Squamous cell carcinoma and adenocarcinoma appeared at different cervical sites: a rare case report

Squamous cell carcinoma and adenocarcinoma appeared at different cervical sites: a rare case report | 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 Squamous cell carcinoma and adenocarcinoma appeared at different cervical sites: a rare case report Huihui Chen, Qingqi Wang, Min King, Wei Huang, Hao zhang, Jiaxin Li, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4558733/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 May, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background The concurrent development of adenocarcinoma and squamous cell carcinoma in separate regions of the cervix is extremely rare. We report a case of HPV-related adenocarcinoma and squamous cell carcinoma occurring at distinct locations within the cervix in a patient with primary cervical cancer stage IA1. Case presentation A 54-year-old female patient was found to be HPV type 18 positive during a routine physical examination, with Liquid-based Cytology Test (LCT) of the cervix indicating Atypical Squamous Cells of Undetermined Significance (ASCUS). Subsequent colposcopy-directed cervical biopsies identified mid-to-low grade squamous cell carcinoma at several locations (3, 6, 9, 12 o'clock positions and the ECC),and the clinical diagnosis was stage IA1. Preoperative comprehensive abdominal magnetic resonance imaging, including contrast enhancement, did not indicate any lymph node enlargement, and computed tomography urography of the urinary system was unremarkable. The squamous cell carcinoma antigen level was within the normal range. On May 22, 2023, the patient underwent laparoscopic radical resection of cervical cancer under general anesthesia and the postoperative pathology indicated HPV-related squamous cell carcinoma of the cervix (at 11-12 o'clock positions) and HPV-related cervical adenocarcinoma (at 1 o'clock and 3-4 o'clock positions). No cancer invasion was found in the vagina, vaginal margin, or bilateral parametrium. There was no lymphovascular, blood vessel, or nerve invasion. Immunohistochemistry: Adenocarcinoma: Ki-67(90%+), P40(-), P16(diffuse+), MLH1(+), MSH2(+), MSH6(+), PMS2(+), P53(-, mutant type), CK7(+), CEA(+), ER(-), PR(-); Squamous cell carcinoma: P40(partial+), P63(+), ki-67(90%+), CK7(+), P16(diffuse+). Conclusions In this instance, the concurrent manifestation of both squamous cell carcinoma and adenocarcinoma in the cervix, both associated with HPV infection, underscores the likely pivotal role of HPV infection in this unusual phenomenon.Proactive HPV vaccination at an early stage is an effective preventive measure, and regular cervical cancer screenings can aid in the early identification of lesions, leading to improved treatment results. Squamous cell carcinoma Aadenocarcinoma Cervical cancer HPV Case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Cervical cancer is one of the more common malignancies worldwide. In 2020, there were approximately 604,000 new cases and 342,000 deaths globally. The incidence and mortality rates of cervical cancer vary significantly among different countries and regions, with 85% of deaths occurring in developing countries. Particularly, countries in sub-Saharan Africa have the highest mortality rate[1]。 The incidence of cervical cancer is significantly associated with age, primarily occurring in women aged 35 to 55 years. Approximately 84% of cervical cancers are caused by persistent high-risk human papillomavirus (HPV) infection[2], with types 16 and 18 being the primary oncogenic high-risk HPV viruses. HPV induces the transformation of normal epithelial cells into cancer cells mainly through oncogenic E proteins. Currently, the pathological types of cervical cancer are mainly squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and other rare types such as neuroendocrine carcinoma, small cell carcinoma, mucinous carcinoma, clear cell carcinoma, serous carcinoma, and endometrioid adenocarcinoma. Usually, a single type of cancer occurs, with mixed types being less common. In terms of clinical treatment guidance, the current pathological classification further categorizes cervical cancers into HPV-associated and HPV-independent types. This is considered one of the most important developments in gynecological pathology over the past 50 years, leading to a shift in the classification system of cervical cancer. In this case, HPV-related adenocarcinoma and HPV-related squamous cell carcinoma occurred at different sites of the cervix, which is a very rare phenomenon. Both types of cancer were HPV-related, and the patient was diagnosed with a single HPV type 18 positive. This suggests that high-risk HPV type 18 infection may be the cause of this phenomenon. Case presentation A 54-year-old asymptomatic female patient was found to be HPV type 18 positive during a routine physical examination on April 27, 2023. The Liquid-based Cytology Test (LCT) of the cervix indicated Atypical Squamous Cells of Undetermined Significance (ASCUS). Further colposcopy-guided cervical biopsy revealed mid-to-low grade squamous cell carcinoma at multiple sites (3, 6, 9, 12 o'clock positions and ECC). The clinical diagnosis was stage IA1. Preoperative full abdominal magnetic resonance imaging scanning and enhancement, as well as urinary system CTU did not show any abnormalities(Fig. 1 ). The SCC antigen level was 1.61 ng/ml, and CEA, AFP, CA199, CA125 were all within the normal range. The patient had a history of tubal ligation via laparotomy, no underlying diseases, did not smoke or drink alcohol, and worked as a regular company employee without engaging in high-risk occupations. In terms of family history, her father had liver cancer, and her brother had colon cancer. On May 22, 2023, the patient underwent a radical hysterectomy and bilateral adnexectomy, pelvic lymphadenectomy, and para-aortic lymphadenectomy under general anesthesia. During the surgery, the uterus was found to be of normal size, with a smooth surface and good mobility. No abnormalities were observed in the appearance of both ovaries and fallopian tubes. No enlarged lymph nodes were found in the pelvic and retroperitoneal areas. Upon exploration of the upper abdomen, no obvious abnormalities were observed on the surface of the intestines, peritoneum, and omentum. The liver, gallbladder, and appendix appeared normal upon examination. A whole uterus specimen was removed after surgery, there was no obvious macroscopic lesion in the cervix(Fig. 2 ). Postoperative pathology of the surgical specimen indicated: I. (Total uterus) Tumor location: cervix. Tumor size: at 1 o'clock, 3–4 o'clock, and 11–12 o'clock positions of the cervix. Histological type: HPV-related squamous cell carcinoma of the cervix (at 11–12 o'clock positions) and HPV-related cervical adenocarcinoma (at 1 o'clock and 3–4 o'clock positions). Cervical infiltration depth: The squamous cell carcinoma had a maximum width of 0.4cm and a maximum infiltration depth of 0.2cm under microscopy; the adenocarcinoma had a maximum width of 1cm and a maximum infiltration depth of 0.4cm. The invasion of the cervix was less than 1/2 (cervical wall thickness was about 2cm). Involvement at the uterine junction: none, serosal involvement: none, cervical stromal involvement: none, involvement of other tissues/organs: none. Margins: No cancer invasion was found in the vagina, vaginal margin, or bilateral parametrium. No lymphovascular, blood vessel, or nerve invasion was observed.Immunohistochemistry: Adenocarcinoma: Ki-67(90%+), P40(-), P16(diffuse+), MLH1(+), MSH2(+), MSH6(+), PMS2(+), P53(-, mutant type), CK7(+), CEA(+), ER(-), PR(-); Squamous cell carcinoma: P40(partial+), P63(+), ki-67(90%+), CK7(+), P16(diffuse+). Detailed in the Fig. 3 . Genetic testing revealed 3 somatic mutations, including 1 mutation related to targeted therapy and 1 mutation related to immunotherapy. The gene mutations related to targeted therapy include an activating NRAS mutation p.Q61K (mutation rate % copy number 3.06), and EP300 (mutation rate % copy number 6.26). Genes not detected include: ALK, BRAF, BRCA1, BRCA2, EGFR, PIK3CA, FGFR2, FGFR3, ERBB2(HER2), KIT, KRAS, MET, IDH1, etc. For immunotherapy, PD-L1 TPS < 1%, CPS < 1 was detected, and KEAP1 (mutation rate % copy number 4.46). Microsatellite instability (MSI) suggests microsatellite stability (MSS). The tumor mutation burden (TMB) is 0.66 Muts/Mb. Both HLA-I and HLA-II are heterozygous. Viral sequence detection indicates HPV type 18 positive. No mutations were detected in homologous recombination repair (HRR) related genes; pathogenic germline mutation testing suggests no familial cancer genetic risk. The specific mutation situation is detailed in the Table 1 . Table 1 The mutations detected in surgical specimen. Type Gene Detection target Result Target NRAS p.Q61K 3.06 (mutation rate % copy number ) EP300 Exon31 6.26(mutation rate % copy number ) ALK Fusions、G1202R not detected Immune-related gene PD-L1 - TPS < 1%,CPS < 1 KEAP1 Exon2, P.A191T 4.46(mutation rate % copy number ) The tumor mutation burden (TMB) - - 0.66Muts/Mb human leucocyte antigen(HLA) HLA-I, HLA-II HLA-A,HLA-B,HLA-C,HLA-DPB1,HLA-DQB1,HLA-DRB1 hybrid subtype Viral sequence detection HPV HPV-16/18/58/52/33/31/45/6b/11 HPV type 18 positive pathogenic germline mutation testing - - no familial cancer genetic risk The patient recovered well after surgery and received three cycles of TC regimen chemotherapy. Postoperative tumor markers including SCC, CEA, AFP, and CA125 were all within the normal range. A full abdominal MR scan and enhancement were performed three months after the surgery, as shown in Fig. 4 . On August 13, 2023, the HPV test result was negative.The patient is currently under regular follow-up. Discussion and conclusions In this case, the patient developed adenocarcinoma and squamous cell carcinoma at different sites of the cervix after infection with HPV type 18, which is a rare phenomenon. The pathological types of cervical cancer are divided into squamous cell carcinoma (accounting for about 70%-90%),adenocarcinoma (accounting for about 10%-20%), and rare types of cancer (accounting for about 2%-5%), including mixed carcinoma, small cell carcinoma, etc[3]. The surface of the cervix is composed of stratified squamous epithelium and columnar epithelium covering the cervical canal and the area around the cervical os. The area where the squamous and columnar epithelia meet is called the transformation zone. This area is susceptible to HPV infection and is a common site for tumor development[4].The histological origin of cervical cancer is still unclear. In recent years, with the rise of the cancer stem cell theory, some scholars believe that cervical cancer stem cells may be the histological origin of cervical cancer[5],Cervical stem cells are special cells located in the cervical transformation zone. They have high proliferative and differentiation potential and are the basis for the transformation between squamous epithelium and columnar epithelium in the transformation zone. When cervical stem cells are persistently infected with HPV,they proliferate and differentiate abnormally under the interaction of HPV oncogenes and cellular changes, forming squamous cell carcinoma, adenocarcinoma, or other types of cancer [6, 7]. High-risk human papillomavirus (HPV) infection is the main cause of cervical cancer, especially HPV types 16 and 18 (which account for about 70% of cervical cancer patients) [8],Human papillomavirus 18 (HPV18) is the second most carcinogenic HPV type after HPV16, accounting for about 12% of cervical squamous cell carcinoma (SCC) and 37% of adenocarcinoma (ADC) globally[9].The mechanism by which HPV causes cervical cancer is related to the oncogenic E proteins. The E6/E7 genes can integrate into the DNA of cervical epithelial cells, disrupting the regulation of proliferation and differentiation, and ultimately leading to transformation[10]. The histological differentiation of human papillomavirus (HPV) infected cells is not yet explained. Research by Yao et al[5]. found that the oncogenic E6/E7 genes in HPV can integrate into the DNA of cervical stem cells, disrupting the regulation of cell proliferation and differentiation, and affecting Notch signaling, causing cancerous cervical stem cells to differentiate into different pathological types.Khelil et al [11]. performed RNA sequencing and immunofluorescence mapping on 279 cases of HPV-related cervical cancer and found three molecular subtypes of cervical cancer, with cervical reserve cell tumors being the most common, and the phenotype of cervical reserve cells being a proliferative phenotype.Kusakabe et al. performed genomic and transcriptomic analysis on 42 cases of HPV-positive cervical cancer tissues, and through phylogenetic analysis and evaluation of HPV integration sites, they found that cancer cells of different histological types have a common cellular origin, especially HPV18-positive cancer tissues retain the immune-cold component of stem cell characteristics, and are more likely to develop mixed cancers[12].Therefore, in this case, the HPV18 infection may be closely linked to the occurrence of two different histological types at different sites in the cervix, although further studies are needed for confirmation. This case is a HPV18-positive cervical cancer. In the detection of tumor tissues, a mutation in the EP300 gene related to the Notch signaling pathway was found. The Notch signaling pathway is mainly related to cell proliferation and tumor suppression functions. The detection also found a mutation in the NRAS gene related to the MAPK and PIK3 signaling pathways, and these pathways are related to cell carcinogenesis. This suggests that the HPV18 virus can cause carcinogenesis by affecting and changing multiple signaling pathways, thereby altering cell proliferation, immune functions, etc. Therefore, it is also possible that HPV18 infected cervical stem cells and differentiated into different cancers at different sites, leading to this rare phenomenon. Unfortunately, this case did not perform cell homology analysis at different sites, so it is not possible to confirm whether the adenocarcinoma and squamous cell carcinoma in this case are homologous. However, the fact that HPV18 tends to cause rare pathological types of cervical cancer is still worth attention. Additionally, the prognosis and treatment sensitivity of this mixed carcinoma warrant long-term follow-up and monitoring Vaccination against cervical HPV at an early age is recommended. Studies have shown that vaccination can effectively reduce infection and effectively prevent cervical cancer[13].Regular screening for cervical cancer is also important. If persistent infection with type 16 or 18 is detected, active annual screening for cervical cancer should be carried out for early detection and treatment[14].In conclusion, although high-risk HPV infection is common, it should be taken seriously,and active prevention and screening are necessary. Declarations Funding No funds to support this work. Conflicts of interest/Competing interests I declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Ethics approval and consent to participate This study was approved by the institutional ethics committee of Zhuhai Hospital of Traditional Chinese and Western Medicine (Ethic code:20190412001). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee, and the consent for participate was approved by the ethics committee. Availability of data and material Not applicable Consent for publication Not applicable. Authors' contributions Huihui Chen; Data collection, Manuscript writing and editing, and Protocol. Qingqi Wang ;Manuscript editing.MinKing; Project development, Manuscript editing. Wei Huang;Data collection Hao Zhang,Jiaxin Li, Donghan Xu,Lin Zhao,Bowen Wu,Xin Lin,Liqi Li,Yuhong Zheng,Yihao Niu;Project development and Manuscript editing. Peiyu Yan and Donghui Huang; Project development and Manuscript editing.All authors read and approved the final manuscript. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries . CA-CANCER J CLIN 2021, 71 (3):209-249. Perkins RB, Wentzensen N, Guido RS, Schiffman M: Cervical Cancer Screening: A Review . JAMA-J AM MED ASSOC 2023, 330 (6):547-558. Siegel RL, Miller KD, Wagle NS, Jemal A: Cancer statistics, 2023 . CA-CANCER J CLIN 2023, 73 (1):17-48. Small WJ, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, Jhingran A, Kitchener HC, Mileshkin LR, Viswanathan AN et al : Cervical cancer: A global health crisis . CANCER-AM CANCER SOC 2017, 123 (13):2404-2412. Yao T, Lu R, Zhang Y, Zhang Y, Zhao C, Lin R, Lin Z: Cervical cancer stem cells . CELL PROLIFERAT 2015, 48 (6):611-625. López J, Ruíz G, Organista-Nava J, Gariglio P, García-Carrancá A: Human papillomavirus infections and cancer stem cells of tumors from the uterine cervix . Open Virol J 2012, 6 :232-240. Herfs M, Yamamoto Y, Laury A, Wang X, Nucci MR, McLaughlin-Drubin ME, Münger K, Feldman S, McKeon FD, Xian W et al : A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer . P NATL ACAD SCI USA 2012, 109 (26):10516-10521. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, Tous S, Felix A, Bravo LE, Shin HR et al : Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study . LANCET ONCOL 2010, 11 (11):1048-1056. Chen AA, Gheit T, Franceschi S, Tommasino M, Clifford GM: Human Papillomavirus 18 Genetic Variation and Cervical Cancer Risk Worldwide . J VIROL 2015, 89 (20):10680-10687. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC: Human papillomavirus and cervical cancer . LANCET 2013, 382 (9895):889-899. Khelil M, Griffin H, Bleeker M, Steenbergen R, Zheng K, Saunders-Wood T, Samuels S, Rotman J, Vos W, van den Akker BE et al : Delta-Like Ligand-Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis . CANCER RES 2021, 81 (7):1909-1921. Kusakabe M, Taguchi A, Tanikawa M, Wagatsuma R, Yamazaki M, Tsuchimochi S, Toyohara Y, Kawata A, Baba S, Ueno T et al : Cells with stem-like properties are associated with the development of HPV18-positive cervical cancer . CANCER SCI 2023, 114 (3):885-895. Yang X, Li Y, Tang Y, Li Z, Wang S, Luo X, He T, Yin A, Luo M: Cervical HPV infection in Guangzhou, China: an epidemiological study of 198,111 women from 2015 to 2021 . EMERG MICROBES INFEC 2023, 12 (1):e2176009. Skolnik JM, Morrow MP: Vaccines for HPV-associated diseases . MOL ASPECTS MED 2023, 94 :101224. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 22 May, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 17 Jun, 2024 Editor assigned by journal 16 Jun, 2024 Submission checks completed at journal 16 Jun, 2024 First submitted to journal 10 Jun, 2024 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. 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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-4558733","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":315289880,"identity":"8d6ef101-4b74-4fb4-9d2c-7d1b1a276868","order_by":0,"name":"Huihui Chen","email":"","orcid":"","institution":"Macau University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Huihui","middleName":"","lastName":"Chen","suffix":""},{"id":315289881,"identity":"afde4d05-b8e1-424f-840c-c36b8db8e9b4","order_by":1,"name":"Qingqi Wang","email":"","orcid":"","institution":"Zhuhai Hospital of Integrated Traditional Chinese and 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14:46:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4558733/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4558733/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11114-y","type":"published","date":"2025-05-22T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60352679,"identity":"e166452c-3a22-4288-9e96-247eb786a047","added_by":"auto","created_at":"2024-07-15 23:36:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61513,"visible":true,"origin":"","legend":"\u003cp\u003ePreoperative magnetic resonance imaging. (A) PreoperativeT2-weighted sagittal imaging. (B) Preoperative T1-weighted contrast-enhanced sagittal imaging. (C) Preoperative fat-suppressed T2-weighted axial imaging.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4558733/v1/1a9e062b4efa55c0d02eb265.jpg"},{"id":60352678,"identity":"17360955-26b8-4dc2-ba78-7b50063e94c9","added_by":"auto","created_at":"2024-07-15 23:36:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32203,"visible":true,"origin":"","legend":"\u003cp\u003ePostoperative whole uterus specimen.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4558733/v1/dd211573b5422dfeeb1d6f4c.jpg"},{"id":60353862,"identity":"b8876e68-2a30-4b95-9193-1a86121d5715","added_by":"auto","created_at":"2024-07-15 23:44:36","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":162974,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemistry of the specimen. \u003cstrong\u003e(A)\u003c/strong\u003e Cervical squamous cell carcinoma, with cancer cell nests infiltrating the cervical stroma, and single cell keratinization observed (HE×200). \u003cstrong\u003e(B) \u003c/strong\u003eCervical squamous cell carcinoma,Immunohistochemistry P63. \u003cstrong\u003e(C)\u003c/strong\u003eCervical squamous cell carcinoma,Immunohistochemistry P16（IHC×100）.\u003cstrong\u003e(D)\u003c/strong\u003e Cervical adenocarcinoma, with glandular and sieve-like cell nests infiltrating the cervical stroma（HE×100）. \u003cstrong\u003e(E) \u003c/strong\u003eCervical adenocarcinoma,Immunohistochemistry CEA（IHC×100）.\u003cstrong\u003e(F)\u003c/strong\u003eCervical adenocarcinoma,Immunohistochemistry P16（IHC×100）.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4558733/v1/08ab8c9af790e7ff01ae59be.jpg"},{"id":60354438,"identity":"684186ff-c9c5-4dcc-9267-5a7cda84ac36","added_by":"auto","created_at":"2024-07-15 23:52:36","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38134,"visible":true,"origin":"","legend":"\u003cp\u003ePostoperative magnetic resonance imaging. \u003cstrong\u003e(A)\u003c/strong\u003ePostoperative sagittal T1 enhancement. \u003cstrong\u003e(B) \u003c/strong\u003ePostoperative axial fat-suppressed T2-weighted imaging.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4558733/v1/38354039d66f62eb411e2b3b.jpg"},{"id":83459999,"identity":"a30c3d23-369b-4f3c-9a57-8e1f9743370a","added_by":"auto","created_at":"2025-05-26 16:08:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1223947,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4558733/v1/84d160c1-79ec-4fa6-93bc-fedde96fc1e2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Squamous cell carcinoma and adenocarcinoma appeared at different cervical sites: a rare case report","fulltext":[{"header":"Background","content":"\u003cp\u003eCervical cancer is one of the more common malignancies worldwide. In 2020, there were approximately 604,000 new cases and 342,000 deaths globally. The incidence and mortality rates of cervical cancer vary significantly among different countries and regions, with 85% of deaths occurring in developing countries. Particularly, countries in sub-Saharan Africa have the highest mortality rate[1]。\u003c/p\u003e \u003cp\u003eThe incidence of cervical cancer is significantly associated with age, primarily occurring in women aged 35 to 55 years. Approximately 84% of cervical cancers are caused by persistent high-risk human papillomavirus (HPV) infection[2], with types 16 and 18 being the primary oncogenic high-risk HPV viruses. HPV induces the transformation of normal epithelial cells into cancer cells mainly through oncogenic E proteins. Currently, the pathological types of cervical cancer are mainly squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and other rare types such as neuroendocrine carcinoma, small cell carcinoma, mucinous carcinoma, clear cell carcinoma, serous carcinoma, and endometrioid adenocarcinoma. Usually, a single type of cancer occurs, with mixed types being less common.\u003c/p\u003e \u003cp\u003eIn terms of clinical treatment guidance, the current pathological classification further categorizes cervical cancers into HPV-associated and HPV-independent types. This is considered one of the most important developments in gynecological pathology over the past 50 years, leading to a shift in the classification system of cervical cancer. In this case, HPV-related adenocarcinoma and HPV-related squamous cell carcinoma occurred at different sites of the cervix, which is a very rare phenomenon. Both types of cancer were HPV-related, and the patient was diagnosed with a single HPV type 18 positive. This suggests that high-risk HPV type 18 infection may be the cause of this phenomenon.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 54-year-old asymptomatic female patient was found to be HPV type 18 positive during a routine physical examination on April 27, 2023. The Liquid-based Cytology Test (LCT) of the cervix indicated Atypical Squamous Cells of Undetermined Significance (ASCUS). Further colposcopy-guided cervical biopsy revealed mid-to-low grade squamous cell carcinoma at multiple sites (3, 6, 9, 12 o'clock positions and ECC). The clinical diagnosis was stage IA1. Preoperative full abdominal magnetic resonance imaging scanning and enhancement, as well as urinary system CTU did not show any abnormalities(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The SCC antigen level was 1.61 ng/ml, and CEA, AFP, CA199, CA125 were all within the normal range. The patient had a history of tubal ligation via laparotomy, no underlying diseases, did not smoke or drink alcohol, and worked as a regular company employee without engaging in high-risk occupations. In terms of family history, her father had liver cancer, and her brother had colon cancer.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOn May 22, 2023, the patient underwent a radical hysterectomy and bilateral adnexectomy, pelvic lymphadenectomy, and para-aortic lymphadenectomy under general anesthesia. During the surgery, the uterus was found to be of normal size, with a smooth surface and good mobility. No abnormalities were observed in the appearance of both ovaries and fallopian tubes. No enlarged lymph nodes were found in the pelvic and retroperitoneal areas. Upon exploration of the upper abdomen, no obvious abnormalities were observed on the surface of the intestines, peritoneum, and omentum. The liver, gallbladder, and appendix appeared normal upon examination.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA whole uterus specimen was removed after surgery, there was no obvious macroscopic lesion in the cervix(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Postoperative pathology of the surgical specimen indicated: I. (Total uterus) Tumor location: cervix. Tumor size: at 1 o'clock, 3\u0026ndash;4 o'clock, and 11\u0026ndash;12 o'clock positions of the cervix. Histological type: HPV-related squamous cell carcinoma of the cervix (at 11\u0026ndash;12 o'clock positions) and HPV-related cervical adenocarcinoma (at 1 o'clock and 3\u0026ndash;4 o'clock positions). Cervical infiltration depth: The squamous cell carcinoma had a maximum width of 0.4cm and a maximum infiltration depth of 0.2cm under microscopy; the adenocarcinoma had a maximum width of 1cm and a maximum infiltration depth of 0.4cm. The invasion of the cervix was less than 1/2 (cervical wall thickness was about 2cm). Involvement at the uterine junction: none, serosal involvement: none, cervical stromal involvement: none, involvement of other tissues/organs: none. Margins: No cancer invasion was found in the vagina, vaginal margin, or bilateral parametrium. No lymphovascular, blood vessel, or nerve invasion was observed.Immunohistochemistry: Adenocarcinoma: Ki-67(90%+), P40(-), P16(diffuse+), MLH1(+), MSH2(+), MSH6(+), PMS2(+), P53(-, mutant type), CK7(+), CEA(+), ER(-), PR(-); Squamous cell carcinoma: P40(partial+), P63(+), ki-67(90%+), CK7(+), P16(diffuse+). Detailed in the Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGenetic testing revealed 3 somatic mutations, including 1 mutation related to targeted therapy and 1 mutation related to immunotherapy. The gene mutations related to targeted therapy include an activating NRAS mutation p.Q61K (mutation rate % copy number 3.06), and EP300 (mutation rate % copy number 6.26). Genes not detected include: ALK, BRAF, BRCA1, BRCA2, EGFR, PIK3CA, FGFR2, FGFR3, ERBB2(HER2), KIT, KRAS, MET, IDH1, etc.\u003c/p\u003e \u003cp\u003eFor immunotherapy, PD-L1 TPS\u0026thinsp;\u0026lt;\u0026thinsp;1%, CPS\u0026thinsp;\u0026lt;\u0026thinsp;1 was detected, and KEAP1 (mutation rate % copy number 4.46). Microsatellite instability (MSI) suggests microsatellite stability (MSS). The tumor mutation burden (TMB) is 0.66 Muts/Mb. Both HLA-I and HLA-II are heterozygous. Viral sequence detection indicates HPV type 18 positive.\u003c/p\u003e \u003cp\u003eNo mutations were detected in homologous recombination repair (HRR) related genes; pathogenic germline mutation testing suggests no familial cancer genetic risk. The specific mutation situation is detailed in the Table\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe mutations detected in surgical specimen.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetection target\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResult\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eTarget\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNRAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.Q61K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.06 (mutation rate % copy number )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEP300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExon31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.26(mutation rate % copy number )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFusions、G1202R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enot detected\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eImmune-related gene\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePD-L1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTPS\u0026thinsp;\u0026lt;\u0026thinsp;1%,CPS\u0026thinsp;\u0026lt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKEAP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExon2, P.A191T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.46(mutation rate % copy number )\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe tumor mutation burden (TMB)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66Muts/Mb\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehuman leucocyte antigen(HLA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHLA-I,\u003c/p\u003e \u003cp\u003eHLA-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHLA-A,HLA-B,HLA-C,HLA-DPB1,HLA-DQB1,HLA-DRB1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehybrid subtype\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViral sequence detection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHPV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHPV-16/18/58/52/33/31/45/6b/11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHPV type 18 positive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epathogenic germline mutation testing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eno familial cancer genetic risk\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe patient recovered well after surgery and received three cycles of TC regimen chemotherapy. Postoperative tumor markers including SCC, CEA, AFP, and CA125 were all within the normal range. A full abdominal MR scan and enhancement were performed three months after the surgery, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. On August 13, 2023, the HPV test result was negative.The patient is currently under regular follow-up.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and conclusions","content":"\u003cp\u003eIn this case, the patient developed adenocarcinoma and squamous cell carcinoma at different sites of the cervix after infection with HPV type 18, which is a rare phenomenon. The pathological types of cervical cancer are divided into squamous cell carcinoma (accounting for about 70%-90%),adenocarcinoma (accounting for about 10%-20%), and rare types of cancer (accounting for about 2%-5%), including mixed carcinoma, small cell carcinoma, etc[3].\u003c/p\u003e \u003cp\u003eThe surface of the cervix is composed of stratified squamous epithelium and columnar epithelium covering the cervical canal and the area around the cervical os. The area where the squamous and columnar epithelia meet is called the transformation zone. This area is susceptible to HPV infection and is a common site for tumor development[4].The histological origin of cervical cancer is still unclear. In recent years, with the rise of the cancer stem cell theory, some scholars believe that cervical cancer stem cells may be the histological origin of cervical cancer[5],Cervical stem cells are special cells located in the cervical transformation zone. They have high proliferative and differentiation potential and are the basis for the transformation between squamous epithelium and columnar epithelium in the transformation zone. When cervical stem cells are persistently infected with HPV,they proliferate and differentiate abnormally under the interaction of HPV oncogenes and cellular changes, forming squamous cell carcinoma, adenocarcinoma, or other types of cancer [6, 7].\u003c/p\u003e \u003cp\u003eHigh-risk human papillomavirus (HPV) infection is the main cause of cervical cancer, especially HPV types 16 and 18 (which account for about 70% of cervical cancer patients) [8],Human papillomavirus 18 (HPV18) is the second most carcinogenic HPV type after HPV16, accounting for about 12% of cervical squamous cell carcinoma (SCC) and 37% of adenocarcinoma (ADC) globally[9].The mechanism by which HPV causes cervical cancer is related to the oncogenic E proteins. The E6/E7 genes can integrate into the DNA of cervical epithelial cells, disrupting the regulation of proliferation and differentiation, and ultimately leading to transformation[10].\u003c/p\u003e \u003cp\u003eThe histological differentiation of human papillomavirus (HPV) infected cells is not yet explained. Research by Yao et al[5]. found that the oncogenic E6/E7 genes in HPV can integrate into the DNA of cervical stem cells, disrupting the regulation of cell proliferation and differentiation, and affecting Notch signaling, causing cancerous cervical stem cells to differentiate into different pathological types.Khelil et al [11]. performed RNA sequencing and immunofluorescence mapping on 279 cases of HPV-related cervical cancer and found three molecular subtypes of cervical cancer, with cervical reserve cell tumors being the most common, and the phenotype of cervical reserve cells being a proliferative phenotype.Kusakabe et al. performed genomic and transcriptomic analysis on 42 cases of HPV-positive cervical cancer tissues, and through phylogenetic analysis and evaluation of HPV integration sites, they found that cancer cells of different histological types have a common cellular origin, especially HPV18-positive cancer tissues retain the immune-cold component of stem cell characteristics, and are more likely to develop mixed cancers[12].Therefore, in this case, the HPV18 infection may be closely linked to the occurrence of two different histological types at different sites in the cervix, although further studies are needed for confirmation.\u003c/p\u003e \u003cp\u003eThis case is a HPV18-positive cervical cancer. In the detection of tumor tissues, a mutation in the EP300 gene related to the Notch signaling pathway was found. The Notch signaling pathway is mainly related to cell proliferation and tumor suppression functions. The detection also found a mutation in the NRAS gene related to the MAPK and PIK3 signaling pathways, and these pathways are related to cell carcinogenesis. This suggests that the HPV18 virus can cause carcinogenesis by affecting and changing multiple signaling pathways, thereby altering cell proliferation, immune functions, etc. Therefore, it is also possible that HPV18 infected cervical stem cells and differentiated into different cancers at different sites, leading to this rare phenomenon. Unfortunately, this case did not perform cell homology analysis at different sites, so it is not possible to confirm whether the adenocarcinoma and squamous cell carcinoma in this case are homologous. However, the fact that HPV18 tends to cause rare pathological types of cervical cancer is still worth attention. Additionally, the prognosis and treatment sensitivity of this mixed carcinoma warrant long-term follow-up and monitoring\u003c/p\u003e \u003cp\u003eVaccination against cervical HPV at an early age is recommended. Studies have shown that vaccination can effectively reduce infection and effectively prevent cervical cancer[13].Regular screening for cervical cancer is also important. If persistent infection with type 16 or 18 is detected, active annual screening for cervical cancer should be carried out for early detection and treatment[14].In conclusion, although high-risk HPV infection is common, it should be taken seriously,and active prevention and screening are necessary.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funds to support this\u0026nbsp;work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI declare that the authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional ethics committee of Zhuhai Hospital of Traditional Chinese and Western Medicine (Ethic code:20190412001). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee, and the consent for participate was approved by the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuihui Chen; Data collection, Manuscript writing and editing, and Protocol. Qingqi Wang ;Manuscript editing.MinKing; Project development, Manuscript editing. Wei Huang;Data collection Hao Zhang,Jiaxin Li, Donghan Xu,Lin Zhao,Bowen Wu,Xin Lin,Liqi Li,Yuhong Zheng,Yihao Niu;Project development and Manuscript editing. Peiyu Yan and Donghui Huang; Project development and Manuscript editing.All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F: \u003cstrong\u003eGlobal Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries\u003c/strong\u003e. \u003cem\u003eCA-CANCER J CLIN\u003c/em\u003e 2021, \u003cstrong\u003e71\u003c/strong\u003e(3):209-249.\u003c/li\u003e\n\u003cli\u003ePerkins RB, Wentzensen N, Guido RS, Schiffman M: \u003cstrong\u003eCervical Cancer Screening: A Review\u003c/strong\u003e. \u003cem\u003eJAMA-J AM MED ASSOC\u003c/em\u003e 2023, \u003cstrong\u003e330\u003c/strong\u003e(6):547-558.\u003c/li\u003e\n\u003cli\u003eSiegel RL, Miller KD, Wagle NS, Jemal A: \u003cstrong\u003eCancer statistics, 2023\u003c/strong\u003e. \u003cem\u003eCA-CANCER J CLIN\u003c/em\u003e 2023, \u003cstrong\u003e73\u003c/strong\u003e(1):17-48.\u003c/li\u003e\n\u003cli\u003eSmall WJ, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM, Jhingran A, Kitchener HC, Mileshkin LR, Viswanathan AN\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCervical cancer: A global health crisis\u003c/strong\u003e. \u003cem\u003eCANCER-AM CANCER SOC\u003c/em\u003e 2017, \u003cstrong\u003e123\u003c/strong\u003e(13):2404-2412.\u003c/li\u003e\n\u003cli\u003eYao T, Lu R, Zhang Y, Zhang Y, Zhao C, Lin R, Lin Z: \u003cstrong\u003eCervical cancer stem cells\u003c/strong\u003e. \u003cem\u003eCELL PROLIFERAT\u003c/em\u003e 2015, \u003cstrong\u003e48\u003c/strong\u003e(6):611-625.\u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez J, Ru\u0026iacute;z G, Organista-Nava J, Gariglio P, Garc\u0026iacute;a-Carranc\u0026aacute; A: \u003cstrong\u003eHuman papillomavirus infections and cancer stem cells of tumors from the uterine cervix\u003c/strong\u003e. \u003cem\u003eOpen Virol J\u003c/em\u003e 2012, \u003cstrong\u003e6\u003c/strong\u003e:232-240.\u003c/li\u003e\n\u003cli\u003eHerfs M, Yamamoto Y, Laury A, Wang X, Nucci MR, McLaughlin-Drubin ME, M\u0026uuml;nger K, Feldman S, McKeon FD, Xian W\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eA discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer\u003c/strong\u003e. \u003cem\u003eP NATL ACAD SCI USA\u003c/em\u003e 2012, \u003cstrong\u003e109\u003c/strong\u003e(26):10516-10521.\u003c/li\u003e\n\u003cli\u003ede Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, Tous S, Felix A, Bravo LE, Shin HR\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eHuman papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study\u003c/strong\u003e. \u003cem\u003eLANCET ONCOL\u003c/em\u003e 2010, \u003cstrong\u003e11\u003c/strong\u003e(11):1048-1056.\u003c/li\u003e\n\u003cli\u003eChen AA, Gheit T, Franceschi S, Tommasino M, Clifford GM: \u003cstrong\u003eHuman Papillomavirus 18 Genetic Variation and Cervical Cancer Risk Worldwide\u003c/strong\u003e. \u003cem\u003eJ VIROL\u003c/em\u003e 2015, \u003cstrong\u003e89\u003c/strong\u003e(20):10680-10687.\u003c/li\u003e\n\u003cli\u003eCrosbie EJ, Einstein MH, Franceschi S, Kitchener HC: \u003cstrong\u003eHuman papillomavirus and cervical cancer\u003c/strong\u003e. \u003cem\u003eLANCET\u003c/em\u003e 2013, \u003cstrong\u003e382\u003c/strong\u003e(9895):889-899.\u003c/li\u003e\n\u003cli\u003eKhelil M, Griffin H, Bleeker M, Steenbergen R, Zheng K, Saunders-Wood T, Samuels S, Rotman J, Vos W, van den Akker BE\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDelta-Like Ligand-Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis\u003c/strong\u003e. \u003cem\u003eCANCER RES\u003c/em\u003e 2021, \u003cstrong\u003e81\u003c/strong\u003e(7):1909-1921.\u003c/li\u003e\n\u003cli\u003eKusakabe M, Taguchi A, Tanikawa M, Wagatsuma R, Yamazaki M, Tsuchimochi S, Toyohara Y, Kawata A, Baba S, Ueno T\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eCells with stem-like properties are associated with the development of HPV18-positive cervical cancer\u003c/strong\u003e. \u003cem\u003eCANCER SCI\u003c/em\u003e 2023, \u003cstrong\u003e114\u003c/strong\u003e(3):885-895.\u003c/li\u003e\n\u003cli\u003eYang X, Li Y, Tang Y, Li Z, Wang S, Luo X, He T, Yin A, Luo M: \u003cstrong\u003eCervical HPV infection in Guangzhou, China: an epidemiological study of 198,111 women from 2015 to 2021\u003c/strong\u003e. \u003cem\u003eEMERG MICROBES INFEC\u003c/em\u003e 2023, \u003cstrong\u003e12\u003c/strong\u003e(1):e2176009.\u003c/li\u003e\n\u003cli\u003eSkolnik JM, Morrow MP: \u003cstrong\u003eVaccines for HPV-associated diseases\u003c/strong\u003e. \u003cem\u003eMOL ASPECTS MED\u003c/em\u003e 2023, \u003cstrong\u003e94\u003c/strong\u003e:101224.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Squamous cell carcinoma, Aadenocarcinoma, Cervical cancer, HPV,Case report","lastPublishedDoi":"10.21203/rs.3.rs-4558733/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4558733/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe concurrent development of adenocarcinoma and squamous cell carcinoma in separate regions of the cervix is extremely rare. We report a case of HPV-related adenocarcinoma and squamous cell carcinoma occurring at distinct locations within the cervix in a patient with primary cervical cancer stage IA1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 54-year-old female patient was found to be HPV type 18 positive during a routine physical examination, with Liquid-based Cytology Test (LCT) of the cervix indicating Atypical Squamous Cells of Undetermined Significance (ASCUS). Subsequent colposcopy-directed cervical biopsies identified mid-to-low grade squamous cell carcinoma at several locations (3, 6, 9, 12 o'clock positions and the ECC),and the clinical diagnosis was stage IA1. Preoperative comprehensive abdominal magnetic resonance imaging, including contrast enhancement, did not indicate any lymph node enlargement, and computed tomography urography of the urinary system was unremarkable. The squamous cell carcinoma antigen level was within the normal range.\u003c/p\u003e\n\u003cp\u003eOn May 22, 2023, the patient underwent laparoscopic radical resection of cervical cancer under general anesthesia and the postoperative pathology indicated HPV-related squamous cell carcinoma of the cervix (at 11-12 o'clock positions) and HPV-related cervical adenocarcinoma (at 1 o'clock and 3-4 o'clock positions). No cancer invasion was found in the vagina, vaginal margin, or bilateral parametrium. There was no lymphovascular, blood vessel, or nerve invasion. Immunohistochemistry: Adenocarcinoma: Ki-67(90%+), P40(-), P16(diffuse+), MLH1(+), MSH2(+), MSH6(+), PMS2(+), P53(-, mutant type), CK7(+), CEA(+), ER(-), PR(-); Squamous cell carcinoma: P40(partial+), P63(+), ki-67(90%+), CK7(+), P16(diffuse+).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this instance, the concurrent manifestation of both squamous cell carcinoma and adenocarcinoma in the cervix, both associated with HPV infection, underscores the likely pivotal role of HPV infection in this unusual phenomenon.Proactive HPV vaccination at an early stage is an effective preventive measure, and regular cervical cancer screenings can aid in the early identification of lesions, leading to improved treatment results.\u003c/p\u003e","manuscriptTitle":"Squamous cell carcinoma and adenocarcinoma appeared at different cervical sites: a rare case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-15 23:36:31","doi":"10.21203/rs.3.rs-4558733/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-17T08:37:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-17T00:52:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-17T00:52:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2024-06-10T14:44:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d958f3c1-33ae-40f0-9abb-d0d9f43f35ff","owner":[],"postedDate":"July 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:00:53+00:00","versionOfRecord":{"articleIdentity":"rs-4558733","link":"https://doi.org/10.1186/s12879-025-11114-y","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-05-22 15:57:26","publishedOnDateReadable":"May 22nd, 2025"},"versionCreatedAt":"2024-07-15 23:36:31","video":"","vorDoi":"10.1186/s12879-025-11114-y","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11114-y","workflowStages":[]},"version":"v1","identity":"rs-4558733","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4558733","identity":"rs-4558733","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}