A case report and literature review of a rare primary multiple small intestinal sarcomatoid carcinoma with co-driver gene mutations

A case report and literature review of a rare primary multiple small intestinal sarcomatoid carcinoma with co-driver gene mutations | 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 A case report and literature review of a rare primary multiple small intestinal sarcomatoid carcinoma with co-driver gene mutations Dan Liu, Xulin Li, Hui Xie, Yi Tang, Yanhong Xie, Qing Cheng Li, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4433771/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 Sarcomatoid carcinoma (SCA) is a relatively rare malignant tumor, and primary SCA occurring in the small intestine is even rarer, characterized by the co-existence of malignant epithelial cells and sarcomatoid differentiation (spindle/giant cell) components. Compared with other malignant tumors in the small intestine, it has greater invasiveness and earlier metastasis. Case presention We provide a complete case report on the clinical, imaging, genetic characterization, and treatment process of primary multiple small intestinal SCA. The patient underwent surgery, XELOX chemotherapy, and exploratory application of a multi-target tyrosine kinase inhibitor—anlotinib, however the condition progressed rapidly and he died within 3 months. This is the second report of systematic gene sequencing in the small intestine SCA, and co-mutations in key driving genes of KRAS, TP53, and PTPRT have been identified, with PTPRT being the first reported mutation in SCA. Conclusion Small intestine SCA has highly invasiveness and poor prognosis, while according to our statistical data primary multifocal small intestine SCA may have an even poor prognosis. This case was treated exploratorily with a multi-target tyrosine kinase inhibitor, anlotinib, but did not effectively control tumor growth and disease progression. This case provides reference guidance for the treatment of rare diseases such as sarcomatoid carcinoma in the future. Small intestine SCA Driver genes KRAS TP53 PTPRT Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Primary sarcomatoid carcinoma (SCA) of the small intestine is an extremely rare malignant tumour characterized by the coexistence of carcinomatous (epithelial) and sarcomatous (stromal) components and its marked invasiveness (Reid-Nicholson et al. 2004 ). SCA mainly occurs in the respiratory tract, breast, thyroid, pancreas, kidneys, and uterus, while SCA occurring in the small intestine is particularly rare (Andrawes et al. 2017 ). To date, only 36 cases have been reported in the literature, and most previous reports have mainly discussed the pathology, diagnosis, and treatment of the disease, with little exploration of its genetic phenotype. Reviewing the reported literature, we found that only one patient with primary SCA of the small intestine have performed whole-exome sequencing analysis (Zhu et al. 2021 ). Herein, we report a case of multiple SCA of the small intestine with co-driver mutations in KRAS, TP53, and PTPRT genes. Despite postoperative XELOX regimen chemotherapy and anlotinib treatment, the patient deteriorated and died rapidly. Written informed consent was obtained from the patient’s family for the publication of the details of this case. Case presentation A 56-year-old Chinese male presented to the hospital on December 16, 2021 with persistent upper abdominal pain and intermittent exacerbation of abdominal distension, accompanied by nausea. The laboratory date obtained on admission revealed a white blood cell count of 14×10 9 /L and a neutrophil percentage of 82%. The tumour markers CA199, CA125, AFP, and CEA were all negative. Chest and abdominal enhanced CT imaging (Fig. 1 a,b,c,d) showed multiple segments of the small intestinal tumour suspicious of carcinoma and Multiple enlarged lymph nodes. 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) imaging (Fig. 1 e,f,g,h,i) indicated multiple segments of uneven thickening of the intestinal wall with active glucose metabolism abnormalities. Additionally, a nodular lesion with active glucose metabolism abnormalities was noted in the left adrenal gland. Therefore, we diagnosed multifocal intestinal cancer with multiple lymph node and left adrenal gland metastases. On December 27, 2021, the patient underwent laparoscopic exploration. Intraoperatively, surgeon discovered multiple (>6) palpable lumps in small intestinal wall with indistinct borders. Among them, the largest mass, measuring approximately 3*3*2.5cm, invaded the serosal layer. Suspected needle-like perforation was found 110cm away from the Treitz ligament, surrounded by attached purulent exudate. In addition, multiple enlarged mesenteric lymph nodes were observed. Based on the intraoperative findings, a palliative partial small bowel resection (total length of 34cm) was performed, centred on the site of the needle-tip perforation. Meanwhile 15 enlarged mesentery lymph nodes were resected. Postoperative gross pathological examination (Fig. 2 a) showed a segment of the small intestine had multiple ulcerated masses exhibiting infiltrative growth and necrotic surfaces. Six resected lymph nodes were metastases. Microscopically, the tumor exhibited poorly differentiated carcinoma with rhabdomyoid and anamorphic large cell morphology. The scattered and diffuse distribution of tumor cells was growing in a poorly cohesive formation (Fig. 2 b). Some tumor cells had pleomorphic giant nuclei and abnormal mitotic figures (Fig. 2 c). Immunohistochemistry revealed diffuse positivity for pancytokeratin (pan-CK) (Fig. 3 a, b) and vimentin (Vim) (Fig. 3 c, d), positivity for epithelial membrane antigen (EMA), partial positivity for CK7 and Bcl6, and positivity for Bcl2, c-Myc, and CD10, with Ki-67 reaching 80% (Fig. 3 e, f). In contrast, desmin, synaptophysin (Syn), smooth muscle actin (SMA), S-100, β-catenin, Myogenin and SALL4 were all negative. According to the immunohistochemical results, it was suspected to be rhabdomyoid undifferentiated carcinoma accompanied by multiple mesenteric lymph node metastases. As the pathological manifestations were not typical, we sent the pathological sections for consultation to the Pathology Department of the Second Xiangya Hospital of Central South University, Hunan Province, China. Further IHC staining analysis shows that the mismatch repair function is complete and programmed death ligand 1(PD-L1) expression was negative. His pathological test was diagnosed with SCA of the small intestine. One month after partial small bowel resection, the patient was admitted to the Oncology Department of the Second Xiangya Hospital of Central South University, Hunan Province, China, for chemotherapy. On January 27, 2022, the patient received the first cycle of the XELOX regimen (oxaliplatin 200 mg/d1 + capecitabine 1500 mg/d2-14). On February 18, 2022, re-examination of the chest CT scan revealed a new mass in the upper left lung hilum, while abdominal CT showed multiple retroperitoneal lymph node metastases, liver and bilateral adrenal metastases. The above revealed disease progression. Considering the ineffective response to one cycle of chemotherapy, low PD-L1 expression and the patient's refusal to undergo genetic testing for precise targeted therapy guidance, the patient did not have effective anti-cancer drugs yet. On February 23, 2022, the patient voluntarily started exploratory treatment with oral anlotinib 10mg once daily. After a course of treatment, the patient was re-admitted to our hospital. CT scans of the chest and abdomen showed larger metastases in the lungs (Fig. 4 a), bilateral adrenal glands (Fig. 4 b) and liver (Fig. 4 c), compared to previous scans, and peritoneum were seeded new metastases. On March 21, 2022, the patient succumbed to worsening of the disease, cachexia, and concomitant infection. To explore the molecular characteristics of primary sarcomatoid carcinoma of the small intestine in this patient, formalin-fixed paraffin-embedded (FFPE) tissue samples were sent to Guangzhou Kingmed Diagnostics Group Co., Ltd., for genetic testing of 710 commonly mutated genes using the Illumina NovaSeq 6000 system. A total of 26 nonsynonymous mutations were detected (Table 1 in the attachment), among which the most abundant and clinically significant mutations included a missense mutation in exon 12 of KRAS (c.35G > C, p.G12A, 63.8%), a nonsense mutation in exon 8 of TP53 (c.892G > T, 59.4%), and a missense mutation in exon 8 of PTPRT (c.1185C > G, 15.6%). Additionally, 22 class III variants of unclear clinical significance were detected. No mutations in mismatch repair genes were found, no fusion genes with clear clinical significance were detected, and no microsatellite stability (MSS) was observed. Literature Review and Discussion We conducted a thorough literature search on PubMed, Web of Science and the China National Knowledge Infrastructure (CNKI), covering all reports published up to January 2024 regarding sarcomatoid carcinoma of the small intestine. The search terms included "sarcomatoid carcinoma", "undifferentiated cancer", "pleomorphic cancer", "metaplastic carcinoma", "anaplastic carcinoma", "jejunum" and "small intestine". Reports of SCA occurring outside the small intestine were excluded. A total of 28 case reports, comprising 36 cases (Table 2 ) were identified. Primary small intestinal tumours are relatively rare gastrointestinal neoplasms, accounting for less than 5% of all gastrointestinal tumours (Mellouki et al. 2018 ). The most common types of malignant tumours of the small intestine are adenocarcinomas (40%), followed by neuroendocrine tumours (25%), lymphomas, and sarcomas (Zhao et al. 2017 ). The small intestine SCA is extremely rare. The first case of SCA of the small intestine, initially termed intestinal blastoma, was reported in 1973 by Dikman and Toker (Dikman et al. 1973). There have been changes in the nomenclature and classification of SCA over time, with various terms appearing in different studies, including carcinosarcoma, undifferentiated carcinoma, pleomorphic carcinoma, and metaplastic carcinoma. Current cytogenetic and molecular studies have shown that both carcinomatous and sarcomatous components originate from a tumour lineage undergoing sarcomatoid dedifferentiation (Torenbeek et al. 1999 ); hence, the most commonly accepted term is sarcomatoid carcinoma. Clinical features The data analysis from 37 small intestine SCA patients in the statistical table (Table 2 ) revealed that elderly patients were dominant (average age 60.05 ± 11.48 years), with a male-to-female ratio of 22:15. Clinical presentations lack specificity and may include anaemia, abdominal pain, gastrointestinal bleeding, and weight loss. The average tumour size at discovery was 6.6 cm (range 2.5–16 cm), with distant metastasis occurring in 59% of patients at the time of initial diagnosis. The median overall survival (OS) (Fig. 5 b) is only 7 months (range 0.33-36 months). SCA of the small intestine typically presents as a solitary tumour lesion, however, there are also 7 cases (Kwok, 2016 ; Chen et al., 2017 ; Han et al., 2017 ; Yin et al., 2019 ; Fan et al., 2021; Zhu et al., 2021 ) (including this case) of multifocal small intestine masses. The survival time for these seven patients was significantly shorter than the median OS of 7 months, with the exception of the 10-month survival reported by Yin. Most patients underwent surgical resection, but patients died from tumour metastasis or recurrence. CT scan Imaging and molecule imaging Currently, relying on CT imaging features to distinguish small intestine SCA from other types of small intestine tumors, such as adenocarcinomas and lymphomas, poses a significant challenge. According to previous reports, the imaging features of the small intestinal SCA are similar to those of other malignant tumours of the small intestine, and the imaging findings are closely related to the gross pathological type. Endophytic, polypoid, and nodular types of the small intestinal SCA CT imaging often present as large masses with uneven enhancement. Ulcerative types manifest as irregular thickening of the intestinal wall and incomplete mucosal lines and can lead to intestinal perforation. In addition, the Small intestinal SCA CT imaging often presents as mild-moderate enhancement and unclear boundaries. In recent years, PET/CT has been widely used for the imaging of small intestine tumours. 18 F-FDG PET/CT, a molecule imaging method, has the unique advantage of simultaneously displaying both the anatomical and metabolic functions of tumours. Reports in the literature (Mankoff et al. 2017 ) suggested that 18 F-FDG PET/CT can detect malignant lesions in the early stages of metabolic abnormalities, and a single imaging session can capture the status of lesions throughout the body, decrease the likelihood of missed distant metastases and aid in clinical staging. In our case, PET/CT identified a newly discovered left adrenal nodule, which exhibited high FDG uptake (SUVmax 5.7), compared to what was observed on enhanced CT. At present, there is no research report on PET/CT imaging features of the small intestine SCA. Previous studies have reported that primary pulmonary SCA tumours exhibit abnormal uptake of 18 F-FDG, with maximum standardized uptake values (SUVmax) ranging from 4.1 to 35.5 (Luo et al. 2024 ); the SUVmax of these lesions is often higher than that observed in other types of non-small cell lung cancer (NSCLC). In their retrospective analysis of 24 patients with pulmonary SCA, Wu et al. reported that the SUVmax in the KRAS mutation group was significantly higher than that in the non-KRAS mutation group (Wu et al. 2019 ), suggesting a positive correlation between the SUVmax and KRAS expression. This mechanism may be related to the involvement of KRAS oncogenes in metabolic reprogramming. KRAS can up-regulate the expression of the transcription factor MYC through the activation of the MEK/ERK pathway, thereby enhancing glycolytic metabolism to sustain tumour growth (Kerk et al. 2021 ). In our case, the lesion of SCA of the small intestine had a high SUVmax (approximately 11.2) and carried a KRAS gene mutation. Further research is needed to determine whether small intestine SCA carrying KRAS mutation can be distinguished from other small intestine tumors based on the SUVmax. Conventional Pathology The gross morphology of SCA of the small intestine reported in the literature (Fig. 5 a) can be classified into five types: endophytic, polypoid, ulcerative, nodular, and exophytic, with the endophytic type being more common (29.7%). Some cases have mixed types, such as circumferential endophytic and larger nodular types. Most SCAs involve regional lymph node metastasis, invasive growth, and direct infiltration of adjacent structures.In our case, the patient's first examination revealed multifocal masses in over 6 locations in the small intestine, mostly ulcerative, with small perforations discovered during surgery. The tumor exhibited lymph node metastasis and full-thickness invasive growth. Histologically, the morphology of SCA cells of the small intestine is highly heterogeneous and pleomorphic. According to literature reports, some SCA cells exhibit monophasic pattern—cancer cells predominantly show mesenchymal features characterized by pleomorphism and low differentiation changes, with few or no epithelial-like areas(Robey-Cafferty et al. 1989 ). In addition, some exhibit biphasic pattern—cancer cells comprise a mixture of epithelioid tumour cells and mesenchymal-like tumour cells, with the mesenchymal component possibly containing heterologous carcinoma cells (Reid-Nicholson et al. 2004 ).This case is a monophasic pattern. Due to the atypical nature of the disease, the patient was initially misdiagnosed as rhabdomyoid undifferentiated carcinoma Therefore, SCA cannot be diagnosed solely based on HE staining; it requires confirmation through immunohistochemistry with multiple biomarkers (CK and vimentin) and extensive experience (Lee et al. 2015 ). The pathological diagnosis of small intestine SCA requires the use of various immunohistochemical markers and genetic testing to distinguish it from other malignant tumors, such as leiomyosarcoma or SMARC4-deficient undifferentiated cancers. Additionally, the Ki-67 index of this patient was approximately 80% and his prognosis was poor, which was consistent with previous reports that high Ki-67 positivity was associated with poor prognosis. Molecular Pathology SCA of the small intestine has not yet been covered in databases such as the International Cancer Genome Consortium (ICGC), and its molecular genetic characteristics have not been systematically studied. According to the literature from both domestic and international sources, only one case of primary SCA of the small intestine has been reported with whole-exome mutagenesis analysis (Zhu et al. 2021 ), which identified comutations in the KRAS G13C and TP53 driver genes. In our case, the patient was found to carry three driver gene mutations, including the KRAS G12A point mutation (a relatively rare mutation), TP53, and PTPRT missense mutations. KRAS and TP53 are common key driver genes that play important roles in tumour growth, proliferation, differentiation, and apoptosis across various organs in the body (Lee et al. 2022 ). Mutations in KRAS and TP53 were also prevalent in SCA of other organs (Ding et al. 2022 ). However, mutations of PTPRT, an anticancer gene, are relatively rare. A search of the IntOGen database revealed few reports of mutations in colorectal cancer, lung cancer, and skin cancer, with mutations in sarcomatoid carcinoma of the whole body being reported for the first time. PTPRT encodes a tyrosine phosphatase involved in cell adhesion that plays a role in cell-cell adhesion. Variations in PTPRT lead to PTPRT protein inactivation, which results in loss of cell adhesion to the extracellular matrix (ECM) and activation of the epithelial-mesenchymal transition (EMT) program, thereby promoting the metastatic ability of cancer cells (Hu et al. 2019 ). Currently, the co-mutation of multiple driver genes is a hot research topic, with reports indicating a worse prognosis when KRAS and TP53 co-mutate (Shepherd et al. 2017 ). Studies have shown that when Kras and TP53 co-mutate, they can up-regulate the expression of YTHDF1 and Cyclin B1, which reduce the latency period and increase the tendency to metastasize, thereby worsening the prognosis (Lou et al. 2021 ). Notably, Zhu et al. reported a case of small intestine sarcomatoid carcinoma with co-driver gene mutations (KRAS G13C, TP53). The patient's condition worsened further after one cycle of postoperative chemotherapy (IFO + epirubicin), and his survival time was significantly shorter than the median overall survival (7 months). Therefore, further research is needed to investigate the correlation between multiple co-driver gene mutations and the malignancy and invasiveness of small intestinal SCA. Treatment and Prognosis There are currently no specific guidelines for the treatment of SCA of the small intestine. SCAs are generally insensitive to radiotherapy and chemotherapy, and wide tumour resection remains the mainstay of treatment. The rapid development of targeted molecular therapy for tumours has provided more treatment options for cancer patients. However, for cases of SCA such as this one, in which PD-L1 expression is negative, targeted therapy with PD-L1 monoclonal antibodies may not yield significant benefits (Jiang et al. 2019 ). Numerous studies have reported that anlotinib has good anticancer activity against various solid tumours, such as soft tissue sarcoma (Wang et al. 2022 ), non-small cell lung cancer (Han et al. 2018 ), and small cell lung cancer (Zheng et al. 2022 ), prolonging progression-free survival (PFS) and overall survival (OS). It is a novel multi-targeted tyrosine kinase inhibitor that can block angiogenesis induced by vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), effectively inhibiting tumour angiogenesis and inducing tumour apoptosis due to nutrient deprivation (Li 2021 ). Therefore, the patient voluntarily opted for exploratory treatment with anlotinib (The consent form is submitted in the attachment). However, the patient's condition continued to progress after one cycle of standardized oral anlotinib, and the patient subsequently died. Therefore, whether anlotinib has anticancer effects on SCA requires further clinical research. Conclusion Small intestine SCA is extremely rare, highly invasive, prone to early metastasis, and associated with a short median survival time. This report describes a case of primary small intestine multiple sarcomatoid carcinoma, which lacks specificity in CT and molecular imaging.Systematic genetic testing revealed three co-driving gene mutations (KRAS, TP53, PTPRT), with PTPRT being the first reported mutation in sarcomatoid carcinoma. In this case, the multi-target tyrosine kinase inhibitor anlotinib was used for treatment, but the patient still progressed and died in the short term. This case enriches the gene lineage of small intestinal sarcomatoid carcinoma, potentially providing references for the diagnosis and treatment of this disease. Declarations Acknowledgments The authors thank the patient and patient’s kin for agreeing to the publication of the report. Statement of non-duplication We certify that this manuscript is a unique submission and is not being considered for publication by any other source in any medium. Further, the manuscripthas not been published, in part or in full, in any form. Funding This study was supported by the scientific research project of Hunan Provincial Health (Grant NO.D202309047172) Conflict of interest We certify thatwe have no afliations with any organization or entity with any financial interest or non-financial interest. Author Contributions Xiaohua Ruan contributed to the study thesis ideas and design. Dan Liu and Xulin Li wrote the manuscript. Hui Xie and Birong Yin provided images of pathological staining. Qingcheng Li,Yanhong Xie, Yi Tang and Wu Luo were responsible for the clinical treatment and follow-up of the patient. All authors critically reviewed the manuscript. Data availability The data used to support the findings of this study are included within the article. Ethical approval This study was approved by the Ethics Committee of East Hospital of Shaoyang Central Hospital References Andrawes PA, Shariff M, Chang Q, Grinberg R (2017) Primary sarcomatoid carcinoma of the small intestine: very rare and aggressive tumour. BMJ Case Rep 2017:bcr2016217895. https://doi.org/10.1136/bcr-2016-217895 Chen JX, Jiang GM, Li RP, Li LB, Wang JY (2017) Multiple primary sarcomatoid carcinoma of the jejunum with postoperative lung and brain metastases: a case report and literature review. Nan Fang Yi Ke Da Xue Xue Bao 37:1695-inside back cover. https://doi.org/10.3969/j.issn.1673-4254.2017.12.23 Dikman SH, Toker C (1973) Enteroblastoma complicating regional enteritis. Gastroenterology 65:462-466. 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Med. 33:647-656. https://doi.org/10.1007/s12149-019-01374-5 Yin A, Liu Y, He H, Chen MK (2019) A case of multiple sarcomatoid carcinomas of the small intestine. Chin. J. Dig. Endosc. 36:291-292. https://doi.org/10.3760/cma.j.issn.1007-5232.2019.04.016. Zhao Z, Xu G, Chen Y, Wang X (2017) Advances in diagnosis and treatment of primary malignant tumors of the small intestine. Chin. J. Gastrointest. Surg. 20:117-120. https://doi.org/10.3760/cma.j.issn.1671-0274.2017.01.029 Zheng HR, Jiang AM, Gao H, Liu N, Zheng XQ, Fu X, Ruan ZP, Tian T, Liang X, Yao Y (2022) The efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a Chinese multicenter real-world study. Front Oncol 12:894835. https://doi.org/10.3389/fonc.2022.894835 Zhu Z, Liu X, Li W et al (2021) A rare multiple primary sarcomatoid carcinoma (SCA) of small intestine harboring driver gene mutations: a case report and a literature review. Transl Cancer Res 10:1150-1161. https://doi.org/10.21037/tcr-20-2829 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table1.xlsx table2.xls Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4433771","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":305585494,"identity":"7ad525e6-bf2c-4b88-9955-a48bd16e318b","order_by":0,"name":"Dan Liu","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Liu","suffix":""},{"id":305585495,"identity":"88e0c9a0-2ca3-418d-95fc-7a305acb432a","order_by":1,"name":"Xulin Li","email":"","orcid":"","institution":"East Hospital of Shaoyang Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xulin","middleName":"","lastName":"Li","suffix":""},{"id":305585496,"identity":"b8ba7742-d8f6-403d-9bfe-6772f3485dda","order_by":2,"name":"Hui Xie","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Xie","suffix":""},{"id":305585497,"identity":"abb11e21-399b-4031-b6a0-e2cb4aa44735","order_by":3,"name":"Yi Tang","email":"","orcid":"","institution":"East Hospital of Shaoyang Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Tang","suffix":""},{"id":305585498,"identity":"3bb71ea3-845c-4d41-808e-efb04b550869","order_by":4,"name":"Yanhong Xie","email":"","orcid":"","institution":"East Hospital of Shaoyang Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanhong","middleName":"","lastName":"Xie","suffix":""},{"id":305585499,"identity":"dfda3f02-2509-41ca-8206-9979b9a72b7c","order_by":5,"name":"Qing Cheng Li","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"Cheng","lastName":"Li","suffix":""},{"id":305585500,"identity":"b1aee1a3-2af0-4868-a252-10546791d6fd","order_by":6,"name":"Birong Yin","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Birong","middleName":"","lastName":"Yin","suffix":""},{"id":305585501,"identity":"bf0feade-7994-41b6-a286-bccb00ae8215","order_by":7,"name":"Wu Luo","email":"","orcid":"","institution":"East Hospital of Shaoyang Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wu","middleName":"","lastName":"Luo","suffix":""},{"id":305585502,"identity":"5ff3d169-a0f8-4fd9-9469-d33c1d1042a5","order_by":8,"name":"Xiaohua Ruan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYBAC++P933//qbCx4ydez5kDBhI8Z9KSJRuI1nIjwUCCt+0w44YDxOpg7DkA1HPmMLPx8eQNDD8qthHWwszeANRTkc5nduZZAWPPmduEtbDxHATqOWPNbHYjx4CZsY0ILTwSyYwNB9uYGTfPIFaLhEQaM2NjmzPjBglitRjwnGFjZgAGsgTQLweJ8osBew9QCygq25M3PvhRQYQWJJBgcIAk9WAtpOoYBaNgFIyCEQIA7PU+ByEsN14AAAAASUVORK5CYII=","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":true,"prefix":"","firstName":"Xiaohua","middleName":"","lastName":"Ruan","suffix":""}],"badges":[],"createdAt":"2024-05-17 02:39:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4433771/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4433771/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57628271,"identity":"fbf688ad-1f03-45df-8327-5a26017b1491","added_by":"auto","created_at":"2024-06-03 14:28:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5139242,"visible":true,"origin":"","legend":"\u003cp\u003eImages of the patient's chest and abdomen CT enhancement and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT on December 21, 2021 (a) Enhanced CT image of the chest showed an enlarged lymph node (arrow) at the left pulmonary hilum. (e) PET/CT fusion image showed high \u003csup\u003e18\u003c/sup\u003eF-FDG uptake (SUVmax: 12.9) in the lesion (arrow), indicating distant lymph node metastasis. (b) Enhanced CT image showed a suspicious small nodule (arrow) in the left adrenal gland. (f) PET/CT fusion image showed high \u003csup\u003e18\u003c/sup\u003eF-FDG uptake (SUVmax: 5.7) in the lesion (arrow), indicating adrenal metastasis. (c,d) Enhanced CT images showed lesions (white arrows) as multifocal uneven thickening of the small intestinal wall with mild heterogeneous enhancement and lesions (black arrows) as multiple enlarged mesenteric lymph nodes in the small intestine. (g,h) PET/CT fusion images displayed high \u003csup\u003e18\u003c/sup\u003eF-FDG uptake (SUVmax:11.2) in intestinal wall lesions (white arrows) and high \u003csup\u003e18\u003c/sup\u003eF-FDG uptake (SUVmax:7.7) in lymph node lesions (black arrows), indicating multiple small intestinal malignancies with mesenteric lymph node metastasis\u003c/p\u003e","description":"","filename":"fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/bf449a1b4198b9ff1be7caf8.png"},{"id":57628270,"identity":"2746b0b6-9e20-4cab-8c32-af560a8741a7","added_by":"auto","created_at":"2024-06-03 14:28:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":7349341,"visible":true,"origin":"","legend":"\u003cp\u003eGross pathology and hematoxylin and eosin staining (a) Specimen of the small intestine showed scattered ulcers of varying sizes on the mucosal surface, with two ulcerated masses visible. (b) The tumour cells were arranged in a scattered manner, with abundant polymorphic, atypical cells and coagulative necrosis visible in the upper left corner. (c) Increased nuclear-cytoplasmic ratio, large nuclei with prominent nucleoli, and multinucleated giant cells were visible (HE staining)\u003c/p\u003e","description":"","filename":"fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/641eaf316325723a58f92569.png"},{"id":57628272,"identity":"87d26863-e6c2-43d6-b93a-5df387f1c4c8","added_by":"auto","created_at":"2024-06-03 14:28:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":15501107,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical staining showed (a, b) diffusely positive for pan-cytokeratin (pan-CK) . (c, d) diffusely positive for Vimentin (Vim). (e, f) Ki-67 positivity at 80%\u003c/p\u003e","description":"","filename":"fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/7cf1294d7ea54e2f7c0598d3.png"},{"id":57628267,"identity":"8d8e5448-e9c6-4a04-adc3-a479e10aae6e","added_by":"auto","created_at":"2024-06-03 14:28:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1937984,"visible":true,"origin":"","legend":"\u003cp\u003eCT scan images of the patient's chest and abdomen on March 10, 2022 (a) Bronchial occlusion of the left upper lobe and soft tissue mass (arrow) were significantly larger than before. (b) Bilateral adrenal masses increased significantly. (c)The liver nodule (arrow) was larger than before\u003c/p\u003e","description":"","filename":"fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/b0b41aad83dd05b3593e6a1b.png"},{"id":57628269,"identity":"6ff0fc34-0df8-4d82-b9ee-48ecbbbc1016","added_by":"auto","created_at":"2024-06-03 14:28:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":332343,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis on the distribution of macroscopic tumor type and survival analysis of 37 reported small intestine SCA cases (a) Proportion of five general types(P.S. Data on six gross morphological types were missing) . (b) The survival curve shows a generally poor prognosis for SCA, with a median overall survival of 7 months\u003c/p\u003e","description":"","filename":"fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/a27e71fe98f795437887c1c0.png"},{"id":57631689,"identity":"3d371d23-6294-4a34-a96c-b19728cd988f","added_by":"auto","created_at":"2024-06-03 15:01:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":45303828,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/dc685896-7652-409b-8cb0-fc19501afc94.pdf"},{"id":57629580,"identity":"ceebe9b0-a161-47af-a14b-73d367a73cb0","added_by":"auto","created_at":"2024-06-03 14:36:53","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12452,"visible":true,"origin":"","legend":"","description":"","filename":"table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/0541c44b034132ca54dc9867.xlsx"},{"id":57628266,"identity":"8a533c77-2538-4134-8d4e-d283ecb8a363","added_by":"auto","created_at":"2024-06-03 14:28:53","extension":"xls","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":33280,"visible":true,"origin":"","legend":"","description":"","filename":"table2.xls","url":"https://assets-eu.researchsquare.com/files/rs-4433771/v1/2e20aab35d38385edaa1a27c.xls"}],"financialInterests":"No competing interests reported.","formattedTitle":"A case report and literature review of a rare primary multiple small intestinal sarcomatoid carcinoma with co-driver gene mutations","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary sarcomatoid carcinoma (SCA) of the small intestine is an extremely rare malignant tumour characterized by the coexistence of carcinomatous (epithelial) and sarcomatous (stromal) components and its marked invasiveness (Reid-Nicholson et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). SCA mainly occurs in the respiratory tract, breast, thyroid, pancreas, kidneys, and uterus, while SCA occurring in the small intestine is particularly rare (Andrawes et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). To date, only 36 cases have been reported in the literature, and most previous reports have mainly discussed the pathology, diagnosis, and treatment of the disease, with little exploration of its genetic phenotype. Reviewing the reported literature, we found that only one patient with primary SCA of the small intestine have performed whole-exome sequencing analysis (Zhu et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Herein, we report a case of multiple SCA of the small intestine with co-driver mutations in KRAS, TP53, and PTPRT genes. Despite postoperative XELOX regimen chemotherapy and anlotinib treatment, the patient deteriorated and died rapidly. Written informed consent was obtained from the patient\u0026rsquo;s family for the publication of the details of this case.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 56-year-old Chinese male presented to the hospital on December 16, 2021 with persistent upper abdominal pain and intermittent exacerbation of abdominal distension, accompanied by nausea. The laboratory date obtained on admission revealed a white blood cell count of 14\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and a neutrophil percentage of 82%. The tumour markers CA199, CA125, AFP, and CEA were all negative. Chest and abdominal enhanced CT imaging (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea,b,c,d) showed multiple segments of the small intestinal tumour suspicious of carcinoma and Multiple enlarged lymph nodes. \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose positron emission tomography/computed tomography (\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT) imaging (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ee,f,g,h,i) indicated multiple segments of uneven thickening of the intestinal wall with active glucose metabolism abnormalities. Additionally, a nodular lesion with active glucose metabolism abnormalities was noted in the left adrenal gland. Therefore, we diagnosed multifocal intestinal cancer with multiple lymph node and left adrenal gland metastases.\u003c/p\u003e\n\u003cp\u003eOn December 27, 2021, the patient underwent laparoscopic exploration. Intraoperatively, surgeon discovered multiple (\u0026gt;6) palpable lumps in small intestinal wall with indistinct borders. Among them, the largest mass, measuring approximately 3*3*2.5cm, invaded the serosal layer. Suspected needle-like perforation was found 110cm away from the Treitz ligament, surrounded by attached purulent exudate. In addition, multiple enlarged mesenteric lymph nodes were observed. Based on the intraoperative findings, a palliative partial small bowel resection (total length of 34cm) was performed, centred on the site of the needle-tip perforation. Meanwhile 15 enlarged mesentery lymph nodes were resected. Postoperative gross pathological examination (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea) showed a segment of the small intestine had multiple ulcerated masses exhibiting infiltrative growth and necrotic surfaces. Six resected lymph nodes were metastases. Microscopically, the tumor exhibited poorly differentiated carcinoma with rhabdomyoid and anamorphic large cell morphology. The scattered and diffuse distribution of tumor cells was growing in a poorly cohesive formation (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). Some tumor cells had pleomorphic giant nuclei and abnormal mitotic figures (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec). Immunohistochemistry revealed diffuse positivity for pancytokeratin (pan-CK) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea, b) and vimentin (Vim) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, d), positivity for epithelial membrane antigen (EMA), partial positivity for CK7 and Bcl6, and positivity for Bcl2, c-Myc, and CD10, with Ki-67 reaching 80% (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ee, f). In contrast, desmin, synaptophysin (Syn), smooth muscle actin (SMA), S-100, \u0026beta;-catenin, Myogenin and SALL4 were all negative. According to the immunohistochemical results, it was suspected to be rhabdomyoid undifferentiated carcinoma accompanied by multiple mesenteric lymph node metastases. As the pathological manifestations were not typical, we sent the pathological sections for consultation to the Pathology Department of the Second Xiangya Hospital of Central South University, Hunan Province, China. Further IHC staining analysis shows that the mismatch repair function is complete and programmed death ligand 1(PD-L1) expression was negative. His pathological test was diagnosed with SCA of the small intestine.\u003c/p\u003e\n\u003cp\u003eOne month after partial small bowel resection, the patient was admitted to the Oncology Department of the Second Xiangya Hospital of Central South University, Hunan Province, China, for chemotherapy. On January 27, 2022, the patient received the first cycle of the XELOX regimen (oxaliplatin 200 mg/d1\u0026thinsp;+\u0026thinsp;capecitabine 1500 mg/d2-14). On February 18, 2022, re-examination of the chest CT scan revealed a new mass in the upper left lung hilum, while abdominal CT showed multiple retroperitoneal lymph node metastases, liver and bilateral adrenal metastases. The above revealed disease progression. Considering the ineffective response to one cycle of chemotherapy, low PD-L1 expression and the patient\u0026apos;s refusal to undergo genetic testing for precise targeted therapy guidance, the patient did not have effective anti-cancer drugs yet. On February 23, 2022, the patient voluntarily started exploratory treatment with oral anlotinib 10mg once daily. After a course of treatment, the patient was re-admitted to our hospital. CT scans of the chest and abdomen showed larger metastases in the lungs (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea), bilateral adrenal glands (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb) and liver (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec), compared to previous scans, and peritoneum were seeded new metastases. On March 21, 2022, the patient succumbed to worsening of the disease, cachexia, and concomitant infection.\u003c/p\u003e\n\u003cp\u003eTo explore the molecular characteristics of primary sarcomatoid carcinoma of the small intestine in this patient, formalin-fixed paraffin-embedded (FFPE) tissue samples were sent to Guangzhou Kingmed Diagnostics Group Co., Ltd., for genetic testing of 710 commonly mutated genes using the Illumina NovaSeq 6000 system. A total of 26 nonsynonymous mutations were detected (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e in the attachment), among which the most abundant and clinically significant mutations included a missense mutation in exon 12 of KRAS (c.35G\u0026thinsp;\u0026gt;\u0026thinsp;C, p.G12A, 63.8%), a nonsense mutation in exon 8 of TP53 (c.892G\u0026thinsp;\u0026gt;\u0026thinsp;T, 59.4%), and a missense mutation in exon 8 of PTPRT (c.1185C\u0026thinsp;\u0026gt;\u0026thinsp;G, 15.6%). Additionally, 22 class III variants of unclear clinical significance were detected. No mutations in mismatch repair genes were found, no fusion genes with clear clinical significance were detected, and no microsatellite stability (MSS) was observed.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Literature Review and Discussion","content":"\u003cp\u003eWe conducted a thorough literature search on PubMed, Web of Science and the China National Knowledge Infrastructure (CNKI), covering all reports published up to January 2024 regarding sarcomatoid carcinoma of the small intestine. The search terms included \u0026quot;sarcomatoid carcinoma\u0026quot;, \u0026quot;undifferentiated cancer\u0026quot;, \u0026quot;pleomorphic cancer\u0026quot;, \u0026quot;metaplastic carcinoma\u0026quot;, \u0026quot;anaplastic carcinoma\u0026quot;, \u0026quot;jejunum\u0026quot; and \u0026quot;small intestine\u0026quot;. Reports of SCA occurring outside the small intestine were excluded. A total of 28 case reports, comprising 36 cases (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) were identified.\u003c/p\u003e\n\u003cp\u003ePrimary small intestinal tumours are relatively rare gastrointestinal neoplasms, accounting for less than 5% of all gastrointestinal tumours (Mellouki et al. \u003cspan class=\"CitationRef\"\u003e2018\u003c/span\u003e). The most common types of malignant tumours of the small intestine are adenocarcinomas (40%), followed by neuroendocrine tumours (25%), lymphomas, and sarcomas (Zhao et al. \u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e). The small intestine SCA is extremely rare. The first case of SCA of the small intestine, initially termed\u003c/p\u003e\n\u003cp\u003eintestinal blastoma, was reported in 1973 by Dikman and Toker (Dikman et al. 1973). There have been changes in the nomenclature and classification of SCA over time, with various terms appearing in different studies, including carcinosarcoma, undifferentiated carcinoma, pleomorphic carcinoma, and metaplastic carcinoma. Current cytogenetic and molecular studies have shown that both carcinomatous and sarcomatous components originate from a tumour lineage undergoing sarcomatoid dedifferentiation (Torenbeek et al. \u003cspan class=\"CitationRef\"\u003e1999\u003c/span\u003e); hence, the most commonly accepted term is sarcomatoid carcinoma.\u003c/p\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eClinical features\u003c/h2\u003e\n \u003cp\u003eThe data analysis from 37 small intestine SCA patients in the statistical table (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) revealed that elderly patients were dominant (average age 60.05\u0026thinsp;\u0026plusmn;\u0026thinsp;11.48 years), with a male-to-female ratio of 22:15. Clinical presentations lack specificity and may include anaemia, abdominal pain, gastrointestinal bleeding, and weight loss. The average tumour size at discovery was 6.6 cm (range 2.5\u0026ndash;16 cm), with distant metastasis occurring in 59% of patients at the time of initial diagnosis. The median overall survival (OS) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eb) is only 7 months (range 0.33-36 months). SCA of the small intestine typically presents as a solitary tumour lesion, however, there are also 7 cases (Kwok, \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e; Chen et al., \u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e; Han et al., \u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yin et al., \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e; Fan et al., 2021; Zhu et al., \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e) (including this case) of multifocal small intestine masses. The survival time for these seven patients was significantly shorter than the median OS of 7 months, with the exception of the 10-month survival reported by Yin. Most patients underwent surgical resection, but patients died from tumour metastasis or recurrence.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eCT scan Imaging and molecule imaging\u003c/h2\u003e\n \u003cp\u003eCurrently, relying on CT imaging features to distinguish small intestine SCA from other types of small intestine tumors, such as adenocarcinomas and lymphomas, poses a significant challenge. According to previous reports, the imaging features of the small intestinal SCA are similar to those of other malignant tumours of the small intestine, and the imaging findings are closely related to the gross pathological type. Endophytic, polypoid, and nodular types of the small intestinal SCA CT imaging often present as large masses with uneven enhancement. Ulcerative types manifest as irregular thickening of the intestinal wall and incomplete mucosal lines and can lead to intestinal perforation. In addition, the Small intestinal SCA CT imaging often presents as mild-moderate enhancement and unclear boundaries.\u003c/p\u003e\n \u003cp\u003eIn recent years, PET/CT has been widely used for the imaging of small intestine tumours. \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT, a molecule imaging method, has the unique advantage of simultaneously displaying both the anatomical and metabolic functions of tumours. Reports in the literature (Mankoff et al. \u003cspan class=\"CitationRef\"\u003e2017\u003c/span\u003e) suggested that \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT can detect malignant lesions in the early stages of metabolic abnormalities, and a single imaging session can capture the status of lesions throughout the body, decrease the likelihood of missed distant metastases and aid in clinical staging. In our case, PET/CT identified a newly discovered left adrenal nodule, which exhibited high FDG uptake (SUVmax 5.7), compared to what was observed on enhanced CT.\u003c/p\u003e\n \u003cp\u003eAt present, there is no research report on PET/CT imaging features of the small intestine SCA. Previous studies have reported that primary pulmonary SCA tumours exhibit abnormal uptake of \u003csup\u003e18\u003c/sup\u003eF-FDG, with maximum standardized uptake values (SUVmax) ranging from 4.1 to 35.5 (Luo et al. \u003cspan class=\"CitationRef\"\u003e2024\u003c/span\u003e); the SUVmax of these lesions is often higher than that observed in other types of non-small cell lung cancer (NSCLC). In their retrospective analysis of 24 patients with pulmonary SCA, Wu \u003cem\u003eet al.\u003c/em\u003e reported that the SUVmax in the KRAS mutation group was significantly higher than that in the non-KRAS mutation group (Wu et al. \u003cspan class=\"CitationRef\"\u003e2019\u003c/span\u003e), suggesting a positive correlation between the SUVmax and KRAS expression. This mechanism may be related to the involvement of KRAS oncogenes in metabolic reprogramming. KRAS can up-regulate the expression of the transcription factor MYC through the activation of the MEK/ERK pathway, thereby enhancing glycolytic metabolism to sustain tumour growth (Kerk et al. \u003cspan class=\"CitationRef\"\u003e2021\u003c/span\u003e). In our case, the lesion of SCA of the small intestine had a high SUVmax (approximately 11.2) and carried a KRAS gene mutation. Further research is needed to determine whether small intestine SCA carrying KRAS mutation can be distinguished from other small intestine tumors based on the SUVmax.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eConventional Pathology\u003c/h3\u003e\n\u003cp\u003eThe gross morphology of SCA of the small intestine reported in the literature (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea) can be classified into five types: endophytic, polypoid, ulcerative, nodular, and exophytic, with the endophytic type being more common (29.7%). Some cases have mixed types, such as circumferential endophytic and larger nodular types. Most SCAs involve regional lymph node metastasis, invasive growth, and direct infiltration of adjacent structures.In our case, the patient's first examination revealed multifocal masses in over 6 locations in the small intestine, mostly ulcerative, with small perforations discovered during surgery. The tumor exhibited lymph node metastasis and full-thickness invasive growth.\u003c/p\u003e \u003cp\u003eHistologically, the morphology of SCA cells of the small intestine is highly heterogeneous and pleomorphic. According to literature reports, some SCA cells exhibit monophasic pattern\u0026mdash;cancer cells predominantly show mesenchymal features characterized by pleomorphism and low differentiation changes, with few or no epithelial-like areas(Robey-Cafferty et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e1989\u003c/span\u003e). In addition, some exhibit biphasic pattern\u0026mdash;cancer cells comprise a mixture of epithelioid tumour cells and mesenchymal-like tumour cells, with the mesenchymal component possibly containing heterologous carcinoma cells (Reid-Nicholson et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).This case is a monophasic pattern. Due to the atypical nature of the disease, the patient was initially misdiagnosed as rhabdomyoid undifferentiated carcinoma Therefore, SCA cannot be diagnosed solely based on HE staining; it requires confirmation through immunohistochemistry with multiple biomarkers (CK and vimentin) and extensive experience (Lee et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The pathological diagnosis of small intestine SCA requires the use of various immunohistochemical markers and genetic testing to distinguish it from other malignant tumors, such as leiomyosarcoma or SMARC4-deficient undifferentiated cancers. Additionally, the Ki-67 index of this patient was approximately 80% and his prognosis was poor, which was consistent with previous reports that high Ki-67 positivity was associated with poor prognosis.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMolecular Pathology\u003c/h2\u003e \u003cp\u003eSCA of the small intestine has not yet been covered in databases such as the International Cancer Genome Consortium (ICGC), and its molecular genetic characteristics have not been systematically studied. According to the literature from both domestic and international sources, only one case of primary SCA of the small intestine has been reported with whole-exome mutagenesis analysis (Zhu et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), which identified comutations in the KRAS G13C and TP53 driver genes. In our case, the patient was found to carry three driver gene mutations, including the KRAS G12A point mutation (a relatively rare mutation), TP53, and PTPRT missense mutations. KRAS and TP53 are common key driver genes that play important roles in tumour growth, proliferation, differentiation, and apoptosis across various organs in the body (Lee et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Mutations in KRAS and TP53 were also prevalent in SCA of other organs (Ding et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). However, mutations of PTPRT, an anticancer gene, are relatively rare. A search of the IntOGen database revealed few reports of mutations in colorectal cancer, lung cancer, and skin cancer, with mutations in sarcomatoid carcinoma of the whole body being reported for the first time. PTPRT encodes a tyrosine phosphatase involved in cell adhesion that plays a role in cell-cell adhesion. Variations in PTPRT lead to PTPRT protein inactivation, which results in loss of cell adhesion to the extracellular matrix (ECM) and activation of the epithelial-mesenchymal transition (EMT) program, thereby promoting the metastatic ability of cancer cells (Hu et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCurrently, the co-mutation of multiple driver genes is a hot research topic, with reports indicating a worse prognosis when KRAS and TP53 co-mutate (Shepherd et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Studies have shown that when Kras and TP53 co-mutate, they can up-regulate the expression of YTHDF1 and Cyclin B1, which reduce the latency period and increase the tendency to metastasize, thereby worsening the prognosis (Lou et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Notably, Zhu \u003cem\u003eet al.\u003c/em\u003e reported a case of small intestine sarcomatoid carcinoma with co-driver gene mutations (KRAS G13C, TP53). The patient's condition worsened further after one cycle of postoperative chemotherapy (IFO\u0026thinsp;+\u0026thinsp;epirubicin), and his survival time was significantly shorter than the median overall survival (7 months). Therefore, further research is needed to investigate the correlation between multiple co-driver gene mutations and the malignancy and invasiveness of small intestinal SCA.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eTreatment and Prognosis\u003c/h2\u003e \u003cp\u003eThere are currently no specific guidelines for the treatment of SCA of the small intestine. SCAs are generally insensitive to radiotherapy and chemotherapy, and wide tumour resection remains the mainstay of treatment. The rapid development of targeted molecular therapy for tumours has provided more treatment options for cancer patients. However, for cases of SCA such as this one, in which PD-L1 expression is negative, targeted therapy with PD-L1 monoclonal antibodies may not yield significant benefits (Jiang et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Numerous studies have reported that anlotinib has good anticancer activity against various solid tumours, such as soft tissue sarcoma (Wang et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), non-small cell lung cancer (Han et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), and small cell lung cancer (Zheng et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), prolonging progression-free survival (PFS) and overall survival (OS). It is a novel multi-targeted tyrosine kinase inhibitor that can block angiogenesis induced by vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), effectively inhibiting tumour angiogenesis and inducing tumour apoptosis due to nutrient deprivation (Li \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Therefore, the patient voluntarily opted for exploratory treatment with anlotinib (The consent form is submitted in the attachment). However, the patient's condition continued to progress after one cycle of standardized oral anlotinib, and the patient subsequently died. Therefore, whether anlotinib has anticancer effects on SCA requires further clinical research.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSmall intestine SCA is extremely rare, highly invasive, prone to early metastasis, and associated with a short median survival time. This report describes a case of primary small intestine multiple sarcomatoid carcinoma, which lacks specificity in CT and molecular imaging.Systematic genetic testing revealed three co-driving gene mutations (KRAS, TP53, PTPRT), with PTPRT being the first reported mutation in sarcomatoid carcinoma. In this case, the multi-target tyrosine kinase inhibitor anlotinib was used for treatment, but the patient still progressed and died in the short term. This case enriches the gene lineage of small intestinal sarcomatoid carcinoma, potentially providing references for the diagnosis and treatment of this disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe authors thank the patient and patient\u0026rsquo;s kin for agreeing to the publication of the report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of non-duplication\u003c/strong\u003e We certify that this manuscript is a unique submission and is not being considered for publication by any other source in any medium. Further, the manuscripthas not been published, in part or in full, in any form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis study was supported by the scientific research project of Hunan Provincial\u0026nbsp;Health\u0026nbsp;(Grant\u0026nbsp;NO.D202309047172)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWe certify thatwe have no afliations with any organization or entity with any financial interest or non-financial interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eXiaohua Ruan\u0026nbsp;contributed to the study thesis ideas and design.\u0026nbsp;Dan Liu\u0026nbsp;and\u0026nbsp;Xulin Li\u0026nbsp;wrote the manuscript.\u0026nbsp;Hui Xie\u0026nbsp;and\u0026nbsp;Birong\u0026nbsp;Yin\u0026nbsp;provided images of pathological staining.\u0026nbsp;Qingcheng Li,Yanhong\u0026nbsp;Xie,\u0026nbsp;Yi\u0026nbsp;Tang\u0026nbsp;and Wu\u0026nbsp;Luo\u0026nbsp;were responsible for the clinical treatment and follow-up of the patient. All authors critically reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe data used to support the findings of this study are included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThis study was approved by the Ethics Committee of East Hospital of Shaoyang Central Hospital\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAndrawes PA, Shariff M, Chang Q, Grinberg R (2017) Primary sarcomatoid carcinoma of the small intestine: very rare and aggressive tumour. BMJ Case Rep 2017:bcr2016217895. https://doi.org/10.1136/bcr-2016-217895\u003c/li\u003e\n \u003cli\u003eChen JX, Jiang GM, Li RP, Li LB, Wang JY (2017) Multiple primary sarcomatoid carcinoma of the jejunum with postoperative lung and brain metastases: a case report and literature review. 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JAMA Oncol 4:1569-1575. https://doi.org/10.1001/jamaoncol.2018.3039\u003c/li\u003e\n \u003cli\u003eHan XY, Liu J, Pan Q, Shen ZL, Lai LQ, Wei HQ (2017) Multifocal sarcomatoid carcinoma of small intestine with osteogenic differentiation: report of a case. Zhonghua Bing Li Xue Za Zhi 46:118-119. https://doi.org/10.3760/cma.j.issn.0529-5807.2017.02.014\u003c/li\u003e\n \u003cli\u003eHu Z, Ding J, Ma Z et al (2019) Quantitative evidence for early metastatic seeding in colorectal cancer. Nat Genet 51:1113-1122. https://doi.org/10.1038/s41588-019-0423-x\u003c/li\u003e\n \u003cli\u003eJiang Y, Chen M, Nie H, Yuan Y (2019) PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother 15:1111-1122. https://doi.org/10.1080/21645515.2019.1571892\u003c/li\u003e\n \u003cli\u003eKerk SA, Papagiannakopoulos T, Shah YM, Lyssiotis CA (2021) Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat. Rev. Cancer 21:510-525. https://doi.org/10.1038/s41568-021-00375-9\u003c/li\u003e\n \u003cli\u003eKwok CM (2016) Sarcomatoid carcinoma of the jejunum with gastric metastases: a case report and review of the literature. Int J Surg Case Rep 28:161-164. https://doi.org/10.1016/j.ijscr.2016.09.046\u003c/li\u003e\n \u003cli\u003eLee HM, Cho MS, Kim YI (2015) A surgically resected large sarcomatoid carcinoma of the jejunum: a case report and literature review. J Gastric Cancer 15:143-146. https://doi.org/10.5230/jgc.2015.15.2.143\u003c/li\u003e\n \u003cli\u003eLee JK, Sivakumar S, Schrock AB et al (2022) Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol 6:91. https://doi.org/10.1038/s41698-022-00334-z\u003c/li\u003e\n \u003cli\u003eLi S (2021) Anlotinib: a novel targeted drug for bone and soft tissue sarcoma. Front Oncol 11:664853. https://doi.org/10.3389/fonc.2021.664853\u003c/li\u003e\n \u003cli\u003eLou X, Ning J, Liu W, Li K, Qian B, Xu D, Wu Y, Zhang D, Cui W (2021) YTHDF1 promotes cyclin B1 translation through m(6)A modulation and contributes to the poor prognosis of lung adenocarcinoma with KRAS/TP53 co-mutation. Cells 10:1669. https://doi.org/10.3390/cells10071669\u003c/li\u003e\n \u003cli\u003eLuo ZH, Luo XY, Qi WL, Liu Q (2024) \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT imaging in pulmonary sarcomatoid carcinoma. Front Oncol 14:1334156. https://doi.org/10.3389/fonc.2024.1334156\u003c/li\u003e\n \u003cli\u003eMankoff DA, Farwell MD, Clark AS, Pryma DA (2017) Making molecular imaging a clinical tool for precision oncology: a review. JAMA Oncol 3:695-701. https://doi.org/10.1001/jamaoncol.2016.5084\u003c/li\u003e\n \u003cli\u003eMellouki I, Jellali K, Ibrahimi A (2018) Tumors of the small bowel: about 27 cases. Pan Afr Med J 30:13. https://doi.org/10.11604/pamj.2018.30.13.5407\u003c/li\u003e\n \u003cli\u003eReid-Nicholson M, Idrees M, Perino G, Hytiroglou P (2004) Sarcomatoid carcinoma of the small intestine: a case report and review of the literature. Arch Pathol Lab Med 128:918-921. https://doi.org/10.5858/2004-128-918-scotsi\u003c/li\u003e\n \u003cli\u003eRobey-Cafferty SS, Silva EG, Cleary KR (1989) Anaplastic and sarcomatoid carcinoma of the small intestine: a clinicopathologic study. Hum Pathol 20:858-863. https://doi.org/10.1016/0046-8177(89)90097-x\u003c/li\u003e\n \u003cli\u003eShepherd FA, Lacas B, Le Teuff G et al (2017) Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 35:2018-2027. https://doi.org/10.1200/jco.2016.71.2893\u003c/li\u003e\n \u003cli\u003eTorenbeek R, Hermsen MA, Meijer GA, Baak JP, Meijer CJ (1999) Analysis by comparative genomic hybridization of epithelial and spindle cell components in sarcomatoid carcinoma and carcinosarcoma: histogenetic aspects. J Pathol 189:338-343. https://doi.org/10.1002/(sici)1096-9896(199911)189:3\u0026lt;338::Aid-path429\u0026gt;3.0.Co;2-q\u003c/li\u003e\n \u003cli\u003eWang ZM, Zhuang RY, Guo X, Zhang CL, You Y, Chen LS, Liu WS, Zhang Y, Luo RK, Hou YY, Lu WQ, Zhou YH (2022) Anlotinib plus epirubicin followed by anlotinib maintenance as first-line treatment for advanced soft-tissue sarcoma: an open-label, single-arm, phase II trial. Clin Cancer Res 28:5290-5296. https://doi.org/10.1158/1078-0432.Ccr-22-1903\u003c/li\u003e\n \u003cli\u003eWu X, Huang Y, Li Y, Wang Q, Wang H, Jiang L (2019) \u003csup\u003e18\u003c/sup\u003e F-FDG PET/CT imaging in pulmonary sarcomatoid carcinoma and correlation with clinical and genetic findings. Ann. Nucl. Med. 33:647-656. https://doi.org/10.1007/s12149-019-01374-5\u003c/li\u003e\n \u003cli\u003eYin A, Liu Y, He H, Chen MK (2019) A case of multiple sarcomatoid carcinomas of the small intestine. Chin. J. Dig. Endosc. 36:291-292. https://doi.org/10.3760/cma.j.issn.1007-5232.2019.04.016.\u003c/li\u003e\n \u003cli\u003eZhao Z, Xu G, Chen Y, Wang X (2017) Advances in diagnosis and treatment of primary malignant tumors of the small intestine. Chin. J. Gastrointest. Surg. 20:117-120. https://doi.org/10.3760/cma.j.issn.1671-0274.2017.01.029\u003c/li\u003e\n \u003cli\u003eZheng HR, Jiang AM, Gao H, Liu N, Zheng XQ, Fu X, Ruan ZP, Tian T, Liang X, Yao Y (2022) The efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a Chinese multicenter real-world study. Front Oncol 12:894835. https://doi.org/10.3389/fonc.2022.894835\u003c/li\u003e\n \u003cli\u003eZhu Z, Liu X, Li W et al (2021) A rare multiple primary sarcomatoid carcinoma (SCA) of small intestine harboring driver gene mutations: a case report and a literature review. Transl Cancer Res 10:1150-1161. https://doi.org/10.21037/tcr-20-2829\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\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":"Small intestine SCA, Driver genes, KRAS, TP53, PTPRT","lastPublishedDoi":"10.21203/rs.3.rs-4433771/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4433771/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSarcomatoid carcinoma (SCA) is a relatively rare malignant tumor, and primary SCA occurring in the small intestine is even rarer, characterized by the co-existence of malignant epithelial cells and sarcomatoid differentiation (spindle/giant cell) components. Compared with other malignant tumors in the small intestine, it has greater invasiveness and earlier metastasis.\u003c/p\u003e\u003ch2\u003eCase presention\u003c/h2\u003e \u003cp\u003eWe provide a complete case report on the clinical, imaging, genetic characterization, and treatment process of primary multiple small intestinal SCA. The patient underwent surgery, XELOX chemotherapy, and exploratory application of a multi-target tyrosine kinase inhibitor\u0026mdash;anlotinib, however the condition progressed rapidly and he died within 3 months. This is the second report of systematic gene sequencing in the small intestine SCA, and co-mutations in key driving genes of KRAS, TP53, and PTPRT have been identified, with PTPRT being the first reported mutation in SCA.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSmall intestine SCA has highly invasiveness and poor prognosis, while according to our statistical data primary multifocal small intestine SCA may have an even poor prognosis. This case was treated exploratorily with a multi-target tyrosine kinase inhibitor, anlotinib, but did not effectively control tumor growth and disease progression. This case provides reference guidance for the treatment of rare diseases such as sarcomatoid carcinoma in the future.\u003c/p\u003e","manuscriptTitle":"A case report and literature review of a rare primary multiple small intestinal sarcomatoid carcinoma with co-driver gene mutations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 14:28:48","doi":"10.21203/rs.3.rs-4433771/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":"bf74985c-f77d-448b-8c8c-a135769294a2","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-03T14:36:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-03 14:28:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4433771","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4433771","identity":"rs-4433771","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}