Medullary Renal Cell Carcinoma Research Articles

Tertiary lymphoid structures potentially promote immune checkpoint inhibitor response in SMARCB1-deficient medullary renal cell carcinoma.

The WHO's classification of renal cell carcinoma (RCC) has identified loss of SMARCB1 as one of the driven mutations. Despite intensive postoperative interventions, the prognosis for SMARCB1-deficient medullary RCC remains poor, indicating insufficiency in current therapy. Herein, we reported the treatment outcomes of five patients with metastatic SMARCB1-deficient medullary RCC and molecular correlates. Four patients were treated with first-line immune checkpoint inhibitors (ICI) plus tyrosine kinase inhibitors (TKI) combination therapy with a median PFS (mPFS) of 12.3 months. Transcriptomic analysis revealed enrichment of immune-related pathways in SMARCB1-deficient medullary RCC compared to clear-cell and papillary RCC. Multiple immunofluorescence (mIF) revealed the association between the formation of mature tertiary lymphoid structures (TLSs) and the favorable response to ICI-based combination therapy. In conclusion, ICI-based combination therapy showed promising anti-tumor activity in SMARCB1-deficient medullary RCC patients. The presence of mature tertiary TLSs may partially elucidate the mechanism underlying treatment response.

Abstract C091: Uncovering genetic regulators of metabolic plasticity in renal cell carcinoma

Abstract We aim to offer new insights on the regulation of metabolic plasticity in renal cell carcinoma (RCC) and identify novel metabolic regulatory targets that can be used for potential treatment therapies of the disease. RCC affects an estimated 400,000 people worldwide each year with over 100,00 deaths annually that disproportionately affects racial/ethnic minorities in the United States. RCC is a term that covers an array of kidney cancer subtypes differing in incidence, histopathology, genetic and molecular alterations, as well as in clinical outcomes and prognoses. However, a common characteristic of many RCCs is that they are driven by metabolic rewiring, due to a high frequency of mutations in genes that regulate major metabolic processes in the cell. It was recently discovered that patient overall survival and prognosis has been linked to the expression of certain metabolic signatures in RCC tumor cells. Metabolic plasticity allows cancer cells to survive and adapt to different environments and metabolic stress conditions, such as nutrient deprivation. Therefore, exploring and exploiting metabolic rewiring in these cells may reveal genetic vulnerabilities and dependencies. This could lead to discovery of novel biomarkers and molecular targets that can be implicated as future therapeutic interventions for this disease. To this end, we applied functional genomic screening to expose genetic dependencies and vulnerabilities under different physiologic and metabolic conditions in patient derived medullary (PDM) RCC cells. The medullary RCC is a rare and aggressive RCC subtype that disproportionately affects the African American/Black population. We applied a CRISPR- based combinatorial screening platform that is based on co-expression of Cas9 and Cas12a nucleases and libraries of hybrid guide RNAs (hgRNA) to achieve ultra-efficient gene knockout (Aregger et al., 2021; Gonatopoulos-Pournatzis et al., 2020) in PDM RCC cells. Additionally, cells were screened under different media conditions that mimic human physiological nutrient conditions and a media deprived of lipids, one of the major metabolic substrates of the cell. By utilizing a genome-wide pooled CRISPR gene knockout screen we were able to systematically uncover genes required for cell survival and proliferation in a panel of patient-derived RCCs. We have begun to uncover genetic dependencies and major metabolic pathways that can be elucidated and exploited for future studies, such as those involving ferroptosis which is a targetable pathway for the development of cancer treatment therapies. Our findings demonstrate some of the key genetic drivers underlying cellular adaptations to different physiological environments and nutrient deprivation. In future studies we will further explore the relationship between different key metabolic regulatory genes in RCC and map for genetic interactions in major metabolic pathways. Citation Format: Chelsee Holloway, Josef Horak, Youngkyu Jeon, Michael Aregger. Uncovering genetic regulators of metabolic plasticity in renal cell carcinoma [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C091.

Systemic Treatment for Advanced and Metastatic Non-Clear Cell Renal Cell Carcinoma: Examining Modern Therapeutic Strategies for a Notoriously Challenging Malignancy.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians' understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib.

Stimulated Raman histology as a method to determine the adequacy of renal mass biopsy and identify malignant subtypes of renal cell carcinoma.

Renal tumor biopsy requires adequate tissue sampling to aid in the investigation of small renal masses. In some centers the contemporary nondiagnostic renal mass biopsy rate may be as high as 22% and may be as high as 42% in challenging cases. Stimulated Raman Histology (SRH) is a novel microscopic technique which has created the possibility for rapid, label-free, high-resolution images of unprocessed tissue which may beviewed onstandard radiology viewing platforms. The application of SRH to renal biopsy may provide the benefits of routine pathologic evaluation during the procedure, thereby reducing nondiagnostic results. We conducted a pilot feasibility study, to assess if renal cell carcinoma (RCC) subtypes may be imaged and to see if high-quality hematoxylin and eosin (H&E) could subsequently be generated. An 18-gauge core needle biopsy was taken from a series of 25 ex vivo radical or partial nephrectomy specimens. Histologic images of the fresh, unstained biopsy samples were obtained using a SRH microscope using 2 Raman shifts: 2,845 cm-1and 2,930 cm-1. The cores were then processed as per routine pathologic protocols. The SRH images and hematoxylin and eosin (H&E) slides were then viewed by a genitourinary pathologist. The SRH microscope took 8 to 11 minutes to produce high-quality images of the renal biopsies. Total of 25 renal tumors including 1 oncocytoma, 3 chromophobe RCC, 16 clear cells RCC, 4 papillary RCC, and 1 medullary RCC were included. All renal tumor subtypes were captured, and the SRH images were easily differentiated from adjacent normal renal parenchyma. High quality H&E slides were produced from each of the renal biopsies after SRH was completed. Immunostains were performed on selected cases and the staining was not affected by the SRH image process. SRH produces high quality images of all renal cell subtypes that can be rapidly produced and easily interpreted to determine renal mass biopsy adequacy, and on occasion, may allow renal tumor subtype identification. Renal biopsies remained available to produce high quality H&E slides and immunostains for confirmation of diagnosis. Procedural application has promise to decrease the known rate of renal mass nondiagnostic biopsies, and application of convolutional neural network methodology may further improve diagnostic capability and increase utilization of renal mass biopsy among urologists.

Phase 1/2 study of tiragolumab and atezolizumab in patients with relapsed or refractory SMARCB1 or SMARCA4 deficient tumors.

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

Exiguous and Scarce-SMARCB1 Deficient Medullary Renal Cell Carcinoma

Switch / sucrose non fermentable (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin subfamily B member 1 (SMARCB1) deficient medullary renal cell carcinoma is an exceptionally discerned, aggressive carcinoma associated with deficiency of SMARCB1 or integrase interactor 1(INI1).

Medullary renal cell carcinoma (RCC): Genomics and treatment outcomes.

4556Background: Medullary RCC is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait. Recent reports have identified loss of expression of SMARCB1...

Metastatic Medullary Renal Cell Carcinoma Diagnosed by Endobronchial Ultrasound Guided Transbronchial Needle Aspiration

Metastatic Medullary Renal Cell Carcinoma Diagnosed by Endobronchial Ultrasound Guided Transbronchial Needle Aspiration

Characteristics and Outcomes of Tumors Arising From the Distal Nephron

To compare the characteristics and predictors of cancer-specific survival (CSS) of 2 rare distal nephron tumors--medullary renal cell carcinoma (MRCC) and collecting duct carcinoma (CDC). All cases of histologically verified MRCC and CDC reported to The Surveillance, Epidemiology and End Results (SEER) database between 1995 and 2007 were considered. A number of characteristics were compared by tumor histology. Subset analyses were performed for metastatic patients and those managed surgically. CSS was analyzed using Cox proportional hazard models. Overall, 21 cases of MRCC and 227 cases of CDC met the criteria for analysis. Patients with MRCC were younger (median 24 vs 63 years, P < .001), more often black (71.4% vs 22.7%, P < .001), metastatic at presentation (71.4% vs 27.8%, P < .001), and less likely to undergo surgery (61.9% vs 85.6%, P = .015) compared with patients with CDC. Tumor size was similar between MRCC and CDC (median 6 vs 5 cm, P = .70). Median survival was 5 months for MRCC and 30 months for CDC (P < .001). In metastatic MRCC and CDC patients, surgery predicted CSS (HR 4.61 and 2.24, both P ≤.05) despite having larger primary tumors than those managed nonsurgically (median 7.5 vs 5.0 cm, P < .01). Patients with MRCC present younger, at a later stage, and are more often black than patients with CDC. The stage migration toward localized kidney cancer is not apparent for these tumors. Although both cancers have a poor prognosis, the clinical and survival characteristics are distinct. Patients selected for cytoreductive surgery have improved survival.

Clinical features of renal cell carcinoma (RCC) found in 110 nephrectomized Japanese, of which 24 (22%) RCC cases showed 31 double or triple cancers

The causes of renal cell carcinoma (RCC) were investigated in 115 nephrectomized Japanese. Among them, 110 nephrectomized Japanese had RCC as follows: 86 clear cell RCC, 8 papillary RCC, 8 chromophobe RCC, 7 dialytic–multicystic RCC, and 1 liposarcoma, while 5 nephrectomized Japanese had benign renal tumors of oncocytoma (1), angiomyolipoma (2), and hemangioma (2). In the eight chromophobe RCC, three cases that resulted in death involved medullary RCC showing extensive oncogenic features. Double or triple cancers were found in 17 clear cell RCC, 5 papillary RCC, 1 chromophobe RCC, and 1 dialytic–multicystic RCC. Among 31 non-RCC found in 24 RCC cases, 23(74%) non-RCC were removed prenephrectomy. Prenephrectomy adenocarcinoma and postnephrectomy squamous cell carcinoma were their characteristic findings. Compared with those of clear cell RCC, double (triple) cancers of papillary RCC showed more aggressive malignancy. One clear cell RCC had triple cancer of thymoma and rectum cancer. One chromophobe RCC developed thymoma, while one oncocytoma had insulinoma >10 years before. A patient in his sixties with clear cell RCC, who had a past history of pneumothorax, had developed adenocarcinoma of colon polyps and liver adenocarcinoma almost at the same time as triple cancer. His lactate dehydrogenase (LDH) levels were under 300 IU/l. He was suspected of having Birt–Hogg–Dube syndrome. One patient with papillary RCC of Paget’s disease of the bone developed colon polyp adenocarcinoma, osteosarcoma, and additionally exhibited p97/valosin-containing protein downregulation in his sixties. His LHD was increased to 4,289 IU/l with cell lysis reactions. His radical nephrectomy accompanied by adrenalectomy reinforced clinical manifestations of p97 downregulation. For p97 functions, the kidney and adrenal gland had important roles. It was concluded that oxygen stress was stronger in RCC, especially in papillary RCC. Nonsense mutations of protein tyrosine phosphatase receptor delta might be one cause of double (triple) cancers in RCC.

Medullary Renal Cell Carcinoma and Response to Therapy With Bortezomib

TO THE EDITOR: Metastatic non–clear cell renal carcinoma comprises several histologic subtypes, including medullary and collecting duct carcinoma. Medullary renal carcinoma is difficult to separate from collecting duct carcinoma morphologically, but has been diagnosed in patients with sickle cell disease or sickle cell trait. We previously reported a retrospective review of 64 patients with non–clear cell histology and found that patients had a median overall survival time of 9.4 months. Twenty-six (41%) of the 64 patients were identified with collecting duct or medullary pathology. These patients were treated with cytokine therapy or systemic chemotherapy. There were no responses to cytokine therapy. One of the patients with collecting duct/medullary carcinoma had a 5-month-long partial response to systemic chemotherapy. Median survival for the patients of the collecting duct subset was 11 months. Partial responses to systemic chemotherapy have been reported elsewhere, but are rare and of short duration. In the September 15, 2004, issue of the Journal of Clinical Oncology, we reported a phase II study evaluating bortezomib, a proteasome inhibitor, in patients with advanced renal cell carcinoma. Of 37 assessable patients, four patients achieved a partial response to therapy; three patients had clear cell histology and one patient had medullary carcinoma. We now report the updated follow-up of the medullary carcinoma patient. The patient received 7 months of bortezomib and achieved a complete response. He remains without evidence of disease after more than 27 months of follow-up. Metastatic non–clear cell renal carcinoma is a rare entity with a poor outcome. Given the small numbers, patients with non–clear cell renal carcinoma have not been well represented in clinical trials. Better molecular characterization will help to more accurately identify appropriate agents for this subset of patients. Further study of bortezomib in medullary renal carcinoma is indicated.