Sarcomatoid Differentiation Research Articles

Urothelial carcinoma of the renal pelvis with squamous and sarcomatoid differentiation complicated by hydronephrosis and pyelonephritis: a case report and literature review

Urothelial carcinoma of the renal pelvis with squamous and sarcomatoid differentiation complicated by hydronephrosis and pyelonephritis: a case report and literature review

Challenges in the Diagnosis and Management of Renal Cell Carcinoma With Sarcomatoid Differentiation: A Case Report

Challenges in the Diagnosis and Management of Renal Cell Carcinoma With Sarcomatoid Differentiation: A Case Report

Atypical Presentation of Rapidly Progressive Cutaneous Metastases of Clear Cell Renal Carcinoma: A Case Report

Cutaneous metastases from clear cell renal carcinoma (ccRC) are uncommon and often indicate a poor prognosis. These metastases typically occur on the scalp, face, and trunk, and they can be difficult to diagnose due to their resemblance to benign dermatological tumors. We report the case of a 56-year-old patient with a history of ccRC (TNM stage 4) who was referred to our dermatology department with two rapidly enlarging, painful lesions on the left jawline and scalp, which had developed one month and one week earlier, respectively. On examination, the lesions appeared as well-defined, round to oval plaques with a central ulceration and a peripheral red rim, suggestive of an inflammatory appearance. Dermoscopic examination revealed a structureless pink to orange pattern, atypical central vessels, and irregular linear vessels in a corona-like arrangement. Despite the patient’s stable oncological treatment for six months, pain management had recently included paracetamol, tramadol, and NSAIDs. The primary presumptive diagnosis was of cutaneous metastasis, considering the patient’s history of metastatic ccRC. However, given the recent initiation of new pharmacological agents, the rapid progression of the cutaneous lesions, and their clinical presentation, alternative differential diagnoses were considered, including drug-induced reactions such as erythema multiforme or fixed drug eruption. A biopsy of the facial lesion revealed immunohistochemical positivity for CD10, CAIX, and PAX8, confirming the diagnosis of metastatic ccRC with sarcomatoid differentiation. Unfortunately, despite continued targeted therapies and palliative care, the patient’s condition deteriorated rapidly, leading to death two months later. This case highlights the potential for extremely rapidly evolving cutaneous metastases from ccRC and their capacity to occasionally mimic atypical drug eruptions. Additionally, it reaffirms the poor prognosis of such metastases, as evidenced by the patient’s death within two months.

Renal Cell Carcinoma with Venous Tumor Thrombus: 15 Years of Experience in an Oncology Center.

Background: The purpose of this study is to report the experience of a single Portuguese oncology center in the management of patients with renal cell carcinoma (RCC) and venous tumor thrombus (VTT). Methods: This is a retrospective analysis of all patients with RCC and VTT surgically treated in our center between 2008 and 2023. Only patients with VTT up to level III (Mayo Clinic classification) were included. Patient, tumor characteristics and peri-operative outcome data were registered. Administration of systemic therapy was performed upon progression. Survival analysis was conducted with the collected data. Results: A total of 64 patients (n = 16 women) were included in this study. The mean age at diagnosis was 66.3 ± 10.7 years old. The VTT level was 0, I, II and III in 40 (62.5%), 12 (18.7%), 6 (9.4%) and 6 (9.4%) patients, respectively. Nine patients (14.1%) had distant metastasis at diagnosis. No peri-operative deaths occurred, and the major complication rate was 3.1%. Histology revealed 98.4% of clear cell RCC, with sarcomatoid differentiation present in 12.5% of the cases. A negative margin status was achieved in 54 (84.4%) patients. Systemic therapy was administered in 24 (37.5%) patients during follow-up. The median progression-free (PFS), cancer-specific (CSS) and overall (OS) survival were 23, 60 and 48 months, respectively. In multivariable analysis, significant predictors of CSS were tumor size, sarcomatoid differentiation and collecting system invasion. Conclusions: Radical nephrectomy with VTT excision up to level III is a feasible and safe procedure. Patients with large tumor size, sarcomatoid differentiation and collecting system invasion are at the highest risk and should be closely monitored.

Urogenital schistosomiasis, a leading cause of bladder squamous cell carcinoma

Abstract Introduction/Objective Schistosoma, genus of trematodes, commonly known as blood flukes are parasitic flatworms responsible for a group of infections in humans termed schistosomiasis and hundreds of millions of people are infected worldwide. In areas where Shistosoma is not endemic to the region most cases of bladder malignancy are of urothelial origin. In areas where Shistosoma is endemic bladder malignancy is more commonly squamous cell carcinoma. However, with increased travel, migration and tourism it is important to potentially consider Shistosoma infection in areas that are not typically considered endemic regions. Methods/Case Report A 62-year-old male presented to our hospital and revealed through an interpreter he has had 1.5 years hematuria with “pieces of meat or brown dirt”. Cystoscopy was performed and showed a large necrotic mass. CT scan showed an 8.2 cm exophytic bladder dome mass. TURBT was performed and a diagnosis of invasive high-grade urothelial carcinoma with squamous differentiation and with multiple Schistosoma organisms identified.The patient received Schistosoma treatment and was scheduled for radical cystectomy and ileal conduct. A few days before the scheduled procedure the patient presented to our emergency department with acute abdominal pain. He was subsequently diagnosed with progressive bladder cancer with new left malignant ureteral obstruction, which lead to hydronephrosis, DVT, abdominopelvic ascites and intraperitoneal bladder perforation. Abdominal fluid cytology showed atypical keratinizing squamous cells suspicous for malignancy and marked acute inflammation. Patient underwent cystectomy with ileal conduit and the specimen was sent to pathology for examination. Results (if a Case Study enter NA) NA Conclusion Gross examination showed an irregular perforated bladder. Microscopic examination showed a high grade urothelial carcinoma with squamous and sarcomatoid differentiation with detrusor muscle invasion. Additionally, Schistosoma organisms with a terminal spine and calcified eggs were identified. Some of the calcified egg material was engulfed by giant cells. The organisms are surrounded by a prominent eosinophilic infiltrate. Lymphovascular invasion is also noted. Schistosomiasis is associated with the development of squamous cell carcinoma of the bladder. It is important to maintain high oncological alertness for squamous cell carcinoma, particularly for patients arriving from endemic areas. Such as in our case, a patient from Somalia living in Kansas City.

HLA-G expression associates with immune evasion muscle-invasive urothelial cancer and drives prognostic relevance.

Urothelial bladder cancer is frequent and exhibits diverse prognoses influenced by molecular subtypes, urothelial subtype histology, and immune microenvironments. HLA-G, known for immune regulation, displays significant membranous expression in tumor tissues. We studied the protein expression of Human Leucocyte Antigen G (HLA-G) in 241 Muscle-Invasive Bladder Cancer (MIBC) patients, elucidating its potential clinical and biological significance. Protein expression levels were evaluated and correlated with molecular subtypes, histological characteristics, immune microenvironment markers, and survival outcomes. High HLA-G expression associates with poor overall survival (OS) and diseasespecific survival (DSS), independent of clinicopathological parameters. HLA-G expression varies among molecular subtypes and Urothelial Subtype Histology, e.g., elevated expression levels in basal/squamous MIBC and those with sarcomatoid differentiation. Notably, HLA-G is increased in MIBC with an immune evasive microenvironment (high PD-L1 tumor cell expression, NK cell depletion, granzyme B (GZMB)/CD8 ratio reduction, MHC class I (MHCI) expression reduction) that are characterized by immunosuppressive features and poor prognosis. Furthermore, HLA-G correlates with elevated levels of other immune checkpoint proteins (TIGIT, LAG3, CTLA-4), indicating its role in immune evasion. Our findings underscore HLA-G's role as a potential prognostic marker and interesting immunotherapeutic target in MIBC. Its impact on immune evasion mechanisms and broad expression, coupled with associations withpoor survival and distinct tumor phenotypes, positions HLA-G as a promising protein for further exploration in developing targeted immunotherapies for MIBC patients.

Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Dedifferentiation: Clinico Pathological Significance- Review

Introduction Sarcomatoid and/or rhabdoid dedifferentiation are rare histopathological findings which may be heterogeneous in renal cell carcinoma. Sarcomatoid renal cell carcinoma shows marked cytologic atypia and containing enlarged pleomorphic and malignant spindle cells reminiscent of sarcoma. It is highly aggressive with a high metastatic potential and extremely poor prognosis. Case report A 78-year-old male presented with complaints hematuria, pain abdomen, burring maturation of 2 months duration. The patient had a history of hypertension and diabetes mellitus. Computed tomography revealed a well-defined lobulated, exophytic ball-type, isodense lesion, measuring (~ 7.8 x 7.5 x 11.0 cm) arising from mid and lower poles of right kidney involving renal sinus. Features were suggestive of renal cell carcinoma. The patient underwent a right radical nephrectomy. On histopathological findings reported as clear cell RCC, sarcomatoid and rhabdoid dedifferentiation, Fuhrman grade IV. There was no evidence of any metastasis. The immunochemistry was positive for Paired box 8 (PAX8), Carbonic anhydrase 9 (CA9). The BAP1: BRCA1 Associated Protein-1 was retained. Conclusion-Herewith present an uncommon case of highly aggressive tumor clear cell RCC sarcomatoid and rhabdoid differentiation for its clinical, radioimaging, histopathological and immunohistochemitry significance with review.

Targeted gene sequencing reveals disparate genomic mutations between young and older adults in renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a type of cancer that can develop at any point in adulthood, spanning the range of age-related changes that occur in the body. However, the specific molecular mechanisms underlying the connections between age and genetic mutations in RCC have not been extensively investigated.MethodsClinical and genetic data from patients diagnosed with RCC were collected from two prominent medical centers in China as well as the TCGA dataset. The patients were categorized into two groups based on their prognosticated age: young adults (YAs) and older adults (OAs). Univariate and multivariate analysis were employed to evaluate the relationships between age and genetic mutations. Furthermore, a mediation analysis was conducted to assess the association between age and overall survival, with genetic disparities serving as a mediator.ResultsOur analysis revealed significant differences in clinical presentation between YAs and OAs with RCC, including histopathological types, histopathological tumor stage, and sarcomatoid differentiation. YAs were found to have lower mutation burden and significantly mutated genes (SMGs) of RCC. However, we did not observe any significant differences between the two groups in terms of 10 canonical oncogenic signaling pathways-related genes mutation, telomerase-related genes (TRGs) mutation, copy number changes, and genetic mutations associated with clinically actionable targeted drugs. Importantly, we demonstrate superior survival outcomes in YAs, and we confirmed the mediating effect of genetic disparities on these survival outcome differences between YAs and OAs.ConclusionOur findings reveal previously unrecognized associations between age and the molecular underpinnings of RCC. These associations may serve as valuable insights to guide precision diagnostics and treatments for RCC.

Evaluation of American Urological Association Renal Cell Carcinoma Risk Groups for Chromophobe Renal Cell Carcinoma

ObjectivesTo develop and compare various models for risk stratification in chromophobe renal cell carcinoma (chrRCC). Models have been developed to predict progression-free (PFS) and cancer-specific survival (CSS) following surgery for localized renal cell carcinoma (RCC). Notably, chromophobe RCC (chrRCC) is not included in American Urological Association (AUA) risk stratification, as nuclear grading is not recommended. MethodsWe queried our institutional registry to identify patients managed surgically for unilateral, sporadic, M0, chrRCC from 1970-2012. AUA risk groups were defined using reported criteria, excluding grade, and were compared to the Mayo system incorporating nodal involvement, perinephric/renal sinus fat invasion, and sarcomatoid differentiation. PFS and CSS were estimated using the Kaplan-Meier method. Predictive ability was summarized using c-indexes from Cox proportional hazard regression models. ResultsA total of 257 patients were identified. Thirty-nine patients experienced disease progression at a median 30 months (IQR 5.0-84) and 25 died from chrRCC at a median 34 months (IQR 15-79) following surgery. PFS and CSS rates at 10 years after surgery were 84% and 90%, respectively. C-indexes for modified AUA and Mayo risk groups were similar at 0.76 and 0.75, respectively, for PFS, and 0.77 and 0.76, respectively for CSS. ConclusionsThe modified AUA and Mayo risk stratification systems have similarly robust c-indexes for PFS and CSS in chrRCC. These models can be used to counsel patients based on pathologic features, inform clinicians on appropriate follow-up pathways, and identify patients at risk of disease progression for enrollment in adjuvant systemic therapy trials.

44 Liquid biopsy epigenomic profiling for the detection of sarcomatoid renal cell carcinoma

Abstract Background Sarcomatoid differentiation (SD) in renal cell carcinoma (RCC) is associated with poor survival and heightened response to immune checkpoint blockade. Detection of SD can be challenging due to spatial heterogeneity and sampling error. Herein, we introduce a novel tissue–informed epigenomic approach to noninvasively identify sarcomatoid differentiation in patients with RCC from cell-free DNA (cfDNA) using 1mL of plasma. Methods Chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K27ac – a histone modification associated with active regulatory elements (REs) – was performed on pathologically reviewed clear cell RCC frozen tissue samples with and without SD (sarcomatoid-RCC and epithelioid-RCC, resp.) collected at the Dana-Farber Cancer Institute. Differentially marked REs between sarcomatoid and epithelioid subtypes were identified using DESeq2 (false discovery rate of q < 0.01). After establishing tissue signatures, ChIP-seq was then performed on cell-free chromatin (cfChIP-seq) in plasma from patients with sarc-RCC and epi-RCC. A Sarcomatoid Score was derived for each sample by aggregating the plasma H3K27ac signal at tissue-derived sarcomatoid-specific REs (sarc-REs), while normalizing to signal at epithelioid-specific REs (epi-REs). Scores were compared between the two groups using a Wilcoxon rank-sum test. A classifier was built to distinguish sarc-RCC from epi-RCC based on the Sarcomatoid Score and its performance was evaluated using the area under the receiver operating characteristic (AUROC) curve. Results We identified 25,919 differentially marked REs between 8 sarc-RCC and 8 epi-RCC tissue samples at a false discovery rate of q < 0.01. We selected 12,868 REs that are enriched in sarcomatoid vs. epithelioid. We generated cfChIP-seq profiles from plasma of 29 patients, 17 with sarc-RCC and 12 with epi-RCC. The Sarcomatoid Scores were significantly higher in sarc-RCC vs. epi-RCC plasma samples (p=1.6×10-4; Figure 1A). These scores achieved an AUROC curve of 0.9 for classifying patients with sarc-RCC from patients with epi-RCC (Figure 1B). Conclusions We present a proof-of-concept study in 1 cc of plasma for the detection of sarcomatoid differentiation in RCC based on the assessment of histone modification signals in cfDNA. This approach could help overcome the challenges of spatial heterogeneity and sampling error from tissue that make identification of sarc-RCC difficult. More generally, it establishes a paradigm for identifying histologic subtypes of cancer based on their epigenomic correlates from cfDNA, with possible therapeutic implications in real-time. Figure 1. (A) Sarcomatoid Score in plasma from patients with RCC at sarcomatoid-specific REs, comparing sarcomatoid (orange) and epithelioid RCC (blue). (B) ROC curves for distinguishing sarcomatoid from epithelioid RCC plasma samples using H3K27ac cell-free ChIP-seq signal at sarcomatoid-specific REs. ‘AUC’ indicates area under the ROC curve.

Clinical, Prognosis, and Treatment Effect Features Analysis of Metachronous and Synchronous UTUC and BUC

ObjectiveTo provide a comprehensive understanding of the clinical features of patients with synchronous and metachronous upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) and inform surgical and postoperative adjuvant treatment planning. Patients and MethodA total of 292 consecutive patients with synchronous and metachronous UTUC-BUC were retrospectively enrolled and were categorized into three groups: (1) UTUC metachronous BUC (N = 185, UTUC-mBUC), (2) BUC-metachronous UTUC (N = 43, BUC-mUTUC), (3) synchronous UTUC-BUC (N = 64, sUTUC-BUC). We compared pathological characteristics and survival data among groups with Wilcoxon's rank sum tests, Pearson's chi-squared, and the Kaplan–Meier method. ResultsIn the sUTUC-BUC group, a higher proportion of patients exhibited UTUC tumors with grade G3 (56%, P = .001) and stage T4 (6%, P < .001) than group UTUC-mBUC (G3 = 16%, T4 = 0%). The proportion of patients with variant histology subtype in group sUTUC-BUC was higher than that of metachronous UTUC-BUC, involving squamous (P = .003), adenoid (P = .012), and sarcomatoid (P < .001) differentiation. It was also observed that the maximum diameter of the UTUC tumor of group sUTUC-BUC (median = 3.5) was significantly larger than group UTUC-mBUC (median = 2.5, P = .002) and group BUC-mUTUC (median = 2.2, P < .001). Notably, sUTUC-BUC has an increased risk of cancer-specific death compared with UTUC-mBUC (P < .001) and BUC-mUTUC (P < .001). On multivariable Cox regression, synchronous UTUC-BUC was an independent predictor of both RFS (P < .001; vs. UTUC-mBUC: HR 0.555, P = .004; vs. BUC-mUTUC: HR 0.279, P < .001) and CSS (P < .001, HR 29.737). Moreover, sUTUC-BUC showed a better response to intravesical therapy and chemotherapy with higher cancer-specific survival (P < .001) and recurrence-free survival (P = .034). ConclusionsThe prognosis and pathological characteristics among different metachronous and synchronous UTUC and BUC were diverse. The synchronous UTUC-BUC group showed variant histology subtype, high-grade tumors, advanced tumors, multifocal UTUC, worse cancer-specific survival, but better response to intravesical therapy and chemotherapy.

Giant cell carcinoma of the urinary bladder

We present the clinicopathological features of 23 cases of the giant cell subtype of urothelial carcinoma, a rare subtype of bladder cancer recognized in the current World Health Organization classification of urological tumors. Histologically, the architectural pattern of the tumor varied from infiltrating to the solid expansile pleomorphic tumor with giant, bizarre, anaplastic cells. Typical or atypical mitotic figures were frequently present in all cases. Between 10 and 30% of the tumor had a giant cell component. All cases were associated with conventional high-grade urothelial carcinoma, with areas of squamous cell divergent differentiation and micropapillary carcinoma present in six and two cases, respectively. In one case each had sarcomatoid, nested, small cell, or glandular divergent differentiation. At diagnosis, 35% of patients had advanced disease and 12% had distant metastases. When comparing giant cell urothelial carcinoma with conventional urothelial carcinoma in a matched analysis, differences in overall and cancer-specific survival were observed, particularly in the T1 stage category. Immunohistochemical staining showed a similar profile of urothelial lineage with frequent positive expression of uroplakin II, GATA3, CK20, CK7, and S100P in both giant cell and conventional urothelial carcinomas. High Ki67 proliferation (range, 60–90%; mean, 71%) and nuclear p53 accumulation (mutant profile; range, 50–90%; mean, 64%) were observed. Using the 22C3 assay, the expression of PD-L1 was found to be variable in two cases, and beta-HCG was negative. In conclusion, giant cell carcinoma is a subtype of urothelial carcinoma associated with advanced clinical stage and a trend to lower survival rates.

Mucinous tubular and spindle renal cell carcinoma revealed by a trauma of the kidney: a case report

BackgroundMucinous tubular and spindle cell carcinoma is a rare renal tumor. It has been recognized as a distinct entity in the 2004 World Health Organization tumor classification. Since then, several dozen of these tumor have been reported with additional complementary morphologic characteristics, immunohistochemical profile, and molecular genetic features that have further clarified its clinicopathologic aspects.Case presentationWe report the case of a 52-year-old male African patient who was found to have a mucinous tubular and spindle renal cell carcinoma on a nephrectomy specimen for a severe kidney trauma.ConclusionsThis tumor has a histological spectrum ranging from low to high grade, which includes sarcomatoid differentiation that can confer the tumor an aggressive clinical course.

Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations

BackgroundThere is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking.MethodThis was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy.ResultsA total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7–44.2) in the overall study population: 40.0 months (95% CI 32.7–51.6) in males and 38.7 months (95% CI 26.4–41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0–51.6, vs. 24.8 months, 95% CI 16.8–40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8–55.7, vs. 38.7 months, 95% CI 26.0–41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4–59.0, vs. 15.3 months, 95% CI 8.9–41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 − 2.57, p = 0.008).ConclusionsAlthough the female’s innate and adaptive immunity has been observed to be more active than the male’s, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Abstract PR002: Sarcomatoid Histological Variants of Canine Muscle-Invasive Bladder Cancer: Transcription Factor Activation Highlights Pathways of Epithelial-Mesenchymal Transformation Similar to Humans

Abstract The histologic heterogeneity of human Muscle Invasive Bladder Cancer (MIBC) is one of the main contributing factors to poor treatment outcomes. Recent reports on MIBC histological variants have highlighted increased levels of transcription factors (TF) associated with epithelial-mesenchymal transformation (EMT) and epigenetic regulation in the sarcomatoid histology variant of MIBC. Dogs with spontaneously developing MIBC have been shown to display similar histological and molecular features, in addition to closely mimicking the clinical behavior of human MIBC. Here, we add to previously reported data on histological variants in canine MIBC by evaluating 21 tumor biopsies for variant histology and performing bulk RNAseq analyses on 3 organoid cell lines derived from one sarcomatoid subvariant and two conventional urothelial carcinoma (UC). MIBC biopsies from 21 dogs were reviewed for variant histology by a human urologic pathologist. Organoids derived from the urine of canine MIBC patients were cultured, preserved in RNA later, and sequenced for mRNA expression to identify TF associated with sarcomatoid variants versus conventional UC. All canine MIBC biopsies were classified as invasive, high-grade UC. Histologic variants were identified as glandular differentiation in 7/21, sarcomatoid differentiation in 3/21, squamous differentiation in 3/21, micropapillary carcinoma in 1/21 MIBC samples and small nested variants in 1/21 samples; with the rest of the tumors classified as conventional UC. Raw RNAseq analyses revealed no clear clustering of expression profiles between the three organoid cell lines, indicating distinct RNA expression profiles between the sarcomatoid variants and conventional UC of canine MIBC. To evaluate differences in the expression of TF targets between the organoid cell lines, pathway analyses and VIPER algorithms were used. Organoids derived from sarcomatoid variant UC showed increased expression of Snail familiy transcription repressor 1 (SNAI1) along with decreased expression of cadherin 1 (CDH1), indicating a signature of EMT, similar to that previously identified in human MIBC organoids with sarcomatoid variant histology. Canine MIBC organoids derived from conventional UC histology samples showed a TF profile associated with proliferation, metastasis, and progression, such as increased Zinc finger E-box binding homeobox 1 (ZEB1), E2F transcription factor 3 (E2F3), and centromere protein F (CENPF), as previously described in humans with high grade, invasive UC. In conclusion, the frequency of some histologic variants in canine MIBC, such as sarcomatoid UC, appear to be higher than reported in human patients. TF analyses of canine MIBC-derived organoid cell lines showed evidence of EMT, similar to the sarcomatoid variants of MIBC in humans. Organoids derived from canine MIBC could potentially serve as a valuable model for evaluating the efficacy of novel treatment modalities for the rare histologic variants of UC. Citation Format: Karin Allenspach, Mohamed Elbadawy, Hannah Nocholson, Christopher Zdyrski, John Cheville, Eugene Douglass, Elizabeth W. Howerth, Lilian Oliveira, Jonathan P. Mochel. Sarcomatoid Histological Variants of Canine Muscle-Invasive Bladder Cancer: Transcription Factor Activation Highlights Pathways of Epithelial-Mesenchymal Transformation Similar to Humans [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR002.

Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features.

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy.

Advances in immunotherapy for pulmonary sarcomatoid carcinoma

Pulmonary sarcomatoid carcinoma (PSC) is a rare, poorly differentiated non-small cell lung cancer (NSCLC) that contains sarcomatoid components or sarcomatoid differentiation, and accounts for less than 1% of all lung tumors. Compared to other types of NSCLC, PSC has more invasive biological behavior, is prone to metastasis, and has a higher recurrence rate after early surgery. Its greater resistance to traditional treatments leads to a poorer prognosis compared to other NSCLCs. Immunotherapy offers the possibility of long-term survival for PSC patients.

Single nucleotide polymorphism (SNP) chromosomal microarray as a diagnostic tool for mucinous tubular and spindle cell carcinoma: A validation study

Mucinous tubular and spindle cell carcinoma (MTSCC) shows significant overlap with papillary renal cell carcinoma (PRCC), and harbor recurrent copy-number alterations (CNA).We evaluated 16 RCC with features suggestive of MTSCC using chromosomal microarrays.The cohort was comprised of 8 females and males, each, with an age range of 33–79 years (median, 59), and a tumor size range of 3.4–15.5 cm (median, 5.0). Half the tumors were high-grade (8/16, 50%) with features such as necrosis, marked cytologic atypia, and sarcomatoid differentiation, and 5/16 (31%) were high stage (≥pT3a). Three (of 16, 19%) cases had a predominant (>95%) spindle cell component, whereas 5/16 (31%) were composed of a predominant (>95%) epithelial component. Most cases (12/16, 75%) exhibited a myxoid background and/or extravasated mucin, at least focally.Twelve (of 16, 75%) cases demonstrated CNA diagnostic of MTSCC (losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22). In addition, 2 high-grade tumors showed loss of CDKN2A/B, and gain of 1q, respectively, both of which are associated with aggressive behavior. Three (of 16, 19%) cases, demonstrated nonspecific CNA, and did not meet diagnostic criteria for established RCC subtypes. One (of 16, 6%) low-grade epithelial predominant tumor (biopsy) demonstrated characteristic gains of 7, 17, and loss of Y, diagnostic of PRCC.MTSCC can be a morphologically heterogenous tumor. Our study validates the detection of characteristic chromosomal CNA for diagnostic use that may be useful in challenging cases with unusual spindle cell or epithelial predominant features, as well as in high-grade tumors.

Prognostic Factors and Cancer-Specific Survival of Surgically Managed Renal Cell Carcinoma With Venous Thrombus: A 30-Year Experience at a Tertiary Referral Center

Purpose: This study investigated the prognostic factors and cancer-specific survival (CSS) of patients who had renal cell carcinoma (RCC) with venous thrombus and underwent radical nephrectomy with thrombectomy (RNTx).Materials and Methods: From January 1990 to December 2022, we retrospectively reviewed the medical records of patients diagnosed with RCC with venous thrombus who underwent RNTx at a single tertiary medical center. Univariate and multivariable Cox proportional hazard regression analyses were conducted to identify significant prognostic factors affecting CSS. A Kaplan-Meier model was used to calculate CSS rates at 1, 3, and 5 years after RNTx.Results: We included 262 patients in the final analysis (median age, 59 years) with a median follow-up of 28 months. The 1-, 3-, and 5-year CSS rates were 84.1%, 62.5%, and 46.4%, respectively. Multivariable analysis revealed that pathologic T4 stage (hazard ratio [HR], 3.711; 95% confidence interval [CI], 1.599–8.611, p=0.002), pathologic N1 stage (HR, 2.371; 95% CI, 1.231–4.567; p=0.01), sarcomatoid differentiation (HR, 1.89; 95% CI, 1.027–3.477; p=0.041), and tumor necrosis (HR, 2.993; 95% CI, 1.132–7.914; p=0.027) were associated with CSS.Conclusions: Approximately one-third of all RCC patients with venous thrombus remained disease-free, and half survived 5 years after RNTx. Sarcomatoid differentiation and the presence of tumor necrosis in pathology predicted poorer CSS outcomes in our study. Further retrospective studies are required to validate these findings.