Metachronous esophageal squamous cell carcinoma and hepatocellular carcinoma in the absence of common hereditary syndromes: an unusual case report and literature review

Metachronous esophageal squamous cell carcinoma and hepatocellular carcinoma in the absence of common hereditary syndromes: an unusual case report and literature review | 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 Metachronous esophageal squamous cell carcinoma and hepatocellular carcinoma in the absence of common hereditary syndromes: an unusual case report and literature review Min-Hui Fan, Chun-Hui Zhou, Yan-Hua Huang, Jing Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8098409/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 Introduction and Importance Metachronous primary malignancies involving esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC) are rare. Although shared risk factors such as alcohol and tobacco use are recognized, the development of these cancers in a non-cirrhotic liver and in the absence of common hereditary syndromes poses considerable diagnostic and therapeutic challenges. Case Presentation A 78-year-old male with a history of smoking and alcohol use was initially diagnosed with early-stage (pT1bN0M0) ESCC in 2016 and underwent curative radical esophagectomy. Nine years later, he presented with a large (12 cm) liver mass. Imaging revealed features of HCC with vascular invasion, and biopsy confirmed moderately differentiated hepatocellular carcinoma in a non-cirrhotic liver. Immunohistochemistry showed proficient mismatch repair proteins in both tumors, while p53 expression differed between the two malignancies. The markedly elevated PIVKA-II level (5305.27 mAU/mL) further supported primary hepatocarcinogenesis. Clinical Discussion The nine-year interval strongly supports the diagnosis of metachronous primary malignancies over metastatic disease. This case underscores the role of chronic environmental carcinogen exposure and age-related genomic instability in driving multi-organ carcinogenesis outside the context of cirrhosis or inherited syndromes. The diagnostic approach integrated clinical history, distinct histopathology, and specific biomarkers. For advanced HCC, systemic therapy with lenvatinib was selected based on its established efficacy profile. Conclusion This case highlights the importance of a comprehensive diagnostic workup to differentiate a second primary cancer from metastasis in long-term cancer survivors. It demonstrates that ESCC and HCC can develop sequentially due to sporadic, field carcinogenesis mechanisms. These findings support the consideration of individualized long-term surveillance strategies for high-risk survivors, even in the absence of hereditary syndromes or cirrhosis. Esophageal squamous cell carcinoma Hepatocellular carcinoma Metachronous malignancy Lenvatinib PIVKA-II Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Metachronous primary malignancies involving esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC) are rare clinical entities [ 1 , 2 ]. Although both cancers share established risk factors, including tobacco and alcohol use, their sequential occurrence in a patient with a non-cirrhotic liver and without common hereditary cancer syndromes represents a distinctive clinical scenario [ 3 , 4 ]. This presentation poses significant diagnostic challenges, as new hepatic lesions in ESCC survivors are often initially suspected to be metastases. The extended 9-year disease-free interval and the confirmed sporadic nature of both tumors in this case highlight the role of environmental carcinogenesis and aging in multi-organ carcinogenesis outside traditional pathways. Patient Information A 78-year-old male presented on December 8, 2015, reporting a one-week history of black stools. He had a 30-year history of smoking (approximately one pack per day) and regular alcohol consumption. There was no history of viral hepatitis, liver cirrhosis, or other chronic liver diseases. Family history was non-contributory for malignancies, and the patient had no previous major illnesses or surgical history. Clinical Findings Initial physical examination revealed no remarkable abnormalities other than mild epigastric tenderness. Abdominal examination showed no hepatosplenomegaly, jaundice, or ascites. Nine years later, on March 8, 2025, physical examination demonstrated significant right upper quadrant tenderness on deep palpation. No palpable abdominal mass was detected, and there were no stigmata of chronic liver disease. Timeline December 8, 2015: Initial presentation with melena. January 2, 2016: Radical esophagectomy for pT1bN0M0 ESCC. 2016–2024: Annual surveillance showing no recurrence. March 8, 2025: Readmission with right upper quadrant pain. March 11, 2025: Liver biopsy confirming HCC. March 18, 2025: Initiation of lenvatinib therapy. Diagnostic Assessment The initial diagnostic workup in 2015 included gastroscopy, which revealed a 2.5 × 1.5 cm esophageal lesion; biopsy showed severe dysplasia with focal squamous cell carcinoma (Fig. 1 ). Postoperative pathology confirmed a moderately differentiated squamous cell carcinoma (pT1bN0M0) invading the muscularis mucosa (Fig. 1 ). Immunohistochemistry demonstrated positive p53 expression and proficient mismatch repair proteins (MSH2+, MSH6+, MLH1+, PMS2+). (Fig. 2 ). In 2025, diagnostic evaluation revealed a markedly elevated PIVKA-II level (5305.27 mAU/mL), with normal AFP levels. Contrast-enhanced abdominal CT showed a 12 × 11 cm hypervascular liver mass with suspected vascular invasion. Subsequent MRI confirmed characteristics of a giant HCC with compression of the hepatic veins and inferior vena cava (Fig. 3 ). Ultrasound-guided liver biopsy demonstrated hepatocellular carcinoma with trabecular architecture (Fig. 1 ). Immunohistochemistry results included Hepatocyte+, Arginase-1+, GPC3-, wild-type p53, and proficient mismatch repair (Fig. 4 ). The main diagnostic challenge was differentiating primary HCC from metastatic esophageal cancer, which was resolved through histopathological correlation and biomarker analysis. Therapeutic Intervention Therapeutic Intervention The initial ESCC was managed with radical esophagectomy in January 2016; no adjuvant therapy was required given the early stage. For the advanced HCC diagnosed in 2025, multidisciplinary discussion concluded that the tumor was unresectable due to vascular invasion. Systemic therapy with lenvatinib (12 mg daily, based on body weight) was initiated after detailed patient consultation. Dose adjustments were made according to renal function and performance status. Follow-up and Outcomes The patient demonstrated good adherence to lenvatinib therapy during the initial treatment period. Follow-up imaging at three months showed stable disease without significant tumor progression. Treatment-related adverse effects included mild hypertension and grade 1 proteinuria, which were effectively managed with antihypertensive medication and dose modification. The patient maintained satisfactory performance status (ECOG 1) and reported adequate treatment tolerance. Ongoing monitoring includes regular assessment of liver function, tumor markers, and imaging studies every three months, along with management of treatment-related side effects. Discussion The primary strength of this case lies in its detailed longitudinal documentation over nearly a decade, offering a comprehensive perspective on the patient’s progression from initial ESCC diagnosis to subsequent HCC development. The availability of comprehensive histopathological and immunohistochemical profiles for both tumors further strengthens diagnostic certainty, enabling clear exclusion of metastatic spread and common hereditary cancer syndromes. Additionally, the integration of advanced imaging with biomarker data, particularly the markedly elevated PIVKA-II, established a robust multimodal diagnostic framework [ 5 ]. However, as a single case report, the generalizability of the findings is inherently limited. Moreover, although immunohistochemistry provided valuable insights, the lack of comprehensive genomic profiling, such as next-generation sequencing, precluded identification of potential driver mutations underlying both malignancies. Our findings align with previous reports indicating the rare coexistence of ESCC and HCC as separate primary tumors, with incidence rates ranging from 0.52% to 3.2% [ 6 – 8 ]. The nine-year disease-free interval observed in our patient significantly exceeds the typical window for hepatic metastases from ESCC, which usually occur within two to three years post-resection. Earlier studies, including those by Kudou et al. and Pelloni et al., have emphasized the need for tailored treatment strategies based on tumor staging and hepatic function [ 7 – 14 ]. The non-cirrhotic background of our patient’s HCC also aligns with emerging evidence on alternative hepatocarcinogenic pathways, particularly those involving chronic inflammation and aging-related genomic instability [ 4 , 15 ]. A key feature of this case is the confirmed sporadic origin of both malignancies, as evidenced by immunohistochemical findings showing proficient mismatch repair proteins in both tumors. While the ESCC exhibited positive p53 expression, the HCC showed wild-type p53 pattern, indicating different molecular pathways of carcinogenesis in these two distinct primary tumors. These results effectively exclude hereditary syndromes such as Lynch syndrome, directing attention instead to environmental carcinogens and age-related genomic instability as the primary etiological factors [ 16 , 17 ]. The differential p53 status between the two tumors lends strong support to their independent origins and illustrates how prolonged carcinogen exposure can establish a systemic environment conducive to multiple independent malignant transformations through distinct molecular mechanisms [ 18 ]. The diagnosis of metachronous primary malignancies is supported by converging evidence: the prolonged disease-free interval, distinct histopathological characteristics, specific immunohistochemical profiles, and significant biomarker elevation. The absence of cirrhosis or hereditary predisposition further underscores the role of environmental and age-related mechanisms in this unusual presentation. The successful use of lenvatinib in this context reaffirms the applicability of current HCC treatment guidelines in complex clinical settings [ 19 ], while the case as a whole highlights the need for sustained vigilance for second primary tumors among long-term cancer survivors with significant risk factors. Conclusion This case illustrates that metachronous ESCC and HCC may develop through sporadic, environmentally driven mechanisms, even in the absence of cirrhosis or hereditary syndromes. The lengthy interval between the two cancers underscores the importance of lifelong surveillance in high-risk survivors. A multimodal diagnostic approach incorporating histopathology, immunohistochemistry, and biomarkers is essential to accurately distinguish second primary tumors from metastases. These findings advocate for the development of risk-adapted, long-term surveillance protocols tailored to the growing population of aging cancer survivors. Patient Perspective Being diagnosed with two separate cancers nine years apart has been a difficult journey. However, the clear communication from my medical team at each step helped me understand and accept my treatment plan. After my esophageal surgery, I enjoyed a good quality of life for many years. When the liver tumor was found, I valued the thorough diagnostic process before starting treatment. Lenvatinib has been manageable with some adjustments, and I feel reassured by regular follow-up. My experience shows how vital it is to take new symptoms seriously, even long after cancer treatment. Declarations Ethics approval and consent to participate This case report was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Biomedical Ethics Committee of Jiaxing University. The patient provided written informed consent for the publication of this case and any accompanying images Consent for publication All authors consent for publication. Written informed consent was obtained from the patient for publication. Competing interests The authors declare no competing interests. Funding Not applicable. Author Contribution M.-H.F. provided the pathological diagnosis, performed immunohistochemical analysis and interpretation, and contributed to the pathological description in the manuscript.C.-H.Z. and Y.-H.H. were responsible for the clinical management of the patient, including surgical treatment and postoperative care, and collected clinical data.J.C. (corresponding author) designed the study, analyzed and interpreted the patient data, wrote the main manuscript text, and performed the literature review. All authors reviewed and approved the final version of the manuscript. Acknowledgement Not applicable. Data availability All authors consent for publication. Written informed consent was obtained from the patient for publication. References Natsugoe S, Matsumoto M, Okumura H, Ishigami S, Uenosono Y, Owaki T, Takao S, Aikou T. Multiple primary carcinomas with esophageal squamous cell cancer: clinicopathologic outcome. World J Surg. 2005;29:46–9. Su J, Wei S, Li W, Chen H, Li L, Xu L, Zhao P, Zhang G, Yan J. Clinicopathological characteristics of synchronous multiple primary early esophageal cancer and risk factors for multiple lesions. Front Oncol. 2023;13:1219451. Ribeiro Júnior U, Cecconello I, Safatle-Ribeiro AV, Zilberstein B, Pinotti HW. Squamous cell carcinoma of the esophagus and multiple primary tumors of the upper aerodigestive tract. Arq Gastroenterol. 1999;36:195–200. Luciani A, Balducci L. Multiple primary malignancies. Semin Oncol. 2004;31:264–73. Li S, Liu D, Wang Q. A Novel Diagnostic Model for Early Hepatitis B Virus-Related Hepatocellular Carcinoma Diagnosis. Clin Lab 2023; 69. Kyriazanos ID, Tachibana M, Shibakita M, Yoshimura H, Kinugasa S, Dhar DK, Nakamoto T, Fujii T, Nagasue N. Pattern of recurrence after extended esophagectomy for squamous cell carcinoma of the esophagus. Hepatogastroenterology. 2003;50:115–20. Morita M, Kuwano H, Toh Y, Matsuda H, Matsumata T, Sugimachi K. The clinical characteristics of patients with synchronous squamous cell carcinoma of the esophagus and hepatocellular carcinoma. Surg Today. 1994;24:803–8. Kudou M, Shiozaki A, Fujiwara H, Konishi H, Morimura R, Murayama Y, Komatsu S, Kuriu Y, Ikoma H, Kubota T, Nakanishi M, Ichikawa D, Okamoto K, Sakakura C, Otsuji E. [Multiple primary cancers of the esophagus and hepatocellular carcinoma-a report of 4 cases]. Gan Kagaku Ryoho. 2013;40:2164–6. Lee JS, Ahn JY, Choi KD, Song HJ, Kim YH, Lee GH, Jung HY, Ryu JS, Kim SB, Kim JH, Park SI, Cho KJ, Kim JH. Synchronous second primary cancers in patients with squamous esophageal cancer: clinical features and survival outcome. Korean J Intern Med. 2016;31:253–9. Shimizu R, Murakami T, Wadamori K, Yano K, Suzuki T. The surgical management of synchronous hepatocellular carcinoma and thoracic esophageal carcinoma. Surg Today. 1993;23:63–7. Nagahama T, Goseki N, Kato S, Maruyama M, Endo M. Esophageal carcinoma and coexisting hepatocellular carcinoma resected simultaneously. Arch Surg. 1996;131:208–10. Pelloni A, Guerra A, Gertsch P. Surgical treatment of synchronous hepatocellular and esophageal carcinoma: case report and review of literature. Hepatogastroenterology. 2001;48:684–6. Takahashi K, Yoshida H, Mamada Y, Taniai N, Nakamura Y, Mizuguchi Y, Miyashita M, Nomura T, Makino H, Tajiri T. Case report of metachronous hepatocellular carcinoma and early esophageal cancer. J Nippon Med Sch. 2005;72:187–90. Nguyen-Tran BS, Tran-Thi NP, Ngo QT, L LE-T, Nguyen-Thanh T, Dang-Cong T. Synchronous esophageal squamous cell carcinoma and hepatocellular carcinoma: A rare case report. Radiol Case Rep. 2022;17:863–8. Neto AG, Whitaker A, Pei Z. Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma. Semin Oncol. 2016;43:86–96. Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, Frébourg T, Sobol H. Lasset C and Bonaïti-Pellié C. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10. Sassi H, Meddeb R, Cherif MA, Nasr C, Riahi A, Hannachi S, Belguith N, M'Rad R. Li-Fraumeni syndrome in Tunisian carriers with different and rare tumor phenotype: genotype-phenotype correlation. BMC Med Genomics. 2022;15:44. Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol. 2015;28:14–29. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73. Tables Table 1. Reported cases of esophageal squamous cell carcinoma and hepatocellular carcinoma. year Age/Sex First detective cancer Chief complaint Hepatitis /Cirrhosis Smoking Alcohol 1993[10] 73/Male Liver NC Cirrhosis NC NC 1994[7] 68/Male Esophagus No Hepatitis Yes Yes 70/Male Esophagus No Cirrhosis Yes Yes 67/Male Esophagus Dysphagia Cirrhosis Yes Yes 84/Male Esophagus Dysphagia Cirrhosis Yes Yes 1996[11] 72/Male Esophagus Dysphagia Cirrhosis NC NC 68/Male Liver NC Hepatitis NC NC 2001[12] 68/Male NC NC NC NC NC 2005[13] 69/Male Liver NC Cirrhosis NC Yes 2013[8] 63/Male Esophagus NC Hepatitis NC NC 62/Male Esophagus NC Hepatitis NC Yes 61/Male Esophagus NC Hepatitis NC NC 77/Male Liver NC Hepatitis NC NC 2016[9] 77/Male Esophagus NC NC NC NC 2022[14] 62/Male Esophagus Dysphagia Hepatitis/Cirrhosis Yes Yes Our case 78/Male Esophagus black stools Cirrhosis Yes Yes Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":1561468,"visible":true,"origin":"","legend":"\u003cp\u003ePathological result. (A) Endoscopic biopsy showed severe dysplasia with localized cancerous changes in the esophageal squamous epithelium. (B) Postoperative pathology confirmed an ulcerative, moderately differentiated squamous cell carcinoma. (C) Liver biopsy: trabecular growth pattern of malignant hepatocytes with endothelial wrapping and absence of glandular structures.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8098409/v1/4c74d575ca2d37b7c29168da.jpeg"},{"id":97142122,"identity":"47fc5275-fbb2-46c4-a20d-9eb329508b2c","added_by":"auto","created_at":"2025-12-01 10:07:22","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":948470,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemistry of the esophageal squamous cell carcinoma. (A) p53 shows strong nuclear positivity. (B-F) Retained nuclear expression of mismatch repair proteins: (B) MSH2, (C) MSH6, (D) MLH1, and (E) PMS2. (Magnification: 400x).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8098409/v1/db3aa3f952c84286855e9320.jpeg"},{"id":97127472,"identity":"ecd47dea-2ea4-4460-9d38-15cfeac3440f","added_by":"auto","created_at":"2025-12-01 08:29:48","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":409583,"visible":true,"origin":"","legend":"\u003cp\u003eImaging changes. (A) Contrast-enhanced CT (arterial phase): 12 × 11 cm heterogeneously enhancing mass (red arrow). (B) MRI (hepatobiliary phase): Target lesion showing hypointense \"washout\" (red arrow).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8098409/v1/3eca8b86d9cab68bac7d5505.jpeg"},{"id":97127466,"identity":"3a4bcc26-41cc-402a-b10b-f4e065c24395","added_by":"auto","created_at":"2025-12-01 08:29:48","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":799222,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemical profile of the hepatocellular carcinoma. The images confirm hepatocellular differentiation with positive staining for (A) Hepatocyte and (B) Arginase-1. (C) The tumor is negative for GPC-3. (D) p53 shows a wild-type staining pattern. (E-H) The tumor demonstrates proficient mismatch repair, with retained nuclear expression of (E) MSH2, (F) MSH6, (G) MLH1, and (H) PMS2.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8098409/v1/a035b786b08476bd3991eb57.jpeg"},{"id":102037415,"identity":"91242137-672c-460e-9436-e3697a0ab745","added_by":"auto","created_at":"2026-02-06 12:13:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4253916,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8098409/v1/5be89ce4-909c-4896-860a-2c3b9b940083.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Metachronous esophageal squamous cell carcinoma and hepatocellular carcinoma in the absence of common hereditary syndromes: an unusual case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMetachronous primary malignancies involving esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC) are rare clinical entities [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although both cancers share established risk factors, including tobacco and alcohol use, their sequential occurrence in a patient with a non-cirrhotic liver and without common hereditary cancer syndromes represents a distinctive clinical scenario [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This presentation poses significant diagnostic challenges, as new hepatic lesions in ESCC survivors are often initially suspected to be metastases. The extended 9-year disease-free interval and the confirmed sporadic nature of both tumors in this case highlight the role of environmental carcinogenesis and aging in multi-organ carcinogenesis outside traditional pathways.\u003c/p\u003e"},{"header":"Patient Information","content":"\u003cp\u003eA 78-year-old male presented on December 8, 2015, reporting a one-week history of black stools. He had a 30-year history of smoking (approximately one pack per day) and regular alcohol consumption. There was no history of viral hepatitis, liver cirrhosis, or other chronic liver diseases. Family history was non-contributory for malignancies, and the patient had no previous major illnesses or surgical history.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eClinical Findings\u003c/h2\u003e\u003cp\u003eInitial physical examination revealed no remarkable abnormalities other than mild epigastric tenderness. Abdominal examination showed no hepatosplenomegaly, jaundice, or ascites. Nine years later, on March 8, 2025, physical examination demonstrated significant right upper quadrant tenderness on deep palpation. No palpable abdominal mass was detected, and there were no stigmata of chronic liver disease.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTimeline\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eDecember 8, 2015: Initial presentation with melena.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eJanuary 2, 2016: Radical esophagectomy for pT1bN0M0 ESCC.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e2016\u0026ndash;2024: Annual surveillance showing no recurrence.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMarch 8, 2025: Readmission with right upper quadrant pain.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMarch 11, 2025: Liver biopsy confirming HCC.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMarch 18, 2025: Initiation of lenvatinib therapy.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eDiagnostic Assessment\u003c/h3\u003e\n\u003cp\u003eThe initial diagnostic workup in 2015 included gastroscopy, which revealed a 2.5 \u0026times; 1.5 cm esophageal lesion; biopsy showed severe dysplasia with focal squamous cell carcinoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Postoperative pathology confirmed a moderately differentiated squamous cell carcinoma (pT1bN0M0) invading the muscularis mucosa (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Immunohistochemistry demonstrated positive p53 expression and proficient mismatch repair proteins (MSH2+, MSH6+, MLH1+, PMS2+). (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn 2025, diagnostic evaluation revealed a markedly elevated PIVKA-II level (5305.27 mAU/mL), with normal AFP levels. Contrast-enhanced abdominal CT showed a 12 \u0026times; 11 cm hypervascular liver mass with suspected vascular invasion. Subsequent MRI confirmed characteristics of a giant HCC with compression of the hepatic veins and inferior vena cava (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Ultrasound-guided liver biopsy demonstrated hepatocellular carcinoma with trabecular architecture (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Immunohistochemistry results included Hepatocyte+, Arginase-1+, GPC3-, wild-type p53, and proficient mismatch repair (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe main diagnostic challenge was differentiating primary HCC from metastatic esophageal cancer, which was resolved through histopathological correlation and biomarker analysis.\u003c/p\u003e\n\u003ch3\u003eTherapeutic Intervention\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eTherapeutic Intervention\u003c/div\u003e\u003cp\u003eThe initial ESCC was managed with radical esophagectomy in January 2016; no adjuvant therapy was required given the early stage. For the advanced HCC diagnosed in 2025, multidisciplinary discussion concluded that the tumor was unresectable due to vascular invasion. Systemic therapy with lenvatinib (12 mg daily, based on body weight) was initiated after detailed patient consultation. Dose adjustments were made according to renal function and performance status.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Outcomes\u003c/h3\u003e\n\u003cp\u003eThe patient demonstrated good adherence to lenvatinib therapy during the initial treatment period. Follow-up imaging at three months showed stable disease without significant tumor progression. Treatment-related adverse effects included mild hypertension and grade 1 proteinuria, which were effectively managed with antihypertensive medication and dose modification. The patient maintained satisfactory performance status (ECOG 1) and reported adequate treatment tolerance. Ongoing monitoring includes regular assessment of liver function, tumor markers, and imaging studies every three months, along with management of treatment-related side effects.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary strength of this case lies in its detailed longitudinal documentation over nearly a decade, offering a comprehensive perspective on the patient\u0026rsquo;s progression from initial ESCC diagnosis to subsequent HCC development. The availability of comprehensive histopathological and immunohistochemical profiles for both tumors further strengthens diagnostic certainty, enabling clear exclusion of metastatic spread and common hereditary cancer syndromes. Additionally, the integration of advanced imaging with biomarker data, particularly the markedly elevated PIVKA-II, established a robust multimodal diagnostic framework [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, as a single case report, the generalizability of the findings is inherently limited. Moreover, although immunohistochemistry provided valuable insights, the lack of comprehensive genomic profiling, such as next-generation sequencing, precluded identification of potential driver mutations underlying both malignancies.\u003c/p\u003e\u003cp\u003eOur findings align with previous reports indicating the rare coexistence of ESCC and HCC as separate primary tumors, with incidence rates ranging from 0.52% to 3.2% [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The nine-year disease-free interval observed in our patient significantly exceeds the typical window for hepatic metastases from ESCC, which usually occur within two to three years post-resection. Earlier studies, including those by Kudou et al. and Pelloni et al., have emphasized the need for tailored treatment strategies based on tumor staging and hepatic function [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The non-cirrhotic background of our patient\u0026rsquo;s HCC also aligns with emerging evidence on alternative hepatocarcinogenic pathways, particularly those involving chronic inflammation and aging-related genomic instability [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA key feature of this case is the confirmed sporadic origin of both malignancies, as evidenced by immunohistochemical findings showing proficient mismatch repair proteins in both tumors. While the ESCC exhibited positive p53 expression, the HCC showed wild-type p53 pattern, indicating different molecular pathways of carcinogenesis in these two distinct primary tumors. These results effectively exclude hereditary syndromes such as Lynch syndrome, directing attention instead to environmental carcinogens and age-related genomic instability as the primary etiological factors [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The differential p53 status between the two tumors lends strong support to their independent origins and illustrates how prolonged carcinogen exposure can establish a systemic environment conducive to multiple independent malignant transformations through distinct molecular mechanisms [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe diagnosis of metachronous primary malignancies is supported by converging evidence: the prolonged disease-free interval, distinct histopathological characteristics, specific immunohistochemical profiles, and significant biomarker elevation. The absence of cirrhosis or hereditary predisposition further underscores the role of environmental and age-related mechanisms in this unusual presentation. The successful use of lenvatinib in this context reaffirms the applicability of current HCC treatment guidelines in complex clinical settings [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], while the case as a whole highlights the need for sustained vigilance for second primary tumors among long-term cancer survivors with significant risk factors.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case illustrates that metachronous ESCC and HCC may develop through sporadic, environmentally driven mechanisms, even in the absence of cirrhosis or hereditary syndromes. The lengthy interval between the two cancers underscores the importance of lifelong surveillance in high-risk survivors. A multimodal diagnostic approach incorporating histopathology, immunohistochemistry, and biomarkers is essential to accurately distinguish second primary tumors from metastases. These findings advocate for the development of risk-adapted, long-term surveillance protocols tailored to the growing population of aging cancer survivors.\u003c/p\u003e\n\u003ch3\u003ePatient Perspective\u003c/h3\u003e\n\u003cp\u003eBeing diagnosed with two separate cancers nine years apart has been a difficult journey. However, the clear communication from my medical team at each step helped me understand and accept my treatment plan. After my esophageal surgery, I enjoyed a good quality of life for many years. When the liver tumor was found, I valued the thorough diagnostic process before starting treatment. Lenvatinib has been manageable with some adjustments, and I feel reassured by regular follow-up. My experience shows how vital it is to take new symptoms seriously, even long after cancer treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003eThis case report was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Biomedical Ethics Committee of Jiaxing University. The patient provided written informed consent for the publication of this case and any accompanying images\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003e All authors consent for publication. Written informed consent was obtained from the patient for publication.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.-H.F. provided the pathological diagnosis, performed immunohistochemical analysis and interpretation, and contributed to the pathological description in the manuscript.C.-H.Z. and Y.-H.H. were responsible for the clinical management of the patient, including surgical treatment and postoperative care, and collected clinical data.J.C. (corresponding author) designed the study, analyzed and interpreted the patient data, wrote the main manuscript text, and performed the literature review. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e\u003cp\u003eAll authors consent for publication. Written informed consent was obtained from the patient for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNatsugoe S, Matsumoto M, Okumura H, Ishigami S, Uenosono Y, Owaki T, Takao S, Aikou T. Multiple primary carcinomas with esophageal squamous cell cancer: clinicopathologic outcome. World J Surg. 2005;29:46\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSu J, Wei S, Li W, Chen H, Li L, Xu L, Zhao P, Zhang G, Yan J. Clinicopathological characteristics of synchronous multiple primary early esophageal cancer and risk factors for multiple lesions. Front Oncol. 2023;13:1219451.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRibeiro J\u0026uacute;nior U, Cecconello I, Safatle-Ribeiro AV, Zilberstein B, Pinotti HW. Squamous cell carcinoma of the esophagus and multiple primary tumors of the upper aerodigestive tract. Arq Gastroenterol. 1999;36:195\u0026ndash;200.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLuciani A, Balducci L. Multiple primary malignancies. Semin Oncol. 2004;31:264\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi S, Liu D, Wang Q. A Novel Diagnostic Model for Early Hepatitis B Virus-Related Hepatocellular Carcinoma Diagnosis. Clin Lab 2023; 69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKyriazanos ID, Tachibana M, Shibakita M, Yoshimura H, Kinugasa S, Dhar DK, Nakamoto T, Fujii T, Nagasue N. Pattern of recurrence after extended esophagectomy for squamous cell carcinoma of the esophagus. Hepatogastroenterology. 2003;50:115\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorita M, Kuwano H, Toh Y, Matsuda H, Matsumata T, Sugimachi K. The clinical characteristics of patients with synchronous squamous cell carcinoma of the esophagus and hepatocellular carcinoma. Surg Today. 1994;24:803\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKudou M, Shiozaki A, Fujiwara H, Konishi H, Morimura R, Murayama Y, Komatsu S, Kuriu Y, Ikoma H, Kubota T, Nakanishi M, Ichikawa D, Okamoto K, Sakakura C, Otsuji E. [Multiple primary cancers of the esophagus and hepatocellular carcinoma-a report of 4 cases]. Gan Kagaku Ryoho. 2013;40:2164\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee JS, Ahn JY, Choi KD, Song HJ, Kim YH, Lee GH, Jung HY, Ryu JS, Kim SB, Kim JH, Park SI, Cho KJ, Kim JH. Synchronous second primary cancers in patients with squamous esophageal cancer: clinical features and survival outcome. Korean J Intern Med. 2016;31:253\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShimizu R, Murakami T, Wadamori K, Yano K, Suzuki T. The surgical management of synchronous hepatocellular carcinoma and thoracic esophageal carcinoma. Surg Today. 1993;23:63\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNagahama T, Goseki N, Kato S, Maruyama M, Endo M. Esophageal carcinoma and coexisting hepatocellular carcinoma resected simultaneously. Arch Surg. 1996;131:208\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePelloni A, Guerra A, Gertsch P. Surgical treatment of synchronous hepatocellular and esophageal carcinoma: case report and review of literature. Hepatogastroenterology. 2001;48:684\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTakahashi K, Yoshida H, Mamada Y, Taniai N, Nakamura Y, Mizuguchi Y, Miyashita M, Nomura T, Makino H, Tajiri T. Case report of metachronous hepatocellular carcinoma and early esophageal cancer. J Nippon Med Sch. 2005;72:187\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNguyen-Tran BS, Tran-Thi NP, Ngo QT, L LE-T, Nguyen-Thanh T, Dang-Cong T. Synchronous esophageal squamous cell carcinoma and hepatocellular carcinoma: A rare case report. Radiol Case Rep. 2022;17:863\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNeto AG, Whitaker A, Pei Z. Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma. Semin Oncol. 2016;43:86\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBonadona V, Bona\u0026iuml;ti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Nogu\u0026egrave;s C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, Fr\u0026eacute;bourg T, Sobol H. Lasset C and Bona\u0026iuml;ti-Pelli\u0026eacute; C. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSassi H, Meddeb R, Cherif MA, Nasr C, Riahi A, Hannachi S, Belguith N, M'Rad R. Li-Fraumeni syndrome in Tunisian carriers with different and rare tumor phenotype: genotype-phenotype correlation. BMC Med Genomics. 2022;15:44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol. 2015;28:14\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1.\u003c/strong\u003e Reported cases of esophageal squamous cell carcinoma and hepatocellular carcinoma.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eyear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003eAge/Sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eFirst detective cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eChief complaint\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis /Cirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eSmoking\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eAlcohol\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1993[10]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e73/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1994[7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e68/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e70/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e67/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e84/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1996[11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e72/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e68/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2001[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e68/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2005[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e69/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2013[8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e63/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e62/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e61/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e77/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2016[9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e77/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2022[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e62/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eDysphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHepatitis/Cirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eOur case\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e78/Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003eEsophagus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003eblack stools\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCirrhosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":"Esophageal squamous cell carcinoma, Hepatocellular carcinoma, Metachronous malignancy, Lenvatinib, PIVKA-II","lastPublishedDoi":"10.21203/rs.3.rs-8098409/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8098409/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction and Importance\u003c/h2\u003e\u003cp\u003eMetachronous primary malignancies involving esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC) are rare. Although shared risk factors such as alcohol and tobacco use are recognized, the development of these cancers in a non-cirrhotic liver and in the absence of common hereditary syndromes poses considerable diagnostic and therapeutic challenges.\u003c/p\u003e\u003ch2\u003eCase Presentation\u003c/h2\u003e\u003cp\u003eA 78-year-old male with a history of smoking and alcohol use was initially diagnosed with early-stage (pT1bN0M0) ESCC in 2016 and underwent curative radical esophagectomy. Nine years later, he presented with a large (12 cm) liver mass. Imaging revealed features of HCC with vascular invasion, and biopsy confirmed moderately differentiated hepatocellular carcinoma in a non-cirrhotic liver. Immunohistochemistry showed proficient mismatch repair proteins in both tumors, while p53 expression differed between the two malignancies. The markedly elevated PIVKA-II level (5305.27 mAU/mL) further supported primary hepatocarcinogenesis.\u003c/p\u003e\u003ch2\u003eClinical Discussion\u003c/h2\u003e\u003cp\u003eThe nine-year interval strongly supports the diagnosis of metachronous primary malignancies over metastatic disease. This case underscores the role of chronic environmental carcinogen exposure and age-related genomic instability in driving multi-organ carcinogenesis outside the context of cirrhosis or inherited syndromes. The diagnostic approach integrated clinical history, distinct histopathology, and specific biomarkers. For advanced HCC, systemic therapy with lenvatinib was selected based on its established efficacy profile.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis case highlights the importance of a comprehensive diagnostic workup to differentiate a second primary cancer from metastasis in long-term cancer survivors. It demonstrates that ESCC and HCC can develop sequentially due to sporadic, field carcinogenesis mechanisms. These findings support the consideration of individualized long-term surveillance strategies for high-risk survivors, even in the absence of hereditary syndromes or cirrhosis.\u003c/p\u003e","manuscriptTitle":"Metachronous esophageal squamous cell carcinoma and hepatocellular carcinoma in the absence of common hereditary syndromes: an unusual case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:29:43","doi":"10.21203/rs.3.rs-8098409/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":"17e8fd89-f6b7-4232-ab87-60f786ac622d","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-06T12:12:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:29:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8098409","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8098409","identity":"rs-8098409","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}