Chromophobe Renal Cell Carcinoma Research Articles

Chromophobe Renal Cell Carcinoma With Extensive Retraction Artifact: A Potential Diagnostic Pitfall From Micropapillary Urothelial Carcinoma.

In addition to "classic" and eosinophilic subtype, chromophobe renal cell carcinoma (RCC) is well-known to demonstrate various morphological patterns including adenomatoid, microcystic, pigmented, multicystic, papillary, neuroendocrine-like, and small cell-like, all of which are important to appreciate for accurate diagnosis. Herein, we expand on a unique chromophobe RCC morphology not previously described consisting of tumor cells with extensive stromal retraction, mimicking upper urothelial tract micropapillary carcinoma (MPC). Twelve MPC-like chromophobe RCC nephrectomies were reviewed with clinicopathological features recorded; molecular testing was performed on 7 of 12 tumors. Patients were mostly men (n=10) with a mean age of 65 years. Mean tumor size was 6.4 cm with pathological stage distribution as follows: 4 (33%) T1a, 2 (17%) T1b, 1 (8%) T2b, and 3 (25%) T3a. The extent of MPC-like chromophobe RCC foci ranged from 10% to 40% (mean=26%; there was no correlation between the extent of MPC-like chromophobe RCC foci and tumor stage). Other chromophobe RCC morphological patterns were not identified. When performed, all (100%) tumors depicted prototypic chromophobe RCC staining pattern of KIT positivity/KRT7 positivity. Molecular showed 6 of 7 (86%) with multiple chromosomal losses. Clinically significant mutations were identified in NF1, TP53, FLCN (likely somatic), CHEK2, and ZFHX3 genes. Follow up available in 9 patients showed no evidence of disease (mean=23 months). Although the etiology behind the extensive stromal retraction in our tumors is unknown, this may likely be artifactual in nature. Nonetheless, it is important to include MPC-like chromophobe RCC in the spectrum of "variant" morphologies to avoid diagnostic pitfalls from micropapillary carcinoma.

Association between PD-L1 Expression and the Prognosis and Clinicopathologic Features of Non-Clear Cell Renal Cell Carcinoma.

PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance in non-clear cell renal cell carcinoma (non-ccRCC) patients. A total of 41 papillary (pRCC) and 20 chromophobe (chRCC) RCC tumors were examined for PD-L1 expression by immunohistochemistry in the cancer cells and tumor-infiltrating mononuclear cells (TIMCs). PD-L1 positivity was detected in 36.6% pRCC and 85.0% chRCC cancer cells, while PD-L1 positivity was observed in 73.2% pRCC and 50.0% chRCC TIMCs. PD-L1 positivity in both pRCC and chRCC tumor cells was not correlated with any of the examined clinicopathological features, while PD-L1 positivity in TIMCs was associated with the age of patients with pRCC. During follow-up, the death was documented among 6 patients with pRCC. Papillary RCC patients with PD-L1-positive tumor cells were significantly associated with an increased risk of death compared with patients with PD-L1-negative cancer cells. A similar trend was observed when comparing PD-L1 expression in TIMCs. However, no differences in overall survival for PD-L1-positive pRCC patients with compared to PD-L1-negative patients were observed in tumor cells or TIMCs.

External validation of a four-tiered grading system for chromophobe renal cell carcinoma

This study aimed to validate the prognostic value of a four-tiered grading system recently proposed by Avulova et al. and to explore the prognostic ability of another four-tiered classification grading system in which there is a separate Grade 3 for tumor necrosis. Grading of chromophobe renal cell carcinoma (ChRCC) by the Fuhrman system is not feasible because of the inherent nuclear atypia in ChRCC. We collected relevant data of 263 patients with ChRCC who had undergone surgery in our hospital from 2008 to 2020. The Kaplan–Meier method was used to calculate the survival rate and Cox proportional hazard regression models to assess associations with cancer-specific survival and distant metastasis-free survival by hazard ratios (HRs) and 95% confidence intervals (CIs). Ten patients died from ChRCC, and 12 developed metastases. The 5 year CSS rates were 95.9%. Grades 2 (HR = 10.9; CI 1.11–106.4; P = 0.04), 3 (HR = 33.6, CI 3.32–339.1; P = 0.003), and 4 (HR = 417.4, CI 35.0–4976.2; P < 0.001) in a four-tiered grading system were significantly associated with CSS in a multivariate setting. However, the difference in CSS between Grades 2 and 3 was not significant (HR = 2.14, 95% CI 0.43–10.63; P = 0.35). The HRs of the associations between an exploratory grading system that includes a separate Grade 3 for tumor necrosis and CSS were as follows: Grade 2, 10.2 (CI 1.06–97.9, P = 0.045); Grade 3, 11.4 (CI 1.18–109.6, P = 0.04); and Grade 4, 267.9 (CI 27.6–2603.3, P < 0.001). Similarly, Grades 2 and 3 did not differ significantly. The four-tiered grading system studied is useful for predicting death from ChRCC and metastasis. However, Grade 3 did not more accurately predict risk of death and metastasis than did Grade 2. This was also true for the novel exploratory grading system that classifies tumors with necrosis into a separate Grade 3.

Abstract 4357: Examining the role of end-stage kidney as a potential intermediate stage in the development of renal cell carcinomas; understanding the pathogenesis allowing for early detection

Abstract Introduction: Clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC) are both thought to arise from the renal proximal tubules. End stage renal disease (ESRD) patients have an increased incidence of developing PRCC and CCRCC. Some studies showed a progenitor cell population that is inherently present in renal tubules, and is significantly increased after renal injury. The studies have also illustrated similarities between these progenitor cells and PRCC &amp; CCRCC; hypothesizing that they are the cell of origin of these tumors. This trend was not observed in other renal cell carcinomas such as chromophobe renal cell carcinoma (chRCC). This study aims to further examine the possible role of ESRD in the development of PRCC and CCRCC to understand this initial step of renal cell carcinoma pathogenesis. Methods: A cohort of n = 39 PRCC, 25 CCRCC, 63 normal, 10 end-stage and 18 chRCC cases were selected. RNA sequencing was performed and differential-gene-expression analysis was conducted between normal, ESRD and tumor using DESeq2 software. Pathway analysis was performed using GSEA. Genes from oncogenic pathways that have been studied to be involved in renal cancer development were selected to perform consensus clustering analysis on Genepattern. Results: Oncogenic and developmental pathways enriched in ESRD are consistently overlapping with that of CCRCC and PRCC tumors. 50% of end-stage developmental pathways are found in both CCRCC and PRCC but only 4.5% in chRCC. 62.4% and 46.4% of end-stage oncogenic pathways are found in CCRCC and PRCC respectively but only 16% in chRCC. Clustering analysis showed ESRD cases clustered together with CCRCC and PRCC groups and not with chRCC. Overall, the ESRD cases exhibited a gene expression profile more closely resembling that of CCRCC and PRCC than chRCC. Conclusion: Our findings support the hypothesis that ESRD provides a favorable environment for tumor growth promoting pathogenesis of both PRCC and CCRCC. The enrichment of the same developmental pathways in both ESRD and the tumors suggests that the progenitor cell population in the renal tubules, mentioned above, could be the origin of both PRCC and CCRCC lesions. Further analysis would allow the uncovering of the pathways that lead to tumor progression from these cells of origin, and can be used to determine biomarkers for early detection of CCRCC and PRCC. This is of particular benefit for those with increased risk as the ESRD patients. Citation Format: Mingyuan Wan, Vincent Castillo, Rola Saleeb. Examining the role of end-stage kidney as a potential intermediate stage in the development of renal cell carcinomas; understanding the pathogenesis allowing for early detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4357.

Abstract 1049: Prevalence of KDM6A expression loss in human cancer: A tissue microarray study on 6,560 cancers from 114 different tumor types

Abstract KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is an epigenetic regulator constituting a critical part of the COMPASS-like complex. KDM6A mutations occur commonly in cancer. These are of interest because KDM6A loss results in a dependency on EZH2, a potential therapeutic target. Most data on KDM6A have been obtained by next generation sequencing (NGS). However, since most KDM6A mutations are truncating and KDM6A is located on the X chromosome, many mutations result in a complete expression loss which can be detected by immunohistochemistry (IHC). To learn more on the prevalence of KDM6A expression loss and its role in cancer, a tissue microarray containing 6,560 samples from 114 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, KDM6A staining was rather ubiquitously seen in nuclei. In cancer, KDM6A staining was considered weak (1+) in 581 (11.2%), moderate in 1,927 (37%), and strong in 2,362 (45.4%) of 5,206 interpretable tumors. A complete loss of KDM6A staining occurred in 336 (6.5%) of tumors. At least one case with a complete KDM6A expression loss was observed in 51 of 114 tumor categories. KDM6A staining was most commonly lost in different categories of urothelial carcinomas (19.5-39.2%), squamous cell carcinomas of the esophagus (27.1%), hepatocellular carcinoma (18.4%), gastric carcinoma (3.2-12.5%), papillary renal cell carcinoma (9.5%), adenocarcinoma of the prostate (5.9-9.4%), chromophobe renal cell carcinoma (8.9%), Ewing sarcoma (8.3%), pheochromocytoma (8.3%), and metastatic malignant melanoma (8%). A KDM6A expression loss in less than 8% of cases was observed in 32 further tumor entities. KDM6A expression loss was more than twice as frequent in tumors from male (8.4% of 2,526) than in tumors from female patients (3.9% of 2,024; p&amp;lt;0.0001). It is concluded that KDM6A IHC is a suitable method for the detection of truncating KDM6A mutations, especially in males. These make up for about 2/3 of all KDM6A mutations and may exert specific biological effects than differ from the various KDM6A missense mutations known to also occur. Citation Format: Florian Viehweger, Natalia Gorbokon, Maximilian Lennartz, Viktor Reiswich, Florian Lutz, Till Krech, Andreas M. Luebke, Claudia Hube-Magg, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H. Marx, Christian Bernreuther, Martina Kluth, Sarah Minner. Prevalence of KDM6A expression loss in human cancer: A tissue microarray study on 6,560 cancers from 114 different tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1049.

High-Grade, Nonsarcomatoid Chromophobe Renal Cell Carcinoma: A Series of 22 Cases With Novel Molecular Features on a Subset

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma, and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphological features and are associated with a poor prognosis. Although there is limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade non-sarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, non-sarcomatoid components. High-grade ChRCC frequently demonstrated advanced stage at diagnosis (64% ≥pT3a or N1), with regions of extrarenal extension, nodal metastases, and vascular invasion consisting solely of high-grade ChRCC morphologically. We performed spatially guided panel-based DNA sequencing on 11 cases, comparing high- and low-grade regions (n = 22 samples). We identified recurring somatic alterations emblematic of ChRCC, including deletions of chromosomes 1, 2, 6, 10, 13, 17, and 21 in 91% (10/11) of cases and recurring mutations in TP53 (81.8%, n = 9/11) and PTEN (36.4%, n = 4/11). Notably, though PTEN and TP53 alterations were found in both high- and low- grade regions, private mutations were identified in 3 cases, indicating convergent evolution. Finally, we identified recurring RB1 mutations in 27% (n = 3) of high-grade regions leading to selective protein loss by immunohistochemistry not observed in adjacent low-grade regions. This finding was confirmed in the TCGA cohort where 2/66 cases contained RB1 mutations and demonstrated unequivocal high-grade, non-sarcomatoid morphology. We also detected multiple chromosomal gains confined to the high-grade regions, consistent with imbalanced chromosome duplication. These findings broaden our understanding of the molecular pathogenesis of ChRCC and suggest that subclonal RB1 mutations can drive the evolution to high-grade, non-sarcomatoid ChRCC.

L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the “other oncocytic tumors” category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to “Oncocytic Principal Cell Adenoma of the Kidney” may be a better way to define and describe this entity.

Identification of PANoptosis-related signature reveals immune infiltration characteristics and immunotherapy responses for renal cell carcinoma

PANoptosis is a specific type of inflammatory programmed cell death (PCD) modality that can be involved in three key modes of cellular programmed cell death-pyroptosis, apoptosis and necroptosis. We analyzed PANoptosis activity in three common renal cell carcinoma subtypes (Clear cell renal cell carcinoma, Papillary renal cell carcinoma, and Chromophobe renal cell carcinoma) separately and constructed a new PANoptosis immunity index (PANII). In three renal cell carcinomas, we found that PANII was an effective predictor of immunotherapy efficacy in KIRC, KIRP and KICH, and the high PANII group was characterized by high immune infiltration and sensitivity to immunotherapy, while the low PANII group was prone to immune escape and immunotherapy resistance. We performed molecular docking prediction of each core protein comprising PANII and identified natural small molecule compounds with the highest affinity to target proteins. In addition, we found that down-regulation of PYCARD inhibited the proliferation and migration of renal clear cell carcinoma cells by in vitro functional assays, suggesting that PYCARD could be a novel target for renal clear cell carcinoma therapy. Our findings that the PANoptosis characterization-based index (PANII) helps to elucidate the tumor microenvironmental features of three common renal cell carcinoma subtypes and identify patient populations that will benefit from immunotherapy, providing a new tool for the clinical diagnosis and treatment of patients with intermediate- and advanced-stage renal cell carcinoma.

Implications of MTHFD2 expression in renal cell carcinoma aggressiveness.

Renal cell carcinoma (RCC) is the most common type of cancer in kidney and is often diagnosed in advanced stages. Until now, there is no reliable biomarker to assess tumor prognosis during histopathological diagnosis. The Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) overexpression has been suggested as prognostic indicator for RCC, however, its protein profile needs to be clarified. This study investigated the MTHFD2 expression in different RCC cohorts, associating it with tumor characteristics and prognostic factors. Gene expression comparisons between non-neoplastic (NN) and tumor samples, as well as patients' survival analysis, were assessed using KM-Plotter tool. MTHFD2 protein pattern was evaluated in 117 RCC by immunohistochemistry and associations with prognosis, clinical and pathological data were investigated. The tumors exhibited higher MTHFD2 transcript levels than NN, being even higher in the metastatic group. Opposite gene expression patterns were found among clear cell renal cell carcinoma (ccRCC) and pappilary renal cell carcinoma (pRCC) subtypes, showing higher and lower expressions compared to NN samples respectively. Overexpression was associated with shorter overall survival for ccRCC and pRCC subtypes, and shorter recurrence-free survival for pRCC. The immunolabeling profile varied according to tumor subtypes, with lower intensity and expression scores in ccRCC compared to pRCC and to chromophobe renal cell carcinoma (chRCC). MTHFD2 protein expression was associated with larger tumors and higher Fuhrman grades. Although prognostic value of protein immunostaining was not confirmed, patients with higher MTHFD2 tended to have lower survival rates in the pRCC group. The results highlight MTHFD2 different patterns according to RCC histological subtypes, revealing marked variations at both the genetic and protein levels. The mRNA indicated tumor prognosis, and greater expression in the tumor samples. Although MTHFD2 immunolabeling suggests tumor aggressiveness, it needs to be validated in other cohorts as potential prognostic factor.

Metastasis suppressor kisspeptin (KISS1) in serum of patients with renal cell carcinoma

Background. The most important problems in improvement of treatment outcomes in patients with renal cell carcinoma (RCC) are search and validation of molecular markers for its early diagnosis and prognosis. Genes suppressing distant metastasizing but not affecting the primary tumor are called metastasis suppressors. Study of these genes and their products not only improves understanding of the mechanisms of tumor progression, but has practical value for diagnosis, prognosis, and establishment of new molecular targets for antitumor therapy. One of such genes is KISS1 with its product kisspeptin (KISS1) protein.Aim: comparative evaluation of KISS1 concentration in blood serum of practically healthy persons and patients with renal cancer; analysis of correlations between the marker’s level and clinical and morphological characteristics of the disease.Materials and methods. 140 patients with RCC (88 men, 52 women) aged between 29 and 82 years were included in the study. Among them, clear cell RCC was diagnosed in 84 patients, papillary in 38, chromophobe in 18. The control group was comprised of 40 healthy persons of matched age and sex. Pre-treatment KISS1 concentration in blood serum was measured using a direct enzyme immunoassay kit (Kisspeptin 1 – KISS1, Cloud-Clone Corp., USA).Results. Median serum KISS1 concentration in the control group was 51.7 pg/mL which was significantly lower than in the total RCC patient group – 243.6 pg/mL (p &lt;0.0001). ROC analysis of diagnostic value of serum KISS1 level was performed both for the total RCC group and for each of its three histological types. In the total group the sensitivity of the test was 75 %, specificity – 80 % (AUC 0.877; 95 % confidence interval (CI) 0.827–0.927; optimal cut-off level 130.8 pg/mL; р &lt;0.0001). For clear cell RCC, both sensitivity and specificity were 85 % (AUC 0.941; 95 % CI 0.902– 0.979; cut-off 141.8 pg/mL; p &lt;0.0001). In non-clear cell RCC types, sensitivity of this marker was only 58 % while the specificity remained 80 % (for papillary RCC AUC 0.787; 95 % CI 0.684–0.889; cut-off level 135.5 pg/mL; p &lt;0.0001, and for chromophobe RCC AUC 0.774; 95 % CI 0.617–0.929; cut-off level 132.1 pg/mL; p &lt;0.001). KISS1 level increased with disease progression: it is significantly higher at more advanced stages above stage I, and in patients with distant metastases compared to those without metastases. Higher serum KISS1 level is also observed in patients with poorly differentiated high-grade (per Furhman) clear cell RCC and papillary RCC (G3–G4) than in those with well differentiated low-grade (G1–G2) tumors.Conclusion. KISS1 level is significantly increased in patients with RCC compared to healthy controls and is a stagedependent marker of this disease. It has relatively high diagnostic sensitivity and specificity (both 85 %) for the most frequent histological type of RCC – clear cell RCC. Thus, clinical significance of kisspeptin in RCC requires further investigation.

VDRA downregulate β-catenin/Smad3 and DNA damage and repair associated with improved prognosis in ccRCC patients

The clear cell renal cell carcinoma (ccRCC) spotlighted the poorest survival, while chromophobe renal cell carcinoma (chRCC) was associated with the best survival. Earlier studies corroborated vitamin D receptor (VDR) was a promising molecular for improving the prognosis of RCC. In contrast to VDRA, the one of VDR isoforms, VDRB1 (VDR isoform B1) has an N-terminal extension of 50 amino acids and is less ligand-dependent. However, the functional differences between VDRA and VDRB1, and their roles in the prognosis of ccRCC and chRCC, have not been investigated. In the present study, we uncovered that the transcripts related to vitamin D pathway and cellular calcium signaling were effectively decreased in the context of ccRCC, yet failed to exert a comparable effect within chRCC. Specially, minimally levels of VDRA wherein kidneys of patients suffering from ccRCC predict shorter survival time. In addition, the protein expressions for β-catenin/Smad3 pathway and DNA damage and repair pathways were obviously impeded in VDRA-overexpressed ccRCC cells, yet this inhibitory effect was conspicuously absent in enable VDRB1 cells. Our results provide a new idea to improve the prognosis of ccRCC via VDRA upregulation.

Elevated Plasma Concentration of 4-Pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) Highlights Malignancy of Renal Cell Carcinoma.

Nicotinamide (NA) derivatives play crucial roles in various biological processes, such as inflammation, regulation of the cell cycle, and DNA repair. Recently, we proposed that 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR), an unusual derivative of NA, could be classified as an oncometabolite in bladder, breast, and lung cancer. In this study, we investigated the relations between NA metabolism and the progression, recurrence, metastasis, and survival of patients diagnosed with different histological subtypes of renal cell carcinoma (RCC). We identified alterations in plasma NA metabolism, particularly in the clear cell RCC (ccRCC) subtype, compared to papillary RCC, chromophobe RCC, and oncocytoma. Patients with ccRCC also exhibited larger tumor sizes and elevated levels of diagnostic serum biomarkers, such as hsCRP concentration and ALP activity, which were positively correlated with the plasma 4PYR. Notably, 4PYR levels were elevated in advanced stages of ccRCC cancer and were associated with a highly aggressive phenotype of ccRCC. Additionally, elevated concentrations of 4PYR were related to a higher likelihood of mortality, recurrence, and particularly metastasis in ccRCC. These findings are consistent with other studies, suggesting that NA metabolism is accelerated in RCC, leading to abnormal concentrations of 4PYR. This supports the concept of 4PYR as an oncometabolite and a potential prognostic factor in the ccRCC subtype.

Optimized reconstruction of the absorption spectra of kidney tissues from the spectra of tissue components using the least squares method.

With the objective of developing new methods to acquire diagnostic information, the reconstruction of the broadband absorption coefficient spectra (μa [λ]) of healthy and chromophobe renal cell carcinoma kidney tissues was performed. By performing a weighted sum of the absorption spectra of proteins, DNA, oxygenated, and deoxygenated hemoglobin, lipids, water, melanin, and lipofuscin, it was possible to obtain a good match of the experimental μa (λ) of both kidney conditions. The weights used in those reconstructions were estimated using the least squares method, and assuming a total water content of 77% in both kidney tissues, it was possible to calculate the concentrations of the other tissue components. It has been shown that with the development of cancer, the concentrations of proteins, DNA, oxygenated hemoglobin, lipids, and lipofuscin increase, and the concentration of melanin decreases. Future studies based on minimally invasive spectral measurements will allow cancer diagnosis using the proposed approach.

Intratumoral metastasis of sigmoid colon cancer to chromophobe renal cell carcinoma: a case report

We herein report an extremely rare case of intratumoral metastasis of colon cancer to chromophobe renal cell carcinoma. A 71-year-old woman was diagnosed with lung metastasis of sigmoid colon cancer and underwent sigmoid colon resection with D3 lymph node dissection. Preoperative contrast-enhanced computed tomography (CT) revealed a left renal tumor; however, colon resection was prioritized, and the renal tumor was placed under observation. Two years later, CT revealed enlargement of the left renal tumor, and laparoscopic partial left nephrectomy was performed 1 month later. Histopathologic examination showed that the resected renal tumor was a chromophobe renal cell carcinoma with intratumoral metastasis of colon cancer to the renal tumor center, and adjuvant chemotherapy with bevacizumab plus SOX (L-OHP + S-1) was initiated. Because of severe chemotherapy-induced fatigue and nausea, the patient was switched to bevacizumab + S-1. However, the patient’s nausea did not improve after this change, and postoperative adjuvant chemotherapy was discontinued at the patient’s request 4 months after the partial nephrectomy. Two months after discontinuation of chemotherapy, CT showed no renal recurrence; however, increased lung metastases and a new bone metastasis in the left sciatic bone were observed. Palliative treatment was then initiated because of severe adverse events that made it difficult to continue treatment. In patients who have multiple cancers and an increase in renal tumor size, the possibility of intratumoral metastasis to the renal tumor should be considered.

Real world data on treatment of chromophobe renal cell carcinoma.

409 Background: Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma (RCC), accounting for 5%–7% of all RCCs. ChRCCs are generally viewed to have a favorable clinical outcome compared to clear cell RCC, yet up to 10% of patients with ChRCC will develop metastases. To date, there are no genomic biomarkers that predict post-surgical metastatic recurrence, and no standard of care exists for treating metastatic chRCC. We sought to better understand real world patient experiences in this underrepresented and understudied patient population. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure) and was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Those who agreed to participate were surveyed for demographics (age, gender, race, income, country) and clinical characteristics (date of the diagnosis, disease stage, treatment history). Out of 1,062 participants 121 patients self-identified with chRCC, 34 patients had metastatic disease, and 23 patients had received systemic therapy. Results: The majority of patients were from the United States (75%), median age was 49.7 years (range 19-74), 70 percent of patients identified as female, and 30 percent of patients identified as male. Stage distribution at initial diagnosis was stage 1 in 37.3%, 27.3% were stage 2 and stage 3 respectively, 8.3% were metastatic at diagnosis. 14% of patients reported having sarcomatoid dedifferentiation. 20 percent of patients (24) experienced recurrent metastatic disease after a median duration of 3.3 years (range 1-6). Of the 23 patients who received treatment, first line therapy consisted of TKI monotherapy (9), combination IO and TKI (7), combination IO/IO (4), mTOR mono-therapy (1), other therapies (2). Second and later line therapies were combination IO/IO (3), IO and TKI (9), Lenvatinib and everolimus (7), TKI monotherapy (5), mTOR monotherapy (5) and other therapies (5). Median duration of therapy was 43 months (range 2-196). The most used TKIs were cabozantinib and lenvatinib. In the metastatic setting, 4 patients reported being treated as part of a clinical trial, 9 patients reported that no one had ever talked to them about participating in a clinical trial. 6 patients said that no trials were being held at their treating center. Conclusions: Patients reported higher rates of recurrence than what is usually reported in ChRCC, however this could reflect sample bias as patients with more aggressive disease may be more likely to engage with patient communities. No standardized treatment for metastatic disease could be identified. Overall treatment duration was comparable to clear cell carcinoma. Very few patients had access to clinical trials. ChRCC-specific clinical trials and tailored treatment regimens are urgently needed.

Management, outcomes and predictors of recurrence in chromophobe renal cell carcinoma: Results from the Canadian Kidney Cancer information system (CKCis).

Management, outcomes and predictors of recurrence in chromophobe renal cell carcinoma: Results from the Canadian Kidney Cancer information system (CKCis).

Tuberous Sclerosis Complex (TSC) Identified by Genetic Testing After Histologic Diagnosis of Chromophobe Renal Cell Carcinoma

We report the case of a female patient with a histologic diagnosis of chromophobe renal cell carcinoma (ChRCC) after a left laparoscopic radical nephrectomy. Due to the unusual histologic diagnosis, a genetic test was ordered identifying tuberous sclerosis disease.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

The Expression of Alamandine Receptor MrgD in Clear Cell Renal Cell Carcinoma Is Associated with a Worse Prognosis and Unfavorable Response to Antiangiogenic Therapy.

Renal cell carcinoma (RCC) ranks among the most prevalent malignancies in Western countries, marked by its notable heterogeneity, which contributes to an unpredictable clinical trajectory. The insufficiency of dependable biomarkers adds complexity to assessing this tumor progression. Imbalances of several components of the intrarenal renin-angiotensin system (iRAS) significantly impact patient prognoses and responses to first-line immunotherapies. In this study, we analyzed the immunohistochemical expression of the Mas-related G-protein-coupled receptor D (MrgD), which recognizes the novel RAS peptide alamandine (ALA), in a series of 87 clear cell renal cell (CCRCCs), 19 papillary (PRCC), 7 chromophobe (ChRCC) renal cell carcinomas, and 11 renal oncocytomas (RO). MrgD was expressed in all the renal tumor subtypes, with a higher mean staining intensity in the PRCCs, ChRCCs, and ROs. A high expression of MrgD at the tumor center and at the infiltrative front of CCRCC tissues was significantly associated with a high histological grade, large tumor diameter, local invasion, and locoregional node and distant metastasis. Patients with worse 5-year cancer-specific survival and a poorer response to antiangiogenic tyrosine-kinase inhibitors (TKIs) showed higher MrgD expression at the center of their primary tumors. These findings suggest a possible role of MrgD in renal carcinogenetic processes. Further studies are necessary to unveil its potential as a novel biomarker for CCRCC prognosis and response to frontline therapies.

Metabolic alterations in hereditary and sporadic renal cell carcinoma.

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites - fumarate and succinate - that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.