Management of Renal Cell Carcinoma of Variant Histology.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma are rare aggressive neoplasms of putative distal nephron origin. First described in 1949, case reports and review articles constitute a major source of information on collecting duct carcinoma, whereas Davis and colleagues and the pediatric tumor registry have contributed the seminal works on renal medullary carcinoma. Here we present a detailed study of collecting duct carcinoma (n=39) and renal medullary carcinoma (n=13), characterizing these rare neoplasms and analyzing their interrelationship. Both collecting duct carcinoma and renal medullary carcinoma exhibited significant similarities, such as predilection for the right kidney, tumor mass with an epicenter in the renal medulla, and a mean size of 7 cm. Overall, both tumors exhibited a poorly differentiated adenocarcinoma histology with desmoplastic stromal response (100%), inflammatory infiltrate (100%), frequent perinephric extension (collecting duct carcinoma: 97%; renal medullary carcinoma: 83%), lymphovascular invasion (100%), intraluminal mucin (collecting duct carcinoma: 42%; renal medullary carcinoma: 73%), high nuclear grade (97%), overlapping immunoreactivity for Ulex europaeus agglutinin 1 (collecting duct carcinoma: 75%; renal medullary carcinoma:55%), CK7 (collecting duct carcinoma: 44%; renal medullary carcinoma: 71%), and high-molecular weight cytokeratin (collecting duct carcinoma: 26%; renal medullary carcinoma: 29%), and nonimmunoreactivity for Ksp-cadherin. Histologically, collecting duct carcinoma frequently had tubular, tubulopapillary, or irregular glandular architecture, whereas renal medullary carcinoma commonly demonstrated islands of anastomosing tubules and cords forming irregular microcystic spaces. Multiple metastases to the lymph nodes, lung, bone, and liver were observed in both categories at presentation (collecting duct carcinoma: 17%; renal medullary carcinoma: 36%). Only patients with organ-confined small tumors were disease free beyond the median survival time. Differential clinical features between collecting duct carcinoma and renal medullary carcinoma included proclivity for younger male individuals of African ancestry with hemoglobin abnormalities and a shorter median survival of 17 weeks (vs. 44 wk for collecting duct carcinoma) for renal medullary carcinoma. The markedly overlapping clinical features, histology, immunophenotype, metastasis patterns, and uniformly aggressive outcome in collecting duct and renal medullary carcinomas suggest that renal medullary carcinoma is a distinctive clinicopathologic subtype within the entity of collecting duct carcinoma. The extremely poor prognosis and ongoing clinical trials with specific therapeutic protocols argue for their accurate distinction from other renal cell carcinoma subtypes.

699 Background: AcSe Nivolumab (N), is a non-randomised, open-label, multicentric study to investigate the efficacy and safety of nivolumab monotherapy in patients (pts) with specific rare cancers (NCT03012581). We report on the non-clear cell renal cell carcinoma (RCC) cohort. Methods: Primary endpoint was objective response rate (ORR) at 12 weeks according to RECIST1.1. All pts receives N at 240mg IV every 2 weeks. Secondary endpoints included progression free survival (PFS), overall survival (OS), best response, and safety. Results: Between 07/2017 and 02/2019, 50 pts have been enrolled across 13 institutions. Median age was 61.4 years old, 70% were male. ECOG PS was 0, 1, 2, in 29%, 63% and 8% of pts respectively. Histological types were papillary (pRCC) type 2 (41%), chromophobe (18%), pRCC type I (10%), pRCC unclassified (8%), collecting duct carcinoma (CDC) (8%), and others (including predominant sarcomatoid, renal medullary carcinoma, MITF associated RCC, unclassified RCC). N was used in first line in 16%, second line in 54% and third line or beyond in 30%. IMDC risk group was 14%, 70% and 16% for good, intermediate and poor risk respectively. With a median follow up of 10.4 months (mo), 42 pts had discontinued N. The 12 weeks-ORR was 6% (3 PR), with stable disease in 49% and PD in 44% of pts. The best ORR was 10%. Median PFS was 3.9 mo (IC95% [2.9; 8.3]). At time of analysis, 25 pts (50%) had died and 12-months OS rate was 47.7% (IC95% [33.5; 67.8]). Overall, 31 pts (62%) have presented at least one grade ≥ 3 AE. No new safety signal with N was reported. 12 weeks-ORR and best ORR according to distinct histology are presented in table 1. Pts with PR were 1pRCC type 2, 1pRCC type 1, 1 CDC, 1 MITF RCC and 1 unclassified. Conclusions: We report the first prospective study of N single agent in non-clear cell RCC. N demonstrates limited activity in a pretreated and heterogeneous non- clear cell RCC population. Interestingly 1/4 CDC developed PR while no response was noted in chromophobe RCC. Clinical trial information: NCT03012581. [Table: see text]

BACKGROUND: Metastatic and unresectable non-clear cell renal cell carcinoma comprises more than a quarter of kidney cancers but does not have standardized treatment. Non-clear renal carcinoma consists of a variety of diverse histologic subtypes, including papillary, chromophobe, collecting duct, translocation, and medullary histologies, many of which carry a poor prognosis. Many prospective clinical trials exclude these kidney cancers, and for most clinical trials of non-clear cell renal cell carcinoma, only a small number of patients are enrolled. OBJECTIVE: To perform a systematic review of recently published and currently enrolling prospective clinical trials for advanced non-clear cell renal cell carcinoma. METHODS: A systematic search of Pubmed and MEDLINE (Ovid) was conducted as per PRISMA guidelines to identify recent prospective clinical trials in non-clear cell renal cell carcinoma. To ensure a thorough search, terms not only included non-clear cell renal carcinoma but also molecular subtypes. A review of currently enrolling clinical trials was conducted on Clinicaltrials.gov and the EU Clinical Trials Register as well. RESULTS: A total of 33 prospective clinical trials with published results and 10 currently enrolling clinicals trials were identified. About half (48.5%) of these studies were reported in 2020 or 2021, and 36.4% were in the first-line setting. Treatments investigated in these trials included mTOR inhibitors, VEGF- and MET-targeted tyrosine kinase inhibitors, immune checkpoint inhibitors, and combinatorial strategies. Outcomes from these data revealed a wide range of response rate and progression free survival, favoring TKIs and immune checkpoint inhibitors -based combination regimens. CONCLUSIONS: Novel targeted therapies and immunotherapies have changed the landscape of treatment for advanced non-clear cell renal cell carcinoma. Combination regimens may provide even further clinical benefit and warrant further investigation in larger, randomized prospective clinical trials.

Simple SummaryCollecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare cancers with a very poor prognosis. Currently, first-line treatment is a platinum-based doublet, but very few studies have evaluated the effectiveness of treatments for subsequent lines. Additionally, despite the advent of new therapies in renal clear cell carcinoma, data are lacking on these types of cancers. Thus, we conducted a retrospective study in 11 centers in France to evaluate the different types and effectiveness of treatments received beyond first-line treatment in patients with metastatic CDC or RMC. Subsequent treatments showed limited efficacy regardless of the type of therapy received. This study supports the importance of finding therapeutic targets and/or biomarkers to improve patient outcomes.Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

640 Background: Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) represent rare tumors that arise in the renal medulla are therapy resistant tumors that progress rapidly. Methods: DNA was extracted from 40 microns of FFPE specimen from refractory CDC (46 cases) and RMC (24 cases). CGPwas performed using a hybrid-capture, adaptor ligation based next generation sequencing assayto a mean coverage depth of > 800X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. Microsatellite instability status (MSI) was determined on 114 loci. Results: All CDC patients were older and more frequently male (Table). Sickle cell trait was identified in both CDC and RMC, but far more frequently associated with RMC. All (100%) of CDC and RMC were clinically advanced Stage III and IV tumors with the primary tumor used for CGP in 70% of cases and a metastasis biopsy was sequenced in 30%. All (100%) CDC and RMC were intermediate (Grade 3) or high grade (Grade 4). In both tumor types, the GA/tumor was relatively low and there were no (0%) VHL GA. SMARCB1 GA were significantly more frequent in RMC than CDC but common in both tumors. Targeted therapies for kinase ( EGFR, RET) and MTOR ( NF2, TSC2) pathways were more frequent in CDC than RMC. At 1.8 mut/Mb, the median TMB was low for both tumor types with no (0%) of cases showing≥20 mut/Mb. No (0%) of the CDC or RMC cases featured MSI-high status. Conclusions: In addition to their histologic differences, the frequencies and types of GA seen in CDC differ significantly from that seen in RMC. The opportunities for biomarker driven targeted therapies for bothCDCand RMC appear limited with rare opportunities to target GA in TKGFR and MTOR pathways for CDC. Similarly, the relatively low TMB and absence of MSI-High status in CDC and RMCalso predicts that these tumors may be resistant to immunotherapies.[Table: see text]

Kidney Cancers in Adolescents & Young Adults

Purpose: Collecting duct carcinoma (CDC) is a rare and aggressive subtype of renal carcinoma, posing significant challenges in diagnosis and treatment. Current treatment relies on platinum-based chemotherapy, yet clinical outcomes remain poor. While targeted therapies and immune checkpoint inhibitors (ICIs) show promise in clear-cell renal cell carcinoma (ccRCC), they have not been evaluated in CDC, and their efficacy remains speculative. This underscores a pressing need for personalized treatment approaches, driven by an in-depth molecular understanding of the disease. Experimental Design: We conducted a comprehensive molecular characterization of 22 CDC cases using whole-exome sequencing, RNA-seq, and DNA methylation profiling. Renal medullary carcinoma, ccRCC, type 2 papillary RCC, and chromophobe RCC were included as comparators. To verify mutations of interest, we retrieved 25 CDC samples from GENIE (v15.0). We also assessed the association of genomic alterations with response to ICIs using data from the BIONIKK trial (NCT02960906) and the published CheckMate (-009, -010, -025) trials. Results: We identified frequent mutations in NF2 (20%), LZTR1 (20%), and SMARCB1 (10%), all located on chromosome 22q, along with 22q copy number loss (52%). Mutations in NF2, SAV1, and WWC1—key components of the Hippo signaling pathway—were observed, implicating its disruption (33%) and leading to overexpression of the YAP signature. Notably, a mutually exclusive pattern between DNA damage-related (DDR) mutations (33%) and 22q loss was observed. Transcriptomic analysis highlighted a cell cycle and immune cell enrichment signature in CDC, distinct from other RCC comparators. TME deconvolution revealed two CDC phenotypes tightly associated with genomic alterations. The immune-hot CDC was characterized by enrichment of CD8 T cells, B cells, and tertiary lymphoid structure signatures, and was enriched in DDR mutations. In contrast, the immune-cold CDC was marked by 22q loss and overexpression of the YAP signature. Furthermore, post-hoc analyses using BIONIKK and CheckMate data demonstrated that combining 22q loss and DDR mutations improves the precision of ICI response predictions. We also found a correlation between 22q loss and a CpG Island Methylator Phenotype (CIMP) pattern in CDC, which resembles the aggressive, immune-evasive CIMP subgroup observed in type 2 papillary RCC. Conclusions: Our comprehensive characterization broadens the molecular understanding of CDC, revealing actionable vulnerabilities such as DDR mutations for immunotherapy and YAP activation for targeted interventions. These findings redefine CDC’s therapeutic possibilities, offering a roadmap for precision oncology in this rare malignancy. Citation Format: Xiaofan Lu, Wenxuan Cheng, Nassim Tawanaie Pour Sedehi, Li Xu, Xiaoping Su, Roger Mouawad, Nizar M. Tannir, Gabriel G. Malouf. Comprehensive molecular characterization reveals hallmarks and therapeutic insights of collecting duct carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1123.

Collecting duct carcinoma (CDC) and related tumors [ie, renal medullary carcinoma (RMC)] are rare types of highly aggressive renal cell carcinomas (RCC) with poor prognosis. Because of the rarity and diagnostic uncertainty of them, their molecular pathology and significance have not yet been fully elucidated. CDC, RMC, fumarate hydratase-deficient RCC (including hereditary leiomyomatosis and RCC-associated RCC HLRCC-RCC), and recently reported anaplastic lymphoma kinase (ALK)-rearrangement RCC have significant morphologic overlaps, but they are separately distinct entities having different molecular pathway and clinical settings. CDC is more likely to occur in middle to old age population with immunoreactivity for PAX8 and integrase interactor-1 proteins (INI-1). Various chromosomal and genomic alterations have been reported with inconsistent results. In contrast, RMC is more likely to occur in younger patients with sickle cell trait. In RMC, loss of INI-1 expression and OCT3/4 expression are distinguished compared with other RCCs. Finally, ALK-rearrangement RCC seems to have 2 different clinical settings, one with sickle cell trait (VCL-ALK fusion) and the other without (other fusions such as TPM3-ALK, EML4-ALK, and STRN-ALK fusions). Interestingly, VCL-ALK fusion was found in pediatric patients with sickle cell trait, whereas other fusions were detected in adolescent or adult without sickle cell trait. Taken together, CDC and related tumors such as RMC, fumarate hydratase-deficient RCC (including hereditary leiomyomatosis and RCC-associated RCC), and ALK-rearrangement RCC are the distinct entities and their recognition is important for the development of future personalized therapeutic options. This review updates the clinicopathologic features of these tumors with overlapping morphology and outcome.

To investigate whether iodine content can discriminate between benign or malignant renal tumors, malign tumor subtypes, low-grade and high-grade tumors on rapid kv-switching dual-energy CT (rsDECT). This prospective study enrolled 95 patients with renal tumors who underwent rsDECT for tumor characterization between 2016 and 2018. Attenuation on true and virtual unenhanced images, absolute enhancement and enhancement ratio and iodine content of each lesion on nephrographic phase iodine density images were measured. Histopathological diagnosis was obtained following either surgery or core biopsy. Eighty-five tumors were renal cell carcinoma (RCC) (56 clear cell, 20 papillary, 9 chromophobe) and 10 were benign (6 angiomyolipoma,4 oncocytoma). 46 tumors were low-grade and 23 high-grade. There was significant difference between iodine content of clear cell and non-clear cell (papillary + chromophobe) RCC (p < 0.001). However, no significant iodine content differences were found between papillary and chromophobe RCC, benign and malignant tumors, low-grade and high-grade tumors. The best cut-off iodine content for differentiating clear cell from non-clear cell RCC was 3.2mg/ml and clear cell from papillary RCC was 2.9mg/ml with a high sensitivity and specificity. Also, significant difference was found between attenuation values of true and virtual unenhanced images (p = 0.007). Mean iodine content, absolute enhancement and enhancement ratio were highly correlated. rsDECT contributes to renal tumor characterization by showing higher iodine content in clear cell RCCs compared with non-clear cell RCCs.

BACKGROUND To investigate recurrence rates in patients with T1 renal cell carcinoma (RCC) undergone partial nephrectomy (PN), radiofrequency ablation (RFA) or cryoablation (Cryo). METHODS We retrospectively evaluated data from 665 (81.4%), 68 (8.3%) and 83 (10.3%) patients who underwent PN, RFA and Cryo, respectively. Kaplan-Meier curves depict recurrence-free survival (RFS) rates in the overall population and after stratifying according to tumor's histology (namely, clear cell RCC and non-clear RCC) and size (namely < 2 cm and 2-4 cm). Multivariable Cox regression model was used to identify predictors of recurrence. Cumulative-incidence plots evaluated disease recurrence and other causes of mortality (OCM). RESULTS Patients referred to PN experienced higher RFS rate compared to those treated with RFA and Cryo at 60-month in the overall population (96.4% vs. 79.4 % vs. 87.8%), in patients with clear cell RCC (93.3% vs 75% vs. 80.4%) and in those with tumor of 2-4 cm (97.3% vs 78% and 84.4%; all p≤0.01). In patients with non-clear cell RCC and with tumor <2cm, PN showed higher RFS rate at 60-month as compared to RFA (97.9% vs 84.4% and 95.1% vs 78.1%, respectively; all p≤0.02). At multi-variate analysis, ablative techniques (RFA [HR=4.03] and Cryo [HR=3.86]) were independent predictors of recurrence (all p<0.03). At competing risks analysis, recurrence rate and OCM were 7.3% and 1.3% vs 25% and 7.2% vs 19.9% and 19.9% for PN, RFA and Cryo, respectively. CONCLUSIONS PN and Cryo showed similar RFS rates in patients with non-clear cell RCC and with renal mass < 2cm.

Advances in non-clear cell renal cell carcinoma (RCC) have lagged behind clear cell RCC due to the heterogeneity and relative rarity of the disease. However, more advanced molecular and genetic testing has allowed us to gain a more detailed and nuanced appreciation of these malignancies. This has laid the foundation for the identification of the distinct mutational and molecular patterns such as succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC, and translocation RCC, so that clinicians can create a more personalized approach to their clinical management. Particularly for the rare non-papillary RCC variant histologies, clinical trial representation is lacking. In the discussed studies, no histology enrolled more than 29 patients of any particular RCC aside from Papillary. As such, evidence-based management decisions can be challenging to make for this patient population. We have collected the most up-to-date available evidence to describe the pathophysiology, molecular, and pathologic characteristics of the more commonly seen non-clear cell RCC variants, including papillary, chromophobe, translocation, FH-deficient, as well as a group of "unclassified" RCCs. Additionally, we provide an overview of the available evidence from recent clinical trials for non-clear cell RCC and current treatment paradigms. The diagnostic approach for renal malignancies is rapidly changing, favoring a more molecular and genetically based approach. These techniques will allow for a more detailed understanding of the clinical behavior of these cancers. Most data for non-clear cell RCC are from single-arm phase 2 clinical trials. The clinical response to vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) varies greatly by histology. Molecularly targeted therapy as monotherapy or when combined with immunotherapy have efficacy in non-clear cell RCC, though there are differences in treatment response by histology.

PD46-02 CARCINOMAS OF THE RENAL MEDULLA: A COMPREHENSIVE GENOMIC PROFILING (CGP) STUDY

Adult renal epithelial neoplasms (RENs) comprise several distinct clinicopathologic entities with potential prognostic and therapeutic differences. Individual cases can show overlapping morphologic features, necessitating the use of ancillary methods. The purpose of this study was to determine the diagnostic utility of cytokeratin (CK) subtype expression pattern in a wide range of adult RENs. RENs (including clear cell [conventional] renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, renal oncocytoma, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), urothelial carcinoma, metanephric adenoma (MA), tubulocystic carcinoma (TC) (also known as low-grade collecting duct carcinoma), and mucinous tubular and spindle cell carcinoma) were immunostained for CK subtypes (CK5/CK6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14 (HMWCK), and vimentin (Vim). The expression pattern of normal kidney was also examined and correlated with RENs. Although there is some overlap, subtypes of RENs show distinctive CK expression profiles that may be useful in several differential diagnostic settings. Clear cell RCCs typically showed a restricted expression pattern of CK8, CK18 and Vim. Papillary RCCs typically expressed CK7, CK8, CK18, CK19, and Vim and could be distinguished from MA (CK7-). Chromophobe RCCs were typically CK7+, CK8+, CK18+, and Vim-, and could be distinguished from oncocytomas (typically CK7-). In oncocytomas, nonspecific staining of unblocked endogenous biotin is a potentially significant diagnostic pitfall. CDC, RMC, and TC demonstrated similar CK expression profiles (with the exception of HMWCK expression limited to CDC), supporting a close relationship between these entities. A panel of CK5/CK6, CK17, and Vim may be helpful in distinguishing CDC (typically CK5/CK6-, CK17-, Vim+) and urothelial carcinoma (typically CK5/CK6+, CK17+, Vim-). In conclusion, CK expression patterns may be helpful in several differential diagnostic situations when dealing with adult RENs.

5036 Background: A phase III trial showed that sorafenib (SOR) doubled progression-free survival (PFS) in previously treated pts with clear cell RCC. Activity of SOR in pts with NCC RCC has not been previously reported. Methods: Pts eligible for this open-label, nonrandomized trial in North America were not eligible for other SOR clinical trials, had recovered from prior treatment-related toxicity, and had advanced RCC; ECOG PS of 0–2; age =15 yrs; no treatment with other investigational drugs within 4 wks; life expectancy &gt;2 mos; no active coronary artery disease, ischemia or hypertension; and no severe renal impairment requiring dialysis. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with NCC pts being eligible for an additional 6-mo follow-up in an extension protocol (EP), which was designed to better assess PFS in NCC. Tumor assessments and radiological evaluations were conducted every 4 wks in the main protocol and every 8 wks in the EP. Results: Of 2,488 pts valid for safety in ARCCS, 212 (8.5%) had NCC RCC classified as papillary, chromophobe, collecting duct, or oncocytoma, of whom 24 enrolled in the EP. Baseline characteristics and efficacy are shown in the table . Grade 3 and 4 adverse events (AEs) with &gt; 2% incidence across all histologies included fatigue 7.1%, hand-foot skin reaction 6.6%, rash/ desquamation 6.2%, hypertension 4.7%, abdominal pain 3.8% dyspnea 3.8%, pleural effusion 3.3%, nausea 3.8%, vomiting 2.4%, and ascites 2.4%. Grade 3 and 4 serious AEs were reported in 20% of patients. Of those enrolled in the EP with NCC, median PFS was 34.5 wks (65.2% censored). Conclusions: SOR was well tolerated among pts with NCC RCC. Within the limitations of no central pathologic review, SOR toxicity in NCC RCC was similar to that in the broader ARCCS population and SOR may have antitumor activity in papillary and chromophobe subtypes. [Table: see text] [Table: see text]