Chromophobe renal cell carcinoma with sarcomatoid differentiation: A case report with molecular analysis

Chromophobe renal cell carcinoma with sarcomatoid differentiation: A case report with molecular analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Chromophobe renal cell carcinoma with sarcomatoid differentiation: A case report with molecular analysis AE RI AHN, Young Bum Jeong, Kyoung Min Kim This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3784870/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Chromophobe renal cell carcinoma is a rare type of kidney cancer with a favorable prognosis. Renal cell carcinoma with sarcomatoid change has a more aggressive clinical course with unelucidated pathogenesis. Case presentation A 54-year-old female patient presented to the urology department for evaluation of an incidentally detected left renal mass. Computed tomography demonstrated a 13x10-cm mass in the left upper pole of the kidney. The resected tumor was clearly divided into two distinct components: one showed conventional Chromophobe renal cell carcinoma morphology, while the tumor cells of the other were highly pleomorphic with poorly differentiated morphology. The poorly differentiated component showed immunohistochemical expression for cytokeratin. Next-generation sequencing (NGS) of the two components shared multiple chromosomal losses and variation in the RNF46 gene. Based on these findings, we diagnosed the tumor as Chromophobe renal cell carcinoma with sarcomatoid change. Although the two components shared some genetic changes, there were also significant differences. The area of sarcomatoid change carried chromosomal gain, single nucleotide variants, and MET fusion compared with the conventional Chromophobe renal cell carcinoma component. Furthermore, while PD-L1 was negative in the conventional Chromophobe renal cell carcinoma component, more than 10% of the tumor cells in the sarcomatoid component were PD-L1 positive. Conclusion This case reveals novel genetic features of chromophobe renal cell carcinoma with sarcomatoid change. Kidney Chromophobe renal cell carcinoma Sarcomatoid renal cell carcinoma Next-generation sequencing Figures Figure 1 Figure 2 Figure 3 Background Chromophobe renal cell carcinoma (ChRCC) is rare, accounting for 5–7% of all RCCs. ChRCC has a favorable prognosis compared with other RCC subtypes such as clear cell RCC and papillary RCC.[ 1 ] ChRCC arises from intercalated cells of the renal cortex. Sarcomatoid change occurs in 2–8% of ChRCCs and is associated with poor prognosis.[ 2 ] ChRCC with sarcomatoid change is a rare entity with unelucidated pathogenesis. Analyzing the molecular features of ChRCC with sarcomatoid change may be helpful to clarify its pathogenesis. Here, we report a case of ChRCC with sarcomatoid change and a molecular feature exhibiting markedly bidirectional progression based on distinct genetic-phenotypic abnormalities. Case presentation A 54-year-old female patient with no medical or family history presented to the urology department for evaluation of an incidentally detected left renal mass. Laboratory examination showed serum tumor markers of alpha-fetoprotein (AFP): 2.72 ng/mL [normal < 7.0 ng/mL], carcinoembryonic antigen (CEA), 1.8 ng/mL (normal < 5.2 ng/mL), carbohydrate antigen (CA) 19 − 9, 9.0 U/mL (normal < 34.0 U/mL), and CA 125, 28.4 U/mL (normal < 35.0 U/mL). A computed tomography (CT) scan of the abdomen was performed and revealed a left renal mass measuring 13×10 cm at maximum dimensions. The mass showed heterogeneous enhancement and irregular margins (Fig. 1 A). The patient underwent an open radical nephrectomy for diagnosis and treatment. Gross examination of the specimen revealed a tumor measuring 14.2x9.8 cm. Macroscopically, the tumor consisted of two components: a yellowish hard lesion (lesion 1) and a white-grayish soft lesion (lesion 2). The tumor had an irregular margin and revealed suspicious invasion into perinephric fat and adrenal tissue (Fig. 1 B). Microscopically, the yellowish hard lesion (lesion 1) showed morphologic features typical of ChRCC (Fig. 1 C). The white-grayish soft lesion (lesion 2) showed large cells with marked nuclear pleomorphism and bizarre mitotic figures (Fig. 1 D). Tumor cells invaded into perinephric fat and the adrenal gland (Fig. 1 E). In a limited area, there were some foci showing the transition between lesion 1 and lesion 2 (Fig. 1 F). In lesion 1, immunohistochemical staining showed strong positivity for keratin 7 (KRT7) (Fig. 2 A). Lesion 1 was also positive for Hale’s colloidal iron stain (Fig. 2 B). Lesion 1 and lesion 2 showed opposing staining for KIT (CD117) and vimentin (Fig. 2 C and 2 D). KRT showed diffuse strong positivity in lesion 1 (right side, Fig. 2 E) and focal positivity in lesion 2 (Fig. 2 F). We performed targeted next-generation sequencing (NGS)-based genomic profiling for lesion 1 and lesion 2 using the NGS gene panel Oncomine® Comprehensive Assay Plus. The lesions shared an insertion-deletion (indel) variant; RNF46 (c.349_350delCGinsA, p.Arg117ThrfsTer41). Copy number analysis identified identical chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, X in both lesions. Based on the above findings, the pathological diagnosis confirmed the mass to be a ChRCC with sarcomatoid change. To evaluate the efficacy of immunotherapy, immunohistochemical staining for programmed cell death ligand 1 (PD-L1) was performed. Lesion 1 and lesion 2 showed opposing staining for PD-L1. PD-L1 was negative in the ChRCC component and more than 10% positive in the sarcomatoid area (Fig. 2 G and 2 H). Although the two components shared some genetic changes, there were also significant differences. The sarcomatoid component exhibited distinct genetic features not seen in the ChRCC component. Copy number analysis confirmed chromosomal gains in 1, 2, 6, 10, 13, 15, 17, 21, X along with chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, X in the ChRCC component (Fig. 3 A and 3 B). Additionally, several genomic alterations were identified: single nucleotide variants (SNV)/indel variants in TP53 (c.1176_1179delAGAC, p.Ter394IlefsTer27), TSC2 (c.1675G > A, p.Asp559Asn), NF1 (c.60 + 1G > A, p.?), and CDKN1B (c.384_385insAG, p.His129SerfsTer17) and a MET-CAPZA2 fusion mutation. After diagnosis, the patient underwent chemotherapy with nivolumab and cabozantinib. Despite adjuvant treatment, the patient experienced tumor progression followed by multiple organ metastasis including lung, liver, bone, and lymph nodes. The patient’s condition deteriorated, and she died within one month. Discussion and conlusions ChRCC was first recognized as a distinct variant and an uncommon subtype of RCC by Thoenes in 1985.[ 3 ] ChRCC has a favorable prognosis compared with clear cell RCC or papillary RCC, with a five-year survival rate of 78–100% and a 10-year survival rate of 80–90%.[ 4 ] However, sarcomatoid change is associated with worse prognosis in ChRCC and reportedly occurs in 2–8% of ChRCC cases.[ 2 ] The pathogenesis of sarcomatoid change is unelucidated. In this case report, we present details of the molecular features of ChRCC and sarcomatoid components using an NGS gene panel. In this case, NGS analysis of the common ChRCC component showed losses in chromosomes 1, 2, 6, 10, 13,15, 17, 21, and X and indel variants in RNF46 . Chromosomal losses from chromosomes 1, 2, 6, 10, and 17 are hallmarks of ChRCC and are consistent with the literature. [ 5 , 6 ] In the sarcomatoid component, NGS analysis showed losses in chromosomes 1, 2, 8, 10, 11, 13,15, 17, 21, and X and gains in chromosomes 3, 5, 7, 9, 12, 13, 14, 19, 22, and X. Previous studies suggest that chromosomal gains play an important role in sarcomatoid transformation of ChRCC.[ 6 ] Additionally, SNV/indel variants were detected in RNF46, TP53, TSC2, NF1 , and CDKN1B , and a MET-CAPZA2 fusion was found. These results indicate that the sarcomatoid component developed from the ChRCC component through chromosomal gain, SNV/indel variants, and MET-CAPZA2 fusion. The MET receptor is a tyrosine kinase receptor in the hepatocyte growth factor/scatter factor (HGF/SF) pathway. In oncogenesis, MET genetic alteration can involve tumor cell proliferation, angiogenesis, invasion, and metastasis.[ 7 , 8 ] MET mutation has been identified in various tumor types including breast cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer.[ 9 ] A recent study indicates that tumors harboring MET fusion could benefit from MET inhibitors. In particular, patients with MET fusion-positive non-small-cell lung carcinoma can receive a clinical benefit from a MET inhibitor such as crizotinib. Management of ChRCC with sarcomatoid change based on genetic alteration has not been standardized. However, molecular analyses from this case can help establish treatment options for patients exhibiting MET fusion. This case revealed opposing staining for PD-L1 between the ChRCC and sarcomatoid components. PD-L1 expression is a valuable predictive factor for evaluation of anti-PD-L1 agent efficacy. Aberrant PD-L1 expression is associated with high-grade histology such as sarcomatoid differentiation.[ 10 ] Previous studies showed that sarcomatoid components express higher PD-L1 expression compared with non-sarcomatoid components[ 11 ], and our case showed a consistent pattern of PD-L1 expression. This finding suggests that ChRCC with sarcomatoid change may be a good candidate for anti-PD-L1 treatment. To our knowledge, this is the first case report of molecular alteration using an NGS gene panel in ChRCC with sarcomatoid change. Further molecular studies will help to develop targeted therapy for this entity. Abbreviations ChRCC Chromophobe renal cell carcinoma AFP Alpha-fetoprotein CEA Carcinoembryonic antigen CA Carbohydrate antigen CT Computed tomography NGS Next-generation sequencing PD-L1 Programmed cell death ligand 1 SNV Single nucleotide variants HGF/SF Hepatocyte growth factor/scatter factor Declarations Author Contribution Ae Ri Ahn and Kyoung Min Kim contributed to the study design, pathological analysis, genetic analysis and interpretation of date, and drafting the manuscript, Young Bum Jeong contributed to the analysis of clinical features and to editing the manuscript, All authors reviewed the final version of the manuscript. Ethics approval This case report was approved by Jeonbuk National University Hospital Institutional Review Board (approval no. IRB 2023-07-004). Patient consent was obtained for publication. This case report was conducted in accordance with the Declaration of Helsinki of 1975. Funding This paper was supported by the Fund of Biomedical Research Institute, Jeonbuk National University Hospital. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed in the reporting of this case References Moch H, Amin MB, Berney DM, Compérat EM, Gill AJ, Hartmann A, et al. The 2022 World Health Organization classification of tumours of the urinary system and male genital organs—part A: renal, penile, and testicular tumours. Eur Urol. 2022;82:458–68. 10.1016/j.eururo.2022.06.016 . http://doi . Lobo J, Ohashi R, Amin MB, Berney DM, Compérat EM, Cree IA, et al. WHO 2022 landscape of papillary and chromophobe renal cell carcinoma. Histopathology. 2022;81:426–38. 10.1111/his.14700 . http://doi . Thoenes W, Störkel S, Rumpelt H-J. Human chromophobe cell renal carcinoma. Virchows Arch B Cell Pathol Incl Mol Pathol. 1985;48:207–17. 10.1007/BF02890129 . http:// . Bian L, Duan J, Wang X, Yang Y, Zhang X, Xiao S. Sarcomatoid chromophobe renal cell carcinoma: a case report and review of the literature. Am J Case Rep. 2019;20:1225–30. http://doi:10.12659/AJCR.916651 . Brunelli M, Gobbo S, Cossu-Rocca P, Cheng L, Hes O, Delahunt B, et al. Chromosomal gains in the sarcomatoid transformation of chromophobe renal cell carcinoma. Mod Pathol. 2007;20:303–9. http://doi:10.1038/modpathol.3800739 . Brunelli M, Eble JN, Zhang S, Martignoni G, Delahunt B, Cheng L. Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma. Mod Pathol. 2005;18:161–9. http://doi:10.1038/modpathol.3800286 . Guo R, Luo J, Chang J, Rekhtman N, Arcila M, Drilon A. MET-dependent solid tumours—Molecular diagnosis and targeted therapy. Nat Rev Clin Oncol. 2020;17:569–87. 10.1038/s41571-020-0377-z . http:// . Rhoades Smith KE, Bilen MA. A review of papillary renal cell carcinoma and MET inhibitors. Kidney cancer. 2019;3:151–61. 10.3233/KCA-190058 . http://doi . Network CGAR. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374:135–45. http://doi:10.1056/NEJMoa1505917 . Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 2006;66:3381–5. http://doi:10.1158/0008-5472.CAN-05-4303 . Kawakami F, Sircar K, Rodriguez-Canales J, Fellman BM, Urbauer DL, Tamboli P, et al. Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer. 2017;123:4823–31. http://doi:10.1002/cncr.30937 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3784870","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":263535930,"identity":"5939bde1-71f0-4cfd-a598-965163f8cf74","order_by":0,"name":"AE RI AHN","email":"","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":false,"prefix":"","firstName":"AE","middleName":"RI","lastName":"AHN","suffix":""},{"id":263535931,"identity":"f0d8ef8a-4854-4fe0-acbe-2225c46c9f0f","order_by":1,"name":"Young Bum Jeong","email":"","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":false,"prefix":"","firstName":"Young","middleName":"Bum","lastName":"Jeong","suffix":""},{"id":263535932,"identity":"71037478-9eca-427d-969c-db6ff09e2ede","order_by":2,"name":"Kyoung Min Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYBACCQY2hgMMFWwJUH4CHrUoWs6QqoWBsQ2ulAgtktOOJR66OY8vz1wigfHDD4a0fIJapKXTDhzO3cZWbDkjgVmyhyHHsoGQFjnp9AaQlsQNNxIYpBkYKgwI2gLRMgeshfk3UVogDmsAa2ED2pJDWIvk7LSEwznH2IoNzjxss+wxSCOsReJ2mvHnnJpjeQbHkw/f+FGRTFgLFBwDYsYGBgaiNTAw1BCvdBSMglEwCkYeAACHizsQGR5b4QAAAABJRU5ErkJggg==","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":true,"prefix":"","firstName":"Kyoung","middleName":"Min","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2023-12-21 04:59:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3784870/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3784870/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49082036,"identity":"49a6e792-589c-4830-bb43-a3b332fb72cd","added_by":"auto","created_at":"2024-01-02 20:10:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":963048,"visible":true,"origin":"","legend":"\u003cp\u003eRadiological and histopathological findings of chromophobe renal cell carcinoma with sarcomatoid change. (A) Computed tomography (CT) demonstrated a 13-cm mass in the upper pole of the left kidney (white arrow). (B) The resected specimen revealed an irregularly margined tumor measuring 14.2 x 9.8 cm. The tumor consisted of two components: yellowish hard lesion (black arrow, lesion 1) and white-grayish soft lesion (white arrow, lesion 2). (C) The chromophobe renal cell carcinoma component consisted of tumor cells arranged in solid sheets, separated by hyalinized vascular septa. Hyperchromatic nuclei and the presence of perinuclear haloes were characteristic (hematoxylin and eosin (H\u0026amp;E) ×200). (D) The sarcomatoid component showed large cells with markers of nuclear pleomorphism and bizarre mitotic figures (H\u0026amp;E ×200). (E) The sarcomatoid component invaded into the adrenal gland (H\u0026amp;E ×200). (F) The transition between the chromophobe renal cell carcinoma component and the sarcomatoid component was identified (H\u0026amp;E ×200).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3784870/v1/66d78782686ba64a1fa7101e.png"},{"id":49082035,"identity":"6e7d78da-f171-4214-86a4-43a593dfc840","added_by":"auto","created_at":"2024-01-02 20:10:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":789344,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical findings of chromophobe renal cell carcinoma with sarcomatoid change. The chromophobe renal cell carcinoma showed strong positivity for (A) keratin 7 (KRT7) and (B) Hale’s colloidal iron stain (original magnification, x200). The components showed opposing staining for (C) KIT (CD117) and (D) vimentin (original magnification, x100). KRT showed diffuse strong positivity in the chromophobe renal cell carcinoma component (E) (original magnification, x100) and focal positivity in the sarcomatoid component (F) (original magnification, x200). Programmed cell death ligand 1 (PD-L1) was (G) negative in the chromophobe renal cell carcinoma component and (H) positive in the sarcomatoid component (original magnification, x200).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3784870/v1/2935a6effd5cd862a56f40d9.png"},{"id":49082034,"identity":"cec1b505-a036-4858-817e-b2e6dd9666c7","added_by":"auto","created_at":"2024-01-02 20:10:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99972,"visible":true,"origin":"","legend":"\u003cp\u003eNext-generation sequencing of chromophobe renal cell carcinoma with sarcomatoid differentiation. (A) In the chromophobe renal cell carcinoma component, copy number analysis identified chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, and X. (B) The sarcomatoid differentiation component exhibited distinct genetic features not seen in the chromophobe renal cell carcinoma component. Copy number analysis identified chromosomal gains in 1, 2, 6, 10, 13, 15, 17, 21, and X.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3784870/v1/ff9fdd8f28c092f0d740afda.png"},{"id":52852171,"identity":"c2dcb4fb-c14c-436b-afe0-23bfd06b625b","added_by":"auto","created_at":"2024-03-18 00:22:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2211612,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3784870/v1/1877c0ea-78a3-423a-b57b-f338755117e1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Chromophobe renal cell carcinoma with sarcomatoid differentiation: A case report with molecular analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eChromophobe renal cell carcinoma (ChRCC) is rare, accounting for 5\u0026ndash;7% of all RCCs. ChRCC has a favorable prognosis compared with other RCC subtypes such as clear cell RCC and papillary RCC.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] ChRCC arises from intercalated cells of the renal cortex. Sarcomatoid change occurs in 2\u0026ndash;8% of ChRCCs and is associated with poor prognosis.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] ChRCC with sarcomatoid change is a rare entity with unelucidated pathogenesis. Analyzing the molecular features of ChRCC with sarcomatoid change may be helpful to clarify its pathogenesis. Here, we report a case of ChRCC with sarcomatoid change and a molecular feature exhibiting markedly bidirectional progression based on distinct genetic-phenotypic abnormalities.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 54-year-old female patient with no medical or family history presented to the urology department for evaluation of an incidentally detected left renal mass. Laboratory examination showed serum tumor markers of alpha-fetoprotein (AFP): 2.72 ng/mL [normal\u0026thinsp;\u0026lt;\u0026thinsp;7.0 ng/mL], carcinoembryonic antigen (CEA), 1.8 ng/mL (normal\u0026thinsp;\u0026lt;\u0026thinsp;5.2 ng/mL), carbohydrate antigen (CA) 19\u0026thinsp;\u0026minus;\u0026thinsp;9, 9.0 U/mL (normal\u0026thinsp;\u0026lt;\u0026thinsp;34.0 U/mL), and CA 125, 28.4 U/mL (normal\u0026thinsp;\u0026lt;\u0026thinsp;35.0 U/mL). A computed tomography (CT) scan of the abdomen was performed and revealed a left renal mass measuring 13\u0026times;10 cm at maximum dimensions. The mass showed heterogeneous enhancement and irregular margins (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The patient underwent an open radical nephrectomy for diagnosis and treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGross examination of the specimen revealed a tumor measuring 14.2x9.8 cm. Macroscopically, the tumor consisted of two components: a yellowish hard lesion (lesion 1) and a white-grayish soft lesion (lesion 2). The tumor had an irregular margin and revealed suspicious invasion into perinephric fat and adrenal tissue (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Microscopically, the yellowish hard lesion (lesion 1) showed morphologic features typical of ChRCC (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). The white-grayish soft lesion (lesion 2) showed large cells with marked nuclear pleomorphism and bizarre mitotic figures (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Tumor cells invaded into perinephric fat and the adrenal gland (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). In a limited area, there were some foci showing the transition between lesion 1 and lesion 2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). In lesion 1, immunohistochemical staining showed strong positivity for keratin 7 (KRT7) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Lesion 1 was also positive for Hale\u0026rsquo;s colloidal iron stain (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Lesion 1 and lesion 2 showed opposing staining for KIT (CD117) and vimentin (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). KRT showed diffuse strong positivity in lesion 1 (right side, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE) and focal positivity in lesion 2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). We performed targeted next-generation sequencing (NGS)-based genomic profiling for lesion 1 and lesion 2 using the NGS gene panel Oncomine\u0026reg; Comprehensive Assay Plus. The lesions shared an insertion-deletion (indel) variant; \u003cem\u003eRNF46\u003c/em\u003e (c.349_350delCGinsA, p.Arg117ThrfsTer41). Copy number analysis identified identical chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, X in both lesions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on the above findings, the pathological diagnosis confirmed the mass to be a ChRCC with sarcomatoid change. To evaluate the efficacy of immunotherapy, immunohistochemical staining for programmed cell death ligand 1 (PD-L1) was performed. Lesion 1 and lesion 2 showed opposing staining for PD-L1. PD-L1 was negative in the ChRCC component and more than 10% positive in the sarcomatoid area (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eH).\u003c/p\u003e \u003cp\u003eAlthough the two components shared some genetic changes, there were also significant differences. The sarcomatoid component exhibited distinct genetic features not seen in the ChRCC component. Copy number analysis confirmed chromosomal gains in 1, 2, 6, 10, 13, 15, 17, 21, X along with chromosomal loss in 1, 2, 6, 10, 13, 15, 17, 21, X in the ChRCC component (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Additionally, several genomic alterations were identified: single nucleotide variants (SNV)/indel variants in \u003cem\u003eTP53\u003c/em\u003e (c.1176_1179delAGAC, p.Ter394IlefsTer27), \u003cem\u003eTSC2\u003c/em\u003e (c.1675G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Asp559Asn), \u003cem\u003eNF1\u003c/em\u003e (c.60\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.?), and \u003cem\u003eCDKN1B\u003c/em\u003e (c.384_385insAG, p.His129SerfsTer17) and a \u003cem\u003eMET-CAPZA2\u003c/em\u003e fusion mutation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter diagnosis, the patient underwent chemotherapy with nivolumab and cabozantinib. Despite adjuvant treatment, the patient experienced tumor progression followed by multiple organ metastasis including lung, liver, bone, and lymph nodes. The patient\u0026rsquo;s condition deteriorated, and she died within one month.\u003c/p\u003e"},{"header":"Discussion and conlusions","content":"\u003cp\u003eChRCC was first recognized as a distinct variant and an uncommon subtype of RCC by Thoenes in 1985.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] ChRCC has a favorable prognosis compared with clear cell RCC or papillary RCC, with a five-year survival rate of 78\u0026ndash;100% and a 10-year survival rate of 80\u0026ndash;90%.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] However, sarcomatoid change is associated with worse prognosis in ChRCC and reportedly occurs in 2\u0026ndash;8% of ChRCC cases.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] The pathogenesis of sarcomatoid change is unelucidated. In this case report, we present details of the molecular features of ChRCC and sarcomatoid components using an NGS gene panel.\u003c/p\u003e \u003cp\u003eIn this case, NGS analysis of the common ChRCC component showed losses in chromosomes 1, 2, 6, 10, 13,15, 17, 21, and X and indel variants in \u003cem\u003eRNF46\u003c/em\u003e. Chromosomal losses from chromosomes 1, 2, 6, 10, and 17 are hallmarks of ChRCC and are consistent with the literature. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] In the sarcomatoid component, NGS analysis showed losses in chromosomes 1, 2, 8, 10, 11, 13,15, 17, 21, and X and gains in chromosomes 3, 5, 7, 9, 12, 13, 14, 19, 22, and X. Previous studies suggest that chromosomal gains play an important role in sarcomatoid transformation of ChRCC.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Additionally, SNV/indel variants were detected in \u003cem\u003eRNF46, TP53, TSC2, NF1\u003c/em\u003e, and \u003cem\u003eCDKN1B\u003c/em\u003e, and a \u003cem\u003eMET-CAPZA2\u003c/em\u003e fusion was found. These results indicate that the sarcomatoid component developed from the ChRCC component through chromosomal gain, SNV/indel variants, and \u003cem\u003eMET-CAPZA2\u003c/em\u003e fusion.\u003c/p\u003e \u003cp\u003eThe MET receptor is a tyrosine kinase receptor in the hepatocyte growth factor/scatter factor (HGF/SF) pathway. In oncogenesis, \u003cem\u003eMET\u003c/em\u003e genetic alteration can involve tumor cell proliferation, angiogenesis, invasion, and metastasis.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] \u003cem\u003eMET\u003c/em\u003e mutation has been identified in various tumor types including breast cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] A recent study indicates that tumors harboring \u003cem\u003eMET\u003c/em\u003e fusion could benefit from \u003cem\u003eMET\u003c/em\u003e inhibitors. In particular, patients with \u003cem\u003eMET\u003c/em\u003e fusion-positive non-small-cell lung carcinoma can receive a clinical benefit from a \u003cem\u003eMET\u003c/em\u003e inhibitor such as crizotinib. Management of ChRCC with sarcomatoid change based on genetic alteration has not been standardized. However, molecular analyses from this case can help establish treatment options for patients exhibiting \u003cem\u003eMET\u003c/em\u003e fusion.\u003c/p\u003e \u003cp\u003eThis case revealed opposing staining for PD-L1 between the ChRCC and sarcomatoid components. PD-L1 expression is a valuable predictive factor for evaluation of anti-PD-L1 agent efficacy. Aberrant PD-L1 expression is associated with high-grade histology such as sarcomatoid differentiation.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Previous studies showed that sarcomatoid components express higher PD-L1 expression compared with non-sarcomatoid components[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and our case showed a consistent pattern of PD-L1 expression. This finding suggests that ChRCC with sarcomatoid change may be a good candidate for anti-PD-L1 treatment. To our knowledge, this is the first case report of molecular alteration using an NGS gene panel in ChRCC with sarcomatoid change. Further molecular studies will help to develop targeted therapy for this entity.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eChRCC Chromophobe renal cell carcinoma\u003c/p\u003e\n\u003cp\u003eAFP Alpha-fetoprotein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCEA Carcinoembryonic antigen\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCA Carbohydrate antigen\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCT Computed tomography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNGS Next-generation sequencing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD-L1 Programmed cell death ligand 1\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSNV Single nucleotide variants\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHGF/SF Hepatocyte growth factor/scatter factor\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAe Ri Ahn and Kyoung Min Kim contributed to the study design, pathological analysis, genetic analysis and interpretation of date, and drafting the manuscript, Young Bum Jeong contributed to the analysis of clinical features and to editing the manuscript, All authors reviewed the final version of the manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was approved by Jeonbuk National University Hospital Institutional Review Board (approval no. IRB 2023-07-004). Patient consent was obtained for publication. This case report was conducted in accordance with the Declaration of Helsinki of 1975.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis paper was supported by the Fund of Biomedical Research Institute, Jeonbuk National University Hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eanalyzed in the reporting of this case\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMoch H, Amin MB, Berney DM, Comp\u0026eacute;rat EM, Gill AJ, Hartmann A, et al. 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Cancer. 2017;123:4823\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi:10.1002/cncr.30937\u003c/span\u003e\u003cspan address=\"http://doi:10.1002/cncr.30937\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Kidney, Chromophobe renal cell carcinoma, Sarcomatoid renal cell carcinoma, Next-generation sequencing","lastPublishedDoi":"10.21203/rs.3.rs-3784870/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3784870/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChromophobe renal cell carcinoma is a rare type of kidney cancer with a favorable prognosis. Renal cell carcinoma with sarcomatoid change has a more aggressive clinical course with unelucidated pathogenesis.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eA 54-year-old female patient presented to the urology department for evaluation of an incidentally detected left renal mass. Computed tomography demonstrated a 13x10-cm mass in the left upper pole of the kidney. The resected tumor was clearly divided into two distinct components: one showed conventional Chromophobe renal cell carcinoma morphology, while the tumor cells of the other were highly pleomorphic with poorly differentiated morphology. The poorly differentiated component showed immunohistochemical expression for cytokeratin. Next-generation sequencing (NGS) of the two components shared multiple chromosomal losses and variation in the RNF46 gene. Based on these findings, we diagnosed the tumor as Chromophobe renal cell carcinoma with sarcomatoid change. Although the two components shared some genetic changes, there were also significant differences. The area of sarcomatoid change carried chromosomal gain, single nucleotide variants, and MET fusion compared with the conventional Chromophobe renal cell carcinoma component. Furthermore, while PD-L1 was negative in the conventional Chromophobe renal cell carcinoma component, more than 10% of the tumor cells in the sarcomatoid component were PD-L1 positive.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis case reveals novel genetic features of chromophobe renal cell carcinoma with sarcomatoid change.\u003c/p\u003e","manuscriptTitle":"Chromophobe renal cell carcinoma with sarcomatoid differentiation: A case report with molecular analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 20:10:37","doi":"10.21203/rs.3.rs-3784870/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d5b76cc-7bc6-412b-bd5f-cba4178e8632","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-18T00:14:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-02 20:10:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3784870","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3784870","identity":"rs-3784870","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}