80-0.94) and 14% (OR 0.86, 95% CI 0.79-0.93) reduced risk, respectively. In the histological subtype analysis, reduced risk with 'ever' use was most pronounced for serous and clear cell tumours. Paracetamol use was associated with a decreased risk of EOC in a dose-response manner. Future studies are needed to validate the findings and investigate the mechanisms behind the association.

The Association of Kidney Function and Inflammatory Biomarkers with Epithelial Ovarian Cancer Risk.

One of the mechanisms of ovarian tumorigenesis is through inflammation. Kidney dysfunction is associated with increased inflammation; thus, we assessed its relationship with ovarian cancer risk. In prospectively collected samples, we evaluated the association of kidney function markers and C-reactive protein (CRP) with ovarian cancer risk in the UK Biobank. We used multivariable-adjusted Cox proportional hazards models to evaluate quartiles of serum and urine markers with ovarian cancer risk overall and by histology. We assessed effect modification by CRP (≤3.0, >3.0 mg/L). Among 232,908 women (1,110 ovarian cancer cases diagnosed from 2006-2020), we observed no association between estimated glomerular filtration rate and ovarian cancer risk (Q4 vs. Q1: HR, 1.00; 95% confidence intervals, 0.83-1.22). Potassium was associated with endometrioid (Q4 vs. Q1: 0.33, 0.11-0.98) and clear cell (4.74, 1.39-16.16) tumors. Poor kidney function was associated with a nonsignificant increase in ovarian cancer risk among women with CRP>3.0 mg/L (e.g., uric acid Q4 vs. Q1; 1.23, 0.81-1.86), but not CRP≤3.0 mg/L (0.83, 0.66-1.05). Other associations did not vary across CRP categories. Kidney function was not clearly associated with ovarian cancer risk. Larger studies are needed to evaluate possible histology specific associations. Given the suggestive trend for increased ovarian cancer risk in women with poor kidney function and high CRP, future work is needed, particularly in populations with a high prevalence of inflammatory conditions. This study provided the first evaluation of markers of kidney function in relation to ovarian cancer risk.

Gene fusions in superficial mesenchymal neoplasms: Emerging entities and useful diagnostic adjuncts.

Cutaneous mesenchymal neoplasms are diagnostically challenging because of their overlapping morphology, and, often, the limited tissue in skin biopsy specimens. Molecular and cytogenetic techniques have identified characteristic gene fusions in many of these tumor types, findings that have expanded our understanding of disease pathogenesis and motivated development of useful ancillary diagnostic tools. Here, we provide an update of new findings in tumor types that can occur in the skin and superficial subcutis, including dermatofibrosarcoma protuberans, benign fibrous histiocytoma, epithelioid fibrous histiocytoma, angiomatoid fibrous histiocytoma, glomus tumor, myopericytoma/myofibroma, non-neural granular cell tumor, CIC-rearranged sarcoma, hybrid schwannoma/perineurioma, and clear cell sarcoma. We also discuss recently described and emerging tumor types that can occur in superficial locations and that harbor gene fusions, including nested glomoid neoplasm with GLI1 alterations, clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation, melanocytic tumor with CRTC1::TRIM11 fusion, EWSR1::SMAD3-rearranged fibroblastic tumor, PLAG1-rearranged fibroblastic tumor, and superficial ALK-rearranged myxoid spindle cell neoplasm. When possible, we discuss how fusion events mediate the pathogenesis of these tumor types, and we also discuss the related diagnostic and therapeutic implications of these events.

Cystic Clear Cell Renal Cell Carcinoma: A Morphological and Molecular Reappraisal.

A wide variety of renal neoplasms can have cystic areas. These can occur for different reasons: some tumors have an intrinsic cystic architecture, while others exhibit pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated with low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway, and they are more frequent in patients suffering from VHL disease. The differential diagnosis of multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumor includes cystic forms, knowledge of the criteria required for a differential diagnosis is mandatory.

Activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) after platinum chemotherapy: Interim results from the phase 2 ARCADIA trial.

4578 Background: Combining multitargeted receptor tyrosine kinase inhibitor (TKI) with checkpoint inhibitors has shown synergistic effect in pts with UC due to the immunomodulatory propriety of VEGFR inhibitors. We investigated if the combination of CABO and DURVA in pts with advanced UC and non-UC histology (VHs) in a phase II study (NCT03824691). Herein the preliminary results of the interim analysis. Methods: Patients affected by UC and VHs recurred or progressed after failure of at least one line of platinum-based chemotherapy for metastatic disease have been treated with CABO 40 mg daily, orally, and are administered DURVA 1500 mg IV, q28 days, until disease progression (PD, by RECIST 1.1) or onset of unacceptable toxicity. Key inclusion criteria were ECOG-PS 0-1 and adequate organ function. Response was evaluated by RECIST criteria v.1.1 every 8 wks. The primary endpoint of the study was OS. Secondary endpoints included safety (CTCAE v.4.03), objective response-rate (ORR), duration of response (DoR), progression-free survival (PFS). The assumption was to detect an improvement in the median OS from ≤6 months (H0) to ≥9 months (H1). Results: Between September 2019 and February 10, 2023, the ARCADIA study enrolled 63 pts: this interim analysis was performed after obtaining at least one post-baseline tumor assessment data from 58 pts. The median follow-up was 23.5 mos (interquartile [IQ] range: 7.7-27.7mos): 27% were female, the median age was 64 yrs (range: 42-81), 20 pts (34%) had a pure/predominant non-UC VH: 9 (45%) a squamous differentiation/sarcomatoid tumor, 5 (25%) an adenocarcinoma, 4 (20%) a small-cell neuroendocrine tumor, 1 (5%) a clear-cell tumor, and 1 a nested VH (5%). Eleven pts (19%) had received ≥2 prior systemic anticancer therapies. In 58 response-evaluable pts, 12 (20%) complete responses (CR) and 11 partial responses (PR) were obtained, the ORR being 39.7% (95%CI: 27.1-53.4) and disease control rate was 69% (95%CI: 55.5-80.5). In the cohort of pts with VH, the ORR was 45% (95%CI: 23.1-68.5). Median PFS was 7.6 mos (95%CI: 4.6-13-6 mos) and median OS was 11.6 (95% CI 6.8-20.3 months). Median exposure of treatment was 4.8 mos; 35 pts (55.5%) of 63 pts had all-grade treatment-related adverse events (AE) and 4 pts (6.3%) reported grade 3 (treatment related) AE with no grade 3-5 events. Dose-reductions of CABO were needed in 25 pts (39%). No treatment-related deaths were reported. Conclusions: CABO in combination with DURVA showed promising preliminary activity with a manageable safety profile in pts with advanced UC and in non-UC VH after previous chemotherapy exposure, deserving further evaluation of the combination that is ongoing with ARCADIA and other clinical trials. More mature results with longer follow-up will be presented. Clinical trial information: NCT03824691 .

Updates in the Systemic Therapy Options for Clear Cell and Non–Clear Cell Renal Cell Carcinoma

At the NCCN 2023 Annual Conference, experts reviewed clinical data on established therapies for patients with metastatic renal cell carcinoma and discussed strategies to effectively manage both clear cell and non–clear cell tumor histologies in the setting of advanced stages. Depicted through 3 separate case studies, they strategized the selection of optimal first-line and subsequent-line therapies based on the individual case study and the tumor characteristics in each.

Clinicopathologic Classification of Renal Cell Carcinoma in Patients ≤40 Years Old From Peru.

There are scant data on renal cell carcinoma (RCC) from relatively younger patients in South America using contemporary classification. Fifty-nine consecutively treated patients with RCC (≤40 years old) were assessed from the National Institute of Neoplastic Diseases in Peru from 2008 to 2020 (34 males; 25 females), age range of 13 to 40 years. Most common presenting symptoms were flank pain (n = 40), hematuria (n = 19), and weight loss (n = 12). Associated conditions included 4 patients with proven or presumed tuberous sclerosis and 1 patient with von Hippel Lindau syndrome, all with clear cell RCC. Tumor histopathology was clear cell RCC in 32 of 59 (54%), chromophobe RCC in 6 of 59 (10%), and 5 of 59 (8%) each of papillary RCC and MiT family translocation-associated RCC. Four of 59 (7%) were FH-deficient RCC and 2 of 59 (3%) remained unclassified. The remaining tumors were isolated examples of clear cell papillary renal cell tumor, eosinophilic solid and cystic RCC (ESC RCC), RCC with fibromyomatous stroma, sarcomatoid RCC, and sarcomatoid clear cell RCC. Of the 4 FH-deficient RCCs, none had the classic morphology. The 5 MiT family translocation RCCs had variable morphology. There were 41 tumors without recurrence or metastases, 3 tumors with local recurrence only, 8 tumors with metastases only, and 7 tumors with both local recurrence and metastases. The current study demonstrates the importance of special studies in accurately classifying RCC in younger individuals. The distribution of RCC subtypes in younger individuals is similar between 2 representative large institutions of the United States and Peru.

Frequencies, clinicopathological features, and risk factors of type I and type II endometrial cancer; a retrospective observational study at a tertiary care hospital in Pakistan

Background: Endometrial cancer (EC) is the most common gynecological malignancy worldwide. The death rates for EC have increased by more than 100% over the past 2 decades. EC is subdivided into two types based on distinct histological and clinical features: type I and type II. Our study aims to determine the risk factors and clinicopathological features of both type I and type II EC and draw a comparison between the two types based on frequency, risk factors and clinicopathological features. Methods: It was a retrospective observational study including patients of a single tertiary care center. The study included Patients diagnosed, treated, and followed up for type I and type II endometrial cancer at the study center over the past 19 years from 1st January 2000 to 31st December 2018. All the patients with metastatic endometrial cancer were excluded from the study. SPSS version 26 was used for statistical analysis. Results: A total of 376 patients were included in this study. Among these 343 (91.7) patients had endometroid adenocarcinoma (Type I) and 32 (8.3) had serous and clear cell tumor (type II). Type I EC had a mean age of 57.56 (SD±10.42) while patients with type II EC presented with a mean age of64.97 (SD±6.59). Hypertension and Diabetes were the most common comorbid in EC patients. HRT prior to EC was found to have an association with risk of EC. Compared to patients who were on HRT, patients who were not on HRT prior to diagnosis of EC had 80% less chance of developing endometrial cancer. (Confidence interval: 0.056-0.114, p=0.016). Conclusions: In summary our study demonstrates that both sub types of endometrial cancer have many risk factors that are similar to each other. Despite the difference between the population of both subgroups we were able to prove associations between risk factors and endometrial cancer. However further research is needed at provincial and national level with larger and relatively comparable sample sizes for both subgroups to recognize risk factors and numerically associate them to EC for Pakistani population.

TSC/MTOR Mutated Renal Cell Carcinoma with Leiomyomatous Stroma is a Distinct Entity: A Comprehensive Study of 12 Cases.

The 2016 World Health Organization (WHO) Classification of Tumors of the Urinary System includes renal cell carcinoma (RCC) with leiomyomatous stroma (RCC-LS) as a provisional category. Recent studies have shown that this category includes at least 4 subtypes: clear cell (CCRCC), clear cell papillary renal cell tumor (CCPRCT), ELOC (TCEB1) mutated, and a subtype of RCC with TSC/MTOR mutations. The most recent 2022 World Health Organization (WHO) Classification of Tumors of the Urinary System includes ELOC mutated RCC-LS as a distinct entity but does not address any other renal tumors with smooth muscle stroma. We reviewed >500 cases of RCC with clear cell phenotype and identified 12 cases that exhibited prominent smooth muscle stroma, of which 4 of the cases had been previously reported. Review of the H&E revealed that all of the tumors were circumscribed with nested, solid, tubular, and tubulopapillary architecture. The epithelium was intimately embedded in the rich smooth muscle stroma. WHO/ISUP grade corresponded to grade 3 and 4. Nuclei were randomly distributed and the cytoplasm had predominantly clear and occasionally flocculent appearance. Immunohistochemically, all the cases showed membranous CAIX staining, although the pattern was combined cup and box-shaped. CK7 was positive in all cases ranging from 25% to 100% of cells. Membranous and apical staining of CD10 was present in all cases. Next generation sequencing (NGS) of these cases identified mutations in TSC1 (n=4), TSC2 (n=3), and MTOR (n=4) with one case exhibiting loss of TSC1. This descriptive study, although small, demonstrates the difficulty in applying the current WHO provisional criteria at a single institution. Given the heterogeneity seen with these cases, we suggest following up an immunohistochemical panel of CAIX, CK7, and CD10 with molecular diagnostic studies to assist in the diagnosis of TSC/MTOR associated RCC-LS, which we believe is a distinct entity.