Understanding m6A changes in chromophobe renal cell carcinoma and predicting patient outcomes survival.

N6-methyladenosine (m6A) is a prevalent mRNA modification known for its implications in various cancer types, yet its role in chromophobe renal cell carcinoma (chRCC) remains largely unexplored. In this study, we performed m6A-SEAL-seq and RNA-seq analyses on tissues from three chRCC subjects, aiming to uncover m6A alterations in chRCC. Our findings revealed reduced expression levels of four m6A regulators in chRCC tissues and highlighted differences in m6A levels compared to normal tissues. Furthermore, we identified specific genes and cancer-related pathways affected by these differences, including notable candidates like NOTCH1 and FGFR1, implicated in chRCC development. Additionally, we developed a predictive model based on the expression level of m6A associated genes, demonstrating promising prognostic capabilities for patient survival prediction. Overall, our study provides valuable insights into the role of m6A in chRCC and its potential as a prognostic indicator.

Chromophobe Renal Cell Carcinoma with Sarcomatoid Differentiation (osteosarcomatous and chondrosarcomatous differentiation)-A Case Report and Comprehensive Review.

Chromophobe renal cell carcinomas (ChRCCs) have a good prognosis and comprise approximately 5-7% of renal cell carcinomas (RCCs). The sarcomatoid differentiation in RCC is found in around 5-10% of cases; however, in ChRCC, it is much less than in other RCCs and poorly responds to chemotherapeutic agents. A study by de Peralta-Venturina et al. found 9% sarcomatoid differentiation in chromophobe RCC. We present the case of a 58-year-old female with a left abdominal mass diagnosed as ChRCC with the existence of sarcomatous differentiation including osteosarcomatous and chondrosarcomatous, which are of adverse prognosis. Osteosarcoma-like divergent differentiation in RCC is extremely rare, with limited documented cases. It should be carefully considered in evaluating and managing renal masses due to its potential impact on clinical outcomes.

Stage IA papillary and chromophobe renal cell carcinoma: effectiveness of cryoablation and partial nephrectomy.

OBJECTIVES: To evaluate the effectiveness of cryoablation compared to partial nephrectomy in patients with stage IA papillary and chromophobe renal cell carcinoma (pRCC; chRCC). MATERIAL AND METHODS: The 2004-2016 National Cancer Database was queried for adult patients with stage IA pRCC or chRCC treated with cryoablation or partial nephrectomy. Patients receiving systemic therapy or radiotherapy, as well as those with bilateral RCC or prior malignant disease were excluded. Overall survival (OS) was assessed using Kaplan-Meier plots and Cox proportional hazard regression models. Nearest neighbor propensity matching (1:1 cryoablation:partial nephrectomy, stratified for pRCC and chRCC) was used to account for potential confounders. RESULTS: A total of 11122 stage IA renal cell carcinoma patients were included (pRCC 8030; chRCC 3092). Cryoablation was performed in 607 (5.5%) patients, and partial nephrectomy in 10515 (94.5%) patients. A higher likelihood of cryoablation treatment was observed in older patients with non-private healthcare insurance, as well as in those with smaller diameter low-grade pRCC treated at non-academic centers in specific US geographic regions. After propensity score matching to account for confounders, there was no statistically significant difference in OS comparing cryoablation vs partial nephrectomy in patients with pRCC (HR = 1.3, 95% CI: 0.96-1.75, p = 0.09) and those with chRCC (HR = 1.38, 95% CI: 0.67-2.82, p = 0.38). CONCLUSION: After accounting for confounders, cryoablation, and partial nephrectomy demonstrated comparable OS in patients with stage IA papillary and chromophobe RCC. Cryoablation is a reasonable treatment alternative to partial nephrectomy for these histological RCC subtypes when radiologically suspected or diagnosed after biopsy. CRITICAL RELEVANCE STATEMENT: Cryoablation might be considered as an upfront treatment alternative to partial nephrectomy in patients with papillary and chromophobe stage IA renal cell carcinoma, as both treatment approaches yield comparable oncological outcomes. KEY POINTS: The utilization of cryoablation for stage IA papillary and chromophobe RCC increases. In the National Cancer Database, we found specific patterns of use of cryoablation. Cryoablation and partial nephrectomy demonstrate comparable outcomes after accounting for confounders.

Asymptomatic ureteral metastasis of chromophobe renal cell carcinoma after radical nephrectomy: A case report and review of literature.

INTRODUCTION: Standard treatment for renal cell carcinomas (RCCs) is radical/partial nephrectomy and unlike upper urothelial carcinoma, complete ureteral removal is not necessary nor is advised in RCCs as tumor recurrence in ureteral remnant has scarcely been reported. Here, we present a rare case of chromophobe RCC (ChRCC) metastasis in remnant ureter following radical nephrectomy and perform a literature review in this regard. CASE PRESENTATION: A 66-year-old man presented with a CT scan-as a surveillance protocol imaging- showing a mass in ipsilateral remnant ureter 9 months after radical nephrectomy due to ChRCC while being completely asymptomatic. Cystoscopy revealed a polypoid mass protruding from right ureterovesical junction and transurethral resection of tumor revealed it to be a ChRCC. Distal ureterectomy was performed confirming pathology without any lymph node involvement. 12 months after ureterectomy, he remained asymptomatic with no sign of metastasis or recurrence in his follow up CT scan. DISCUSSION: RCC metastasis to distal ureter after radical nephrectomy has been rarely reported and only 2 cases of them were ChRCC. Gross hematuria has been the main presentation of such disease. However, our case was completely asymptomatic, highlighting necessity of surveillance imaging. No specific treatment guideline exists for such presentation but tumor resection has been the most common treatment modality. CONCLUSION: Metachronous RCC metastasis may occur in remnant ureter which can be completely asymptomatic, highlighting necessity of surveillance imaging and reviewing them meticulously. Surgical resection of the metastasis by distal ureterectomy seems to be the best treatment option.

Grading Challenges and Prognostic Insights in Chromophobe Renal Cell Carcinoma: A Retrospective Study of 72 Patients.

Chromophobe RCC (ChRCC) carries the best prognosis among all RCC subtypes, yet it lacks a proper grading system. Various systems have been suggested in the past, causing much controversy, and Avulova et al. recently proposed a promising four-tier grading system that takes into consideration tumor necrosis. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway plays a key role in ChRCC pathogenesis, highlighting its molecular complexity. The present retrospective study aimed to evaluate the prognostic factors associated with a more aggressive ChRCC phenotype. Materials and Methods: Seventy-two patients diagnosed with ChRCC between 2004 and 2017 were included in our study. Pathology reports and tissue blocks were reviewed, and immunohistochemistry (IHC) was performed in order to assess the expressions of CYLD (tumor-suppressor gene) and mTOR, among other markers. Univariate analysis was performed, and OS was assessed using the Kaplan-Meier method. Results: In our study, 74% of patients were male, with a mean age of 60 years, and the mean tumor size was 63 mm (±44). The majority (54%) were followed for more than 10 years at intervals ranging between 44 and 222 months. The risk of death was significantly higher for patients that were classified as Grade 4 in the Avulova system (HR: 5.83; 95% CI, 1.37-24.7; p: = 0.017). As far as the IHC is concerned, mTOR expression was associated with an HR of 8.57 (95% CI, 1.91-38.5; p = 0.005), and CYLD expression was associated with an HR of 17.3 (95% CI, 1.57-192; p = 0.02). Conclusions: In our study, the Avulova grading system seems to be positively correlated with OS in patients diagnosed with ChRCC. Furthermore, an elevated mTOR expression also shows a negative correlation with OS, whereas an elevated CYLD expression does not seem to exert a protective role. However, because only a small proportion (4.2%) of our patients died due to ChRCC, despite the long follow-up period, the results must be interpreted with caution. Further research is needed to validate our findings.

Detection of two synchronous histologically different renal cell carcinoma subtypes in the same kidney: a case report and review of the literature.

INTRODUCTION: Renal cell carcinoma (RCC) is the dominant primary renal malignant neoplasm, encompassing a significant portion of renal tumors. The presence of synchronous yet histologically distinct ipsilateral RCCs, however, is an exceptionally uncommon phenomenon that is rather under-described in the literature regarding etiology, diagnosis, management, and later outcomes during follow-up. CASE PRESENTATION: We aim to present the 9th case of a combination chromophobe RCC (ChRCC) and clear cell RCC (ccRCC) in literature, according to our knowledge, for a 69-year-old North African, Caucasian female patient who, after complaining of loin pain and hematuria, was found to have two right renal masses with preoperative computed tomography (CT) and underwent right radical nephrectomy. Pathological examination later revealed the two renal masses to be of different histologic subtypes. CONCLUSION: The coexistence of dissimilar RCC subtypes can contribute to diverse prognostic implications. Further research should focus on enhancing the complex, yet highly crucial, preoperative detection and pathological examination to differentiate multiple renal lesions. Planning optimal operative techniques (radical or partial nephrectomy), selecting suitable adjuvant regimens, and reporting long-term follow-up outcomes of patients in whom synchronous yet different RCC subtypes were detected are of utmost importance.

Radical nephrectomy for a giant chromophobe renal cell carcinoma diagnosed > 17 years previously: a case report and literature review.

Early diagnosis of renal cell carcinoma relies on imaging tests such as ultrasound, computed tomography, or magnetic resonance imaging. Since surgery is associated with a favorable prognosis, the standard treatment for clinically limited renal cell carcinoma remains surgical resection. Among asymptomatic patients with localized renal cell carcinoma, a small number refuse surgical treatment and survive. We report a case involving a 59-year-old female who underwent a difficult radical nephrectomy 17 years after being diagnosed with malignant tumors due to primary renal cell carcinoma.

Comparison of conventional diffusion-weighted imaging and intravoxel incoherent motion in differentiating between chromophobe renal cell carcinoma and renal oncocytoma: a preliminary study.

OBJECTIVE: Quantitative comparison of the diagnostic efficacy of conventional diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM) in differentiating between chromophobe renal cell carcinoma (ChRCC) from renal oncocytoma (RO). METHODS: A total of 48 patients with renal tumours who had undergone DWI and IVIM were divided into two groups-ChRCC (n = 28) and RO (n = 20) groups, and the apparent diffusion coefficient (ADC), true diffusivity (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and their diagnostic efficacy were compared between the two groups. RESULTS: The D* values were higher in the ChRCCs group compared to the RO groups (0.019 ± 0.003 mm2/s vs 0.008 ± 0.002 mm2/s, P < .05). Moreover, the ADC, D and f values were higher in ROs compared to ChRCCs (0.61 ± 0.08 × 10-3 mm2/s vs 0.51 ± 0.06 × 10-3 mm2/s, 1.02 ± 0.15 × 10-3 mm2/s vs 0.86 ± 0.07 × 10-3 mm2/s, 0.41 ± 0.05 vs 0.28 ± 0.02, P < .05). The areas of the ADC, D, D* and f values under the ROC curves in differentiating ChRCCs from ROs were 0.713, 0.839, 0.856 and 0.906, respectively. The cut-off values of ADC, D, D* and f were 0.54, 0.91, 0.013 and 0.31, respectively. The AUC, sensitivity, specificity and accuracy of the f values were 0.906, 89.3%, 80.0% and 89.6%, respectively. For pairwise comparisons of ROC curves and diagnostic efficacy, IVIM parameters, that is, D, D* and f offered better diagnostic accuracy than ADC in differentiating ChRCCs from ROs (P = .013, .016, and .008) with f having the highest diagnostic accuracy. CONCLUSION: IVIM parameters presented better performance than ADC in differentiating ChRCCs from ROs. ADVANCES IN KNOWLEDGE: (1) D* values of ChRCCs were higher, while ADC, D and f values were lower than those of RO tumours. (2) f values had the highest diagnostic efficacy in differentiating ChRCC from RO. (3) IVIM parameters, that is, D, D* and f offered better diagnostic accuracy than ADC in differentiating ChRCC from RO (P=.013, .016, and .008).

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.

A case-report of chromophobe renal cell carcinoma with renal subcapsular hematoma.

INTRODUCTION AND IMPORTANCE: Chromophobe renal cell carcinoma (CHRCC) is a rare subtype of renal cancer, accompanied by subcapsular renal hematoma (SRH) without a history of traumatic or hemorrhagic disease, which is clinically rare. The reason for CHRCC with SRH may be caused by tumor rupture or vascular rupture. In the early stage, it is often asymptomatic and can be easily overlooked and misdiagnosed, leading to delayed treatment and serious consequences. CASE PRESENTATION: A 39-year-old female patient was admitted to the emergency department due to sudden dull pain and discomfort in the lower back. Subsequent ultrasound, CT, and MRI imaging examinations revealed the presence of chromophobe renal cell carcinoma with a volume of 4.5 × 3.5 × 3 cm in the middle and lower pole of the right kidney. In addition, a subcapsular hematoma with an area of approximately 6 × 11 cm was also found. The patient underwent laparoscopic radical nephrectomy. CLINICAL DISCUSSION: Due to its atypical syptmoms and signs, it is often overlooked or misdiagnosed. CHRCC has unique histological features, which distinguish it from other subtypes of renal cell carcinoma. Imaging studies such as CT scan and MRI are helpful in diagnosing and identifying associated complications. In this case, the presence of the perirenal hematoma is a notable finding, which may be caused by tumor-induced vascular disruption. CONCLUSION: This report underscores the importance of recognizing and managing complications associated with CHRCC. Early diagnosis and appropriate surgical treatment are crucial for favorable outcomes in these cases.

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.

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 morphologic features and is associated with a poor prognosis. Although there are limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade, nonsarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, nonsarcomatoid 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-grade 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, although PTEN and TP53 alterations were found in both high-grade 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 Cancer Genome Atlas cohort where 2 of 66 cases contained RB1 mutations and demonstrated unequivocal high-grade, nonsarcomatoid 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, nonsarcomatoid 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.

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.

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.

Sintilimab combined with axitinib in the treatment of advanced chromophobe renal cell carcinoma: a case report.

Chromophobe renal cell carcinoma (ChRCC) is a rare pathological type of renal cell carcinoma (RCC). Related systematic studies involving large numbers of patients are lacking, and more importantly, there is currently no international consensus on post-line treatment guidelines for ChRCC. The rapid development of systemic treatment with molecular targeted therapies and immune checkpoint inhibitors has brought effective approaches for patients with clear cell renal cell carcinoma (ccRCC), while progress in the treatment of ChRCC is still limited. In this case report, the patient was initially diagnosed at the early stage; 4 years post-surgery, she developed lung metastases and the disease progressed once again after being treated with sunitinib monotherapy for 3 years. However, after combining the immunotherapy sintilimab with the targeted therapy axitinib as second-line treatment, imageological examination showed lesions in the lungs that gradually decreased, and the bone metastases remained stable. To date, the patient has been continuously treated for over 2 years and is still undergoing regular treatment and follow-up. This case is the first to report the long-term survival of metastatic disease by using this treatment regimen and to propose a potential therapeutic option for patients with metastatic ChRCC. Since only one case was observed in this report, further study is needed.

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

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

Low grade oncocytic renal tumor (LOT): Clinicopathological characterization of 13 cases.

CONTEXT: Low grade oncocytic tumor (LOT) is a recently recognized renal oncocytic neoplasm with unique morphologic and immunohistochemical pattern (CK7 +, CD117 -) that differentiates them from oncocytoma and chromophobe renal cell carcinoma (ChrRCC). OBJECTIVE: To further evaluate the histomorphological characteristics as well as the clinical outcome of low grade oncocytic tumors, retrospectively. DESIGN: Thirteen cases of LOT were identified from 463 cases of renal oncocytic neoplasm in our pathology archive. All tumors were immunostained with CK7, CD117 and other relevant markers. The pathohistological features and follow up data of these cases were recorded. RESULTS: Median age of patients was 76 years old (range from 36 to 86), with male to female ratio of 2:11. None of the patients had a syndromic association/hereditary condition. Eleven tumors were unifocal in each affected kidney, and two were multifocal with 2 and 3 separated tumors, respectively. On microscopic examination, tumors show variety of growth patterns, namely solid, compact nested, focal tubular/tubuloreticular and trabecular patterns. The stroma can be hypocellular and edematous where the tumor cells are loosely arranged exhibiting cords and scattered single cell arrangement. Immunohistochemically, all thirteen cases displayed strong and diffuse CK7 positivity in tumor cells. Eleven cases were CD117 negative and the other two showed focal and weak CD117 positivity (< 5% of tumor cells). Uniform tumor cell positivity was found for AE1/3, EMA, PAX8, and e-cadherin. Negative staining results include CAIX, AMACR, CD10 and vimentin. All cases in our cohort demonstrate indolent behavior and show no evidence of disease recurrence, progression, or metastases during the follow-up period up to 96 months. CONCLUSION: LOT is an emerging new entity of renal oncocytic neoplasm and demonstrates indolent clinical behavior. Its unique morphologic features and immunohistochemical patterns (CK7 +, CD117 -) set them apart from oncocytoma and ChrRCC.

Genetic Profiling Uncovers Genome-Wide Loss of Heterozygosity and Provides Insight into Mechanisms of Sarcomatoid Transformation in Chromophobe Renal Cell Carcinoma.

Sarcomatoid transformation occurs in ∼8% of chromophobe renal cell carcinoma (chRCC) and is associated with aggressive clinical behavior. In recent years, several studies have identified genomic, transcriptomic, and epigenomic correlates of aggressive behavior in chRCC; however, the molecular mechanisms associated with sarcomatoid transformation remain incompletely understood. In this study, we analyzed paired conventional and sarcomatoid histologic components of individual chRCC to elucidate the genomic alterations that underlie sarcomatoid transformation in this tumor type. Massively parallel sequencing was performed on paired (conventional and sarcomatoid) components from 8 chRCCs. All cases harbored TP53 variants (87.5% showing TP53 variants in both components and 12.5% only in the sarcomatoid component). Intratumor comparisons revealed that TP53 variants were concordant in 71% and discordant in 29% of cases. Additional recurrent single-nucleotide variants were found in RB1 (37.5% of cases) and PTEN (25% of cases), with the remaining single-nucleotide variants detected in these tumors (PBRM1, NF1, and ASXL1) being nonrecurrent. Copy number variant analysis showed the characteristic pattern of chromosomal losses associated with chRCC (1, 2, 6, 10, 13, 17, and 21) in the conventional histologic components only. Interestingly, the sarcomatoid components of these tumors demonstrated widespread loss of heterozygosity but lacked the above chromosomal losses, likely as a consequence of whole-genome duplication/imbalanced chromosomal duplication events. Overall, the findings suggest that TP53 variants followed by whole-genome duplication/imbalanced chromosomal duplication events underlie sarcomatoid transformation in chRCC.

Chromophobe Renal Cell Carcinoma with Sarcomatoid Differentiation: Clinicopathologic Correlation and Molecular Findings.

Introduction: Sarcomatoid differentiation has been reported in approximately 8% of chromophobe renal cell carcinoma (RCC) and is associated with a worse prognosis. We aim to describe the clinicopathologic and molecular findings of chromophobe RCC with sarcomatoid differentiation. Methods: Surgical pathology database was searched to identify chromophobe RCC with sarcomatoid differentiation from January 2015 to December 2021. Results: Five patients were diagnosed with chromophobe RCC with sarcomatoid differentiation. The median age at the time of diagnosis was 57 years (range 51-61 years). Three patients died after median follow-up of 12.1 months (range 1.6-18.2 months). The median tumor size was 10.7 cm (range 5.6-13.6 cm). The median percentage of sarcomatoid component was 60% (range 10-90%), and the median percentage of necrosis was 30% (range 10-50%). One tumor demonstrated osteoid formation. PAX8, keratin 7, KIT (CD117), and Hale colloidal iron were positive in the epithelial component, whereas the sarcomatoid component was positive for vimentin, CD10, and high Ki67 proliferative index. Molecular testing was performed in three specimens: all were TP53 mutated and microsatellite stable. One aggressive tumor had RB1 frameshift mutation and copy number gains for TERT and CUL4A. Conclusion: Chromophobe RCC with sarcomatoid differentiation is a rare entity with aggressive behavior. Percentage of sarcomatoid component, necrosis, and the occurrence of metastasis is associated with worse prognosis. Molecular profiling reveals frequent TP53 mutation. While TERT promoter mutation has no prognostic implication, FLCN inactivation may be associated with a less aggressive course. The clinical significance of RB1 loss is unclear.