Sarcomatoid Renal Cell Carcinoma: Biological Features and Therapeutic Implications-A Narrative Review.

Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with ≤10% sarcomatoid histology (P = .04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7). These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation.

The evolution of collagen expression in sarcomatoid renal cell carcinoma

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.

214 IDENTIFICATION OF CHARACTERISTIC GENE EXPRESSION IN SARCOMATOID RENAL CELL CARCINOMA

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

Sarcomatoid renal cell carcinoma is an uncommon renal tumor consisting of carcinomatous and sarcomatous components. Although this tumor shows highly malignant biologic behavior, little is known about its proliferative activity. Twelve surgically resected sarcomatoid renal cell carcinomas were analyzed in terms of cell proliferative activity and compared with three ordinary grades of renal cell carcinomas (12, Grade 1; 12, Grade 2; and 8, Grade 3). The analysis was achieved by a silver stain for nucleolar organizer regions (AgNOR) and immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA) in formaldehyde-fixed paraffin-embedded sections. The mean number of AgNOR in the nucleus of renal cell carcinoma was 1.5 +/- 0.2 (mean +/- standard deviation) for Grade 1, 2.6 +/- 0.3 for Grade 2, and 5.7 +/- 1.1 for Grade 3, but 7.8 +/- 2.0 was found for sarcomatoid renal cell carcinoma. The differences in the mean number of AgNOR per nucleus among the three grades and sarcomatoid renal cell carcinoma were statistically significant (P < 0.01). PCNA labeling indexes (positive nuclear ratio) were 4.8 +/- 2.7%, 19.8 +/- 5.6%, 37.8 +/- 6.6% in Grades 1, 2, and 3, respectively, and 45.5 +/- 13.3% in sarcomatoid renal cell carcinoma. The differences in the mean number of PCNA labeling indexes between Grades 1 or 2 and sarcomatoid renal cell carcinoma were statistically significant (P < 0.005). The AgNOR count correlated well with the reactivity of tumor cells for PCNA (correlation coefficient, 0.845; P < 0.01). These findings suggest that sarcomatoid renal cell carcinoma is a highly proliferative renal cell carcinoma, which may be related to its aggressive biologic behavior.

Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features

The objective of our study was to determine whether CT findings, including texture analysis, can differentiate sarcomatoid renal cell carcinoma (RCC) from clear cell RCC. A retrospective case-control study was performed of consecutive patients with a histologic diagnosis of sarcomatoid RCC (n = 20) and clear cell RCC (n = 25) who underwent preoperative CT over a 3-year period. The CT images were independently reviewed by two blinded abdominal radiologists; they evaluated the following: tumor heterogeneity, tumor margin, calcification, intratumoral neovascularity, peritumoral neovascularity, renal sinus invasion, renal vein invasion, and adjacent organ invasion. Interobserver agreement was assessed using the Cohen kappa coefficient, and results were compared between groups using an independent Student t test and the chi-square test with a Bonferroni correction. For texture analysis, gray-level co-occurrence and run-length matrix features were extracted and compared using Mann-Whitney U tests. ROC curves for each tumor were constructed, and AUCs were calculated. Overall, sarcomatoid RCCs were larger than clear cell RCCs, measuring 77 ± 27 mm (mean ± SD) compared with 50 ± 29 mm (p = 0.003), respectively; however, there was no difference in tumor size between the tumors that were compared using texture analysis or subjective analysis (p = 0.06 and 0.03, respectively). From the subjective analysis, only peritumoral neovascularity (readers 1 and 2: 70% and 70% sarcomatoid RCCs vs 0% and 41.6% clear cell RCCs, respectively; p = 0.001) and the size of the peritumoral vessels (p < 0.001) differed between sarcomatoid RCCs and clear cell RCCs, and interobserver agreement was fair (κ = 0.38). Other subjective imaging features did not differ between the tumors (p > 0.005). There was greater run-length nonuniformity and greater gray-level nonuniformity in sarcomatoid RCCs than in clear cell RCCs (p = 0.03 and p = 0.04, respectively). The combined textural features identified sarcomatoid RCC with an AUC of 0.81 ± 0.08 (standard error) (p < 0.0001). Large tumor size, the presence of peritumoral neovascularity, and larger peritumoral vessels are features that are more commonly associated with sarcomatoid RCCs than with clear cell RCCs. Sarcomatoid RCCs are also more heterogeneous by texture analysis than clear cell RCCs.

Patient: Female, 63Final Diagnosis: Sarcomatoid chromophobe renal cell carcinomaSymptoms: Painless gross hematuriaMedication: —Clinical Procedure: —Specialty: Renal SurgeryObjective:Rare diseaseBackground:Sarcomatoid renal cell carcinoma is not a distinct histologic entity transformed from different subtypes of renal cell carcinoma. The sarcomatoid transformation was accepted as the result of dedifferentiation of the primary tumor. Here we present a case of sarcomatoid chromophobe renal cell carcinoma and review the clinicopathological characteristics of sarcomatoid chromophobe renal cell carcinoma.Case Report:A 63-year-old female complained of painless gross hematuria for 3 months. Routine urine test showed that urinary protein was ++ and white blood cells were +++; serum CA153 was moderately elevated at 71.08 U/mL (normal <28 U/mL). Ultrasonography and a computed tomography scan showed a mass in the lower pole of the right kidney, measuring 13.4×15.4×11.4 cm. She underwent a right radical nephrectomy with lymph nodes dissection under general anesthetic. There was no evidence of recurrence and lymphadenopathy 12 months after surgery.Conclusions:Sarcomatoid chromophobe renal cell carcinoma is an uncommon tumor characterized by a biphasic tumor with both classical epithelial components and sarcomatoid components. The prognosis of sarcomatoid chromophobe renal cell carcinoma is worse than classical chromophobe renal cell carcinoma. It is important to recognize that sarcomatoid change of chromophobe renal cell carcinoma has the potential to behave aggressively and to metastasize.

Response

359 Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.

Carcinomes rénaux à contingent sarcomatoïde

This study was aimed at building a computed tomography- (CT-) based radiomics approach for the differentiation of sarcomatoid renal cell carcinoma (SRCC) and clear cell renal cell carcinoma (CCRCC). It involved 29 SRCC and 99 CCRCC patient cases, and to each case, 1029 features were collected from each of the corticomedullary phase (CMP) and nephrographic phase (NP) image. Then, features were selected by using the least absolute shrinkage and selection operator regression method and the selected features of the two phases were explored to build three radiomics approaches for SRCC and CCRCC classification. Meanwhile, subjective CT findings were filtered by univariate analysis to construct a radiomics model and further selected by Akaike information criterion for integrating with the selected image features to build the fifth model. Finally, the radiomics models utilized the multivariate logistic regression method for classification and the performance was assessed with receiver operating characteristic curve (ROC) and DeLong test. The radiomics models based on the CMP, the NP, the CMP and NP, the subjective findings, and the combined features achieved the AUC (area under the curve) value of 0.772, 0.938, 0.966, 0.792, and 0.974, respectively. Significant difference was found in AUC values between each of the CMP radiomics model (0.0001 ≤ p ≤ 0.0051) and the subjective findings model (0.0006 ≤ p ≤ 0.0079) and each of the NP radiomics model, the CMP and NP radiomics model, and the combined model. Sarcomatoid change is a common pathway of dedifferentiation likely occurring in all subtypes of renal cell carcinoma, and the CT-based radiomics approaches in this study show the potential for SRCC from CCRCC differentiation.

Sarcomatoid renal cell carcinomas, highly aggressive variants of renal cell carcinoma subtypes, often present with or develop metastases soon after the primary diagnosis. Most metastatic cases do not respond to immunotherapy or aggressive chemotherapy. Recently targeted therapies, particularly those targeting hypoxia inducible pathway molecules, have been tested clinically on metastatic clear cell renal cell carcinoma with promising initial results. No such studies are available on sarcomatoid renal cell carcinoma. We investigated the hypoxia inducible pathway marker immunohistochemical expression profile, and any potential therapeutic implications that such expression may have, in these tumors. Immunohistochemical staining for hypoxia inducible factor-1alpha, glucose transporter 1, carbonic anhydrase IX and vascular endothelial growth factor was performed in 22 clear cell and 12 nonclear cell sarcomatoid renal cell carcinomas. The immunoreactivity in the tumors was graded from 0 to 3+ (0-no staining, 1+-1% to 25% cells positive, 2+-26% to 50% cells positive and 3+-greater than 50% cells positive). The results were then compared with various clinical parameters to assess for associations. Most clear cell renal cell carcinomas over expressed (2+ or 3+) hypoxia inducible factor-1alpha (in 59%), carbonic anhydrase IX (95%), glucose transporter 1 (91%) and vascular endothelial growth factor (95%). None of the nonclear cell sarcomatoid renal cell carcinomas showed 2+ or 3+ expression of hypoxia inducible factor-1alpha, carbonic anhydrase IX or glucose transporter 1, but 92% showed diffuse positivity for vascular endothelial growth factor. Over expression of carbonic anhydrase IX showed no association with survival, unlike that reported in (nonsarcomatoid) clear cell renal cell carcinoma. There was significant discordance in the staining grades among hypoxia inducible factor-1alpha, carbonic anhydrase IX and glucose transporter 1 in clear cell renal cell carcinoma, suggesting that mechanisms other than hypoxia inducible pathway may be involved in some sarcomatoid clear cell renal cell carcinoma. Hypoxia inducible pathway markers continue to be over expressed in sarcomatoid clear cell renal cell carcinoma, and can be of diagnostic usefulness in such high grade tumors. Over expression of vascular endothelial growth factor in the clear and nonclear cell groups raises the possibility that vascular endothelial growth factor targeted therapies may have a role in the management of sarcomatoid renal cell carcinoma, and deserve further investigation.

We report a case of sarcomatoid renal cell carcinoma with a chromophobe component showing significant elevation of beta-human chorionic gonadotropin (beta-HCG) in the peripheral blood. A 35-year-old man was hospitalized because of a large tumor of the left kidney and elevated serum levels of beta-HCG. Extended nephrectomy was performed, after which the serum beta-HCG level decreased. However, 3 months later, masses were discovered in the left renal bed and in the lung in association with elevated serum levels of beta-HCG. The patient was rehospitalized and received combination therapy with interferon-alpha and doxorubicin-based multiple chemotherapy (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). The recurrent mass responded extremely well to treatment, and beta-HCG normalized. However, the patient died 14 months after nephrectomy because of eventual resistance to chemotherapy. Sarcomatoid renal cell carcinoma containing beta-HCG positive cells were pathologically diagnosed with immunohistochemical staining in the left kidney. Sarcomatoid renal cell carcinoma is a variant of renal adenocarcinoma which has a poor prognosis. This patient had an extremely rare sarcomatoid renal cell carcinoma associated with serum levels of beta-HCG which were elevated and strongly correlated with morphologic cancer activity. beta-HCG might be a useful serum marker for detecting and monitoring this renal cell carcinoma.