A clinical report and analysis of metachronous multiple primary cancers occurred in four sites

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Methods We conducted a detailed clinical and histopathological analysis of the case. Repeated imaging and pathological examinations were performed to confirm the diagnosis of each primary malignancy. Results The patient was diagnosed with four distinct primary tumors, and pathological evaluation confirmed each malignancy. Conclusion This case underscores the importance of comprehensive pathological and genetic evaluation in patients with multiple primary malignancies. It highlights the increasing incidence of such tumors among long-term cancer survivors and offers valuable clinical perspectives for diagnosis and management in the context of hereditary cancer syndromes. Multiple primary cancers Hereditary Breast and Ovarian Cancer hereditary TP53-related cancer syndrome breast cancer ovarian cancer Introduction Multiple primary cancers (MPCs) refer to the occurrence of two or more primary malignant tumors in different sites of the same system or different organ systems within the same individual. This concept was first proposed by Billroth in 1889 and later revised by Warren et al[ 1 ]. Based on the time interval between occurrences, MPCs can be further classified into synchronous (interval 6months) types. In oncogenesis, MPCs are considered a rare phenomenon. A study from South Korea revealed that between 2003 and 2022, only 2.3% of 96,174 cancer patients developed MPCs. Breast cancer was the most common first primary tumor, accounting for 15.7% of cases[ 2 ].However, with continuous advancements in cancer diagnosis and treatment, the survival time of patients has significantly increased, leading to a rise in the incidence of MPCs. Breast cancer is one of the most common malignant tumors in women. The Surveillance, Epidemiology, and End Results (SEER) data from 2015–2021 indicate a 5-year survival rate of 91.7%[ 3 ]. Increased patient life expectancy consequently raises the probability of detecting a second primary tumor. Studies have found that among female breast cancer patients without metastasis, the most common sites for second primary tumors are the breast (30%), lung and bronchus (13.4%), uterus (5.8%), thyroid (5.6%), and melanoma (4.5%), among other locations[ 4 ]. Following radiotherapy, the overall cumulative incidence of second primary tumors increases in these patients, with significant elevations observed specifically in the cumulative incidence of breast cancer, respiratory system cancers, skin cancers, leukemia, soft tissue sarcomas (including heart), and orbital cancers[ 5 ]. Stage at diagnosis, whether radical surgery was performed, and the tumor interval are significant survival-related factors for patients with MPCs in the breast or reproductive system[ 6 ]. Currently, there is no specific treatment protocol for MPCs in clinical practice, necessitating further in-depth understanding. This article presents a clinically rare case of primary quadruple cancer and discusses it as follows. Case presentation A 52-year-old woman presented to Xijing Hospital of the Fourth Military Medical University in 2002 with a right breast mass.After completing relevant examinations and laboratory tests, the patient underwent "modified radical mastectomy for right breast cancer". Postoperative pathological examination revealed intraductal carcinoma in the right breast, and immunohistochemistry revealed ER negative and PR negative.The patient underwent 2 cycles of CAF(Cyclophosphamide, Adriamycin and Fluorouracil) regimen chemotherapy and weekly paclitaxel treatment, for a total of 6 cycles. The specific dosage of medication is unknown. Postoperative right chest wall radiotherapy DT 50Gy/25 times, single dose 2.0Gy/f. In 2007, Fluorescence in situ hybridization (FISH) showed HER-2 (++), but the patient did not receive targeted therapy. The patient was subsequently maintained on regular follow-up. In 2012, due to ovarian cancer, a total hysterectomy with double adnexa, partial omentum, and appendectomy was performed at Gansu Provincial People's Hospital. Postoperative pathology showed serous papillary cystadenocarcinoma, cervical and intestinal interstitial tissue: metastatic serous papillary cystadenocarcinoma, (right ovary) serous papillary cystadenocarcinoma, with cancer tissue involvement in the right fallopian tube cavity, and no cancer tissue involvement in the left ovary and fallopian tube; Chronic cervical inflammation, chronic appendicitis, and no involvement of cancer in the omentum tissue. After surgery, TC regimen (paclitaxel combined with carboplatin) was given for 3 cycles of chemotherapy, and paclitaxel liposomes combined with nedaplatin for 5 cycles. The chemotherapy-related toxicities were tolerable. In April 2016, a recurrence of ovarian cancer was identified during a routine follow-up visit, and the patient presented to Gansu Provincial People's Hospital for PET-CT imaging. The results showed that: 1. After right breast, uterus, and bilateral adnexectomy, 2. Nodular abnormal high metabolism in the lower outer quadrant of the left breast, suggesting malignant lesions; 3. Enlarged lymph nodes in the retroperitoneum, suspected of metastasis. Multiple high metabolic nodules in the lower abdominal wall and pelvic cavity are suspected of metastasis, with no other abnormalities. On May 9, 2016, the patient underwent core needle biopsy of the left breast at the Cancer Hospital of the Chinese Academy of Medical Sciences. Histopathological examination revealed invasive ductal carcinoma, not otherwise specified (Grade II). Immunohistochemistry (IHC) demonstrated: ER(> 90% strongly positive),PR(20% moderate-to-strong positive),HER-2(3+),PAX2(-),PAX8(-),GATA 3(3+),GCDFP15(2+),Ki-67(30%+).Pathological consultation at Xijing Hospital of the Fourth Military Medical University confirmed the right breast lesion as intermediate-grade ductal carcinoma in situ with focal intraductal papillary carcinoma. The collective findings support the diagnosis of primary left breast carcinoma, definitively ruling out metastatic disease. Administer 8 cycles of chemotherapy, with specific medication: 270mg intravenous infusion of levonorgestrel and 120mg intravenous infusion of nedaplatin D2, Q3W. The last chemotherapy was administered in October 2016. On August 31, 2017, the patient discovered a mass on the inner side of the right thigh that gradually increased in size, accompanied by pain and discomfort. There were no discomforts such as chills, fever, chest tightness, shortness of breath, etc. After admission, relevant examinations and laboratory tests were completed. On November 16, 2017, a puncture biopsy was performed on the inner right thigh mass under local anesthesia. Postoperative pathological examination showed malignant tumor and sarcoma. IHC demonstrated: CKp (-),EMA (-),Vimentin (2+), CD68 (large cell+),CD163 (3+),Actin (-),Desmin(-),CD34(-),Bel-2(-),STAT6 (-),CD45(-),S-100(-),Melanoma(-) and ki-67(60–70% for large cells and 30–40% for spindle cells).The histopathological features, combined with immunohistochemical findings, support the diagnosis of pleomorphic malignant fibrous histiocytoma (MFH) / undifferentiated high-grade pleomorphic sarcoma.The patient's diagnosis includes postoperative right breast cancer, postoperative ovarian cancer, left breast cancer, and malignant fibrous histiocytoma of the right femur, all of which have been confirmed by pathology to be primary. Following discharge, the patient was continued on Chinese herbal medicine for palliative care with no further antitumor therapy initiated. Due to the patient's repeated chemotherapy in the early stage and poor physical condition, the family requested only symptomatic supportive treatment and respected the wishes of the patient and family. The patient passed away six months after follow-up. Discussion In recent years, there has been an increasing trend of MPCs, and the diagnostic criteria developed by Warren and Gates[ 1 ] are now widely used internationally. (1) Each tumor must be confirmed as malignant by histological examination; (2) Each type of tumor has its unique pathological morphology, and each tumor exists independently of each other; (3) Each tumor must be excluded as a metastatic lesion of other tumors. All four types of tumors in this case have been confirmed by pathology to be primary cancers, and they are metachronous multiple primary cancers. MPCs can occur in any combination of organs and systems, and there are inconsistent literature reports on their common sites. Gursel et al.[ 7 ] reported that the first primary cancer is more likely to occur in the throat, bladder, and breast, while the second primary cancer is more likely to occur in the lungs, breast, and colon. Utada et al.[ 8 ] reported that the first primary cancers are mainly esophageal cancer and laryngeal cancer, followed by ovarian cancer, pharyngeal cancer, oropharyngeal cancer, etc; The second most common sites of primary cancer are the thyroid and esophagus, followed by the breast and colon. Jin-Hee Kwon et al. reported breast, thyroid, stomach, lung, and colorectal cancers comprised the top five first primary cancers. This dominance continued for second primaries, with lung, thyroid, breast, stomach, and colorectal cancers again featuring prominently. The etiology of MPCs is not yet clear, and most scholars believe that it is the result of multiple factors working together, mainly related to aging, host factors, immune status[ 9 ], environmental factors[ 10 ], family genetics[ 11 ], iatrogenic factors[ 12 ], etc. In this case, the patient presented with bilateral breast cancer, ovarian cancer, and a undifferentiated pleomorphic sarcoma (UPS) of the right femur. A hereditary cancer syndrome, such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome or Li-Fraumeni Syndrome (LFS), cannot be excluded out. Breast cancer and ovarian cancer represent the principal tumor phenotypes of HBOC, while breast cancer and soft tissue sarcoma constitute the core tumor phenotypes of LFS. HBOC is an autosomal dominant inherited syndrome. In addition to increased risks of breast and ovarian cancer, HBOC patients may also face elevated risks of developing other cancer types, including melanoma, pancreatic cancer, and prostate cancer[ 13 ].Core genes associated with HBOC include: BRCA1/2, BARD1, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11 and TP53[ 14 ].Among women diagnosed with breast and/or ovarian cancer, the proportion carrying at least one pathogenic variant (PV) was found to be 16.6%. BRCA1/2 PVs were identified in 8.9% of these women (BRCA1: 5.95%; BRCA2: 2.94%), while PVs in other breast and ovarian cancer susceptibility genes were detected in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0%) and TP53 (0.56%)[ 15 ].Mutations in the BRCA1 and BRCA2 genes represent the primary etiological factors for HBOC[ 16 – 18 ].Breast cancers associated with BRCA2 PVs were predominantly lobular tumors, whereas those associated with BRCA1 PVs were predominantly ductal tumors[ 19 ]. LFS is also an autosomal dominant inherited cancer predisposition syndrome characterized by high penetrance and early onset of malignancies. Premenopausal breast cancer is observed in 79% of female LFS patients, while osteosarcoma, central nervous system tumors, adrenocortical carcinoma, and soft tissue sarcomas are found in 27% of patients[ 20 ].Breast cancer, soft tissue sarcomas, adrenocortical tumors, and specific types of brain tumors have been designated as "core" cancers within the LFS spectrum[ 21 ].Female LFS carriers face a very high risk of breast cancer, which increases significantly with age, exceeding 70% by age 70. Beyond breast cancer, lifetime risks for other major cancers are approximately: brain cancer (~ 9%), soft tissue sarcoma (~ 4%), osteosarcoma (~ 3%), and adrenocortical carcinoma (~ 2%)[ 22 ].TP53 mutations are observed in both HBOC and LFS. Null variants were significantly more frequent among patients with HBOC-associated TP53 variants, while missense variants were significantly more frequent in patients with LFS-associated TP53 variants. TP53-associated breast cancers primarily exhibit triple-positive features (ER+/PR+/HER2+), particularly HER2-positive status. TP53 mutations are enriched in breast cancer patients diagnosed between 31 and 35 years of age[ 23 ].Pathogenic germline mutations in the TP53 gene cause approximately 70% of LFS cases[ 24 ].The median age at first cancer diagnosis for individuals with TP53 mutations is 36.1 years (33.7 years for females; 45.0 years for males)[ 25 ].Another study found that among 163 adult female TP53 mutation carriers, 91 were diagnosed with breast cancer, including 72 carriers of the p.R337H variant. Breast cancer was the first diagnosed malignancy in 90% of these cases; 78.2% of patients were diagnosed ≤ 45 years of age (11.5% 45 years)[ 26 ]. Tumor site distribution among TP53 germline mutation carriers is as follows: Breast (31.46%), Soft tissues (12.16%), Brain (11.15%), Adrenal gland (9.53%), Bones (9.3%)[ 27 ].Another study found that approximately 27% of TP53 mutation carriers develop soft tissue sarcomas, most commonly rhabdomyosarcoma, but liposarcoma or pleomorphic sarcoma are also frequent[ 28 ].Therefore, the clinical diversity associated with germline TP53 mutations suggests that a genetically defined hereditary TP53-related cancer (hTP53rc) syndrome encompasses a broader population at high risk than the clinically defined LFS phenotype. Diagnostic criteria for hTP53rc include: Familial presentation: Proband with a TP53 core tumor (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, or adrenocortical carcinoma) before age 46 AND at least one first- or second-degree relative with a core tumor before age 56; or Multiple primary tumors: Proband with multiple tumors, including two TP53 core tumors, the first occurring before age 46, irrespective of family history; or Rare tumors: Patient diagnosed with adrenocortical carcinoma, choroid plexus carcinoma, or embryonal anaplastic rhabdomyosarcoma, irrespective of family history; or Very early-onset breast cancer: Breast cancer diagnosis before age 31, irrespective of family history[ 29 ]. Was radiotherapy administered during the patient's initial breast cancer treatment a risk factor for the development of MPCs? Studies in the literature have summarized that the impact of radiotherapy on the risk of contralateral second primary breast malignancy in HBOC patients has yielded no consistent conclusion[ 18 ].Whether radiation therapy exposure increases the risk of secondary malignancies in LFS patients remains undetermined[ 30 ]. This patient exhibited major tumor types associated with both HBOC (breast cancer and ovarian cancer) and hTP53rc (breast cancer and UPS). The genotypic profile suggested a potential dual BRCA1 and TP53 germline mutation carrier status. A case report described a patient carrying similar BRCA1 and TP53 mutations who presented only with breast cancer and spinal metastasis. A 49-year-old female patient with triple-negative breast cancer, harboring germline pathogenic variants in both BRCA1 and TP53 genes, underwent neoadjuvant chemotherapy followed by total mastectomy and axillary lymph node dissection. She received two months of adjuvant radiotherapy post-surgery, followed by ten months of Poly ADP-ribose polymerase(PARP) inhibitor therapy. Subsequently, a biopsy-confirmed spinal metastasis was discovered. The patient experienced rapid disease progression and died four months after initiating first-line treatment for metastatic disease[ 31 ].However, no cancer history was documented in the patient's first- or second-degree relatives, and definitive genetic testing to confirm the presence of dominant hereditary susceptibility genes was not performed due to financial constraints. In this case, right breast ductal carcinoma in 2002 was in situ carcinoma, with an early stage and low recurrence and metastasis rate. However, ten years later, ovarian cancer recurred and metastasized after chemotherapy, so the presence of left breast nodules and right femoral masses is highly suspected of metastasis. Clinical doctors cannot arbitrarily judge it as metastasis, so the possibility of MPCs should be considered when combining with other organ masses. Due to the fact that the clinical manifestations of MPCs often conceal each other, which requires us to be vigilant. Diagnosis should start from multiple aspects. Firstly, clinical physicians must carefully examine, and secondly, PET/CT is an important diagnostic method. Finally, multi-site pathological biopsy serves as the definitive diagnostic approach for MPCs. By unequivocally establishing clonal independence through histopathological verification, metastatic misdiagnosis is prevented; by definitively confirming secondary primary malignancies, lesion-specific therapeutic strategies are implemented; and by identifying potential hereditary predisposition syndromes, timely cascade screening for patients and relatives is prompted. At present, there is no unified standard for the treatment of MPCs. A comprehensive treatment plan mainly consisting of surgery, radiotherapy, and chemotherapy should be adopted based on the pathological type, primary site, clinical stage, and overall condition. If simultaneous surgery is not suitable, lesions with poor prognosis, rapid progression, and direct life-threatening conditions should be treated first. During systemic chemotherapy, a wider coverage regimen can be chosen, balancing both to minimize patient damage and maximize benefits. The patient was diagnosed with intraductal carcinoma of the right breast in 2002 and received radiotherapy and chemotherapy. FISH indicated HER-2(2+), but trastuzumab was not administered due to prohibitive treatment costs following its initial market approval in China (2007).Additionally,anti-HER2 therapy demonstrates effective pathologic complete response (pCR) rates in HER2-positive LFS patients[ 32 ].The patient was diagnosed with left breast cancer when ovarian cancer recurred in 2016, and was treated with a TP chemotherapy regimen that took into account both factors, in an effort to save the patient's life. The patient passed away in October 2018, and in the following years. In our clinical practice, the authors have not yet encountered additional patients with quadruple primary tumors. MPCs remain a significant challenge for us. Due to the complex etiology and diverse clinical manifestations of MPCs, coupled with insufficient understanding by clinical physicians, they are easily misdiagnosed as metastases or missed diagnoses of the primary tumor, leading to incorrect treatment directions, missed treatment opportunities, and worsening of the condition. Therefore, the importance of accurately identifying MPCs is increasingly being recognized. Clinicians should use high-level technical means to make correct diagnoses, in order to detect and treat them effectively in a timely manner, prolong their survival time, and improve their quality of life. Declarations Competing Interests The authors have no relevant financial or non-financial interests to disclose Ethics approval Written informed consent was obtained from the patient and the patient’s family for publication of this case report and any accompanying data. All data have been anonymized to protect patient identity. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contribution Conceptualization: Qi Li;Writing - Original Draft: Rongze Sun,Hongxia Xie;Writing - Review & Editing: Rongze Sun, Sijia He;Investigation: Sijia He;Supervision: Qi Li;Project Administration: Qi Li. Acknowledgement Thank Qi Li for the valuable suggestions in determining the scope of the report. Grateful to Sijia He for her assistance in language modification. Data Availability All data generated or analyzed during this case report are included in this published article. The original data (e.g., medical images) are available from the corresponding author upon reasonable request, subject to privacy and ethical considerations. References Warren, S., Multiple primary malignant tumors: a survey of the literature and a statistical study. Gastroenterology, 1932. 93 (4): p. 779. Kwon, J.H., et al., Incidence and Characteristics of Multiple Primary Cancers: A 20-Year Retrospective Study of a Single Cancer Center in Korea. Cancers (Basel), 2024. 16 (13). The Surveillance, E., and End Results (SEER) 2025/8/2; Available from: https://seer.cancer.gov/statfacts/html/breast.html. Bao, S., et al., Nonmetastatic breast cancer patients subsequently developing second primary malignancy: A population-based study. Cancer Med, 2021. 10 (23): p. 8662-8672. Hou, N., et al., Radiotherapy and increased risk of second primary cancers in breast cancer survivors: An epidemiological and large cohort study. Breast, 2024. 78 : p. 103824. Xiao, L., et al., Clinical characteristics and prognostic analysis of multiple primary malignant neoplasms in female patients with breast cancer or genitalia malignancies. PeerJ, 2022. 10 : p. e13528. Gursel, B., et al., Multiple primary malignant neoplasms from the black sea region of Turkey. J Int Med Res, 2011. 39 (2): p. 667-74. Utada, M., et al., Incidence of multiple primary cancers and interval between first and second primary cancers. Cancer Sci, 2014. 105 (7): p. 890-6. Yamamoto, S., et al., The risk of multiple primary malignancies with colorectal carcinoma. Dis Colon Rectum, 2006. 49 (10 Suppl): p. S30-6. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144 (5): p. 646-74. Ratajska, M., et al., Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res Treat, 2012. 131 (1): p. 89-97. van Eggermond, A.M., et al., Risk of multiple primary malignancies following treatment of Hodgkin lymphoma. Blood, 2014. 124 (3): p. 319-27; quiz 466. Yoshida, R., Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis. Breast Cancer, 2021. 28 (6): p. 1167-1180. Speiser, D. and U. Bick, Primary Prevention and Early Detection of Hereditary Breast Cancer. Breast Care (Basel), 2023. 18 (6): p. 448-454. Öfverholm, A., et al., Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer. BMC Cancer, 2023. 23 (1): p. 738. Yoshimura, A., I. Imoto, and H. Iwata, Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management. Int J Mol Sci, 2022. 23 (13). El Ansari, F.Z., et al., Screening of BRCA1/2 genes mutations and copy number variations in patients with high risk for hereditary breast and ovarian cancer syndrome (HBOC). BMC Cancer, 2020. 20 (1): p. 747. Gonçalves, D., et al., An Overview on Radiation Sensitivity in Hereditary Breast and Ovarian Cancer Syndrome. Cancers (Basel), 2022. 14 (13). Agostinetto, E., et al., Characteristics and clinical outcomes of breast cancer in young BRCA carriers according to tumor histology. ESMO Open, 2024. 9 (10): p. 103714. Prejac, J., et al., A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor. World J Surg Oncol, 2021. 19 (1): p. 254. Barili, V., et al., Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing. Genes (Basel), 2024. 15 (2). Fortuno, C., et al., Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum. JCO Precis Oncol, 2024. 8 : p. e2300453. Kasper, E., et al., Deciphering dual clinical entities associated with TP53 pathogenic variants: Insights from 53,085 HBOC panel analyses in French laboratories. Int J Cancer, 2025. 157 (5): p. 897-907. Tian, P., et al., Characteristics of TP53 germline variants and their correlations with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients. J Genet Genomics, 2022. 49 (7): p. 645-653. de Andrade, K.C., et al., Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol, 2021. 22 (12): p. 1787-1798. Sandoval, R.L., et al., Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers. Front Oncol, 2022. 12 : p. 836937. Hosseini, M.S., Current insights and future directions of Li-Fraumeni syndrome. Discov Oncol, 2024. 15 (1): p. 561. Consul, N., et al., Li-Fraumeni Syndrome and Whole-Body MRI Screening: Screening Guidelines, Imaging Features, and Impact on Patient Management. AJR Am J Roentgenol, 2021. 216 (1): p. 252-263. Frebourg, T., et al., Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet, 2020. 28 (10): p. 1379-1386. Hendrickson, P.G., et al., Radiation therapy and secondary malignancy in Li-Fraumeni syndrome: A hereditary cancer registry study. Cancer Med, 2020. 9 (21): p. 7954-7963. Ea, V., et al., BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management. Int J Mol Sci, 2024. 25 (11). Bottosso, M., et al., HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome. Eur J Cancer, 2024. 211 : p. 114307. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7544436","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":513876550,"identity":"48a07161-9c82-4bbe-8cbb-c24834a9d067","order_by":0,"name":"Rongze Sun","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Rongze","middleName":"","lastName":"Sun","suffix":""},{"id":513876551,"identity":"b2abcc64-db2a-4723-8029-b8bd0baf4e59","order_by":1,"name":"Hongxia Xie","email":"","orcid":"","institution":"Jiuquan Branch of Shanghai General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongxia","middleName":"","lastName":"Xie","suffix":""},{"id":513876552,"identity":"65a9635e-2955-495b-a079-5aa650b46495","order_by":2,"name":"Sijia He","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Sijia","middleName":"","lastName":"He","suffix":""},{"id":513876553,"identity":"5f7bd965-0db2-4e57-9e49-b937616b492d","order_by":3,"name":"Qi Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACPhCRUMHADObxEKOFDazlDAMzD2laGNugqonTwt588MbDeXXs9hIJjA/etjHImxPUwnMs2SJx22FmHokEZsO5bQyGOxsIaZHIMZNI3HYApIVNmreNIcHgACEt8u+/SSTOqQNpYf9NnBYJHjaJxAZmsC3MxGnhSTO2SDgG9MuZh82Sc85JGG4gpIWf/fDDmz9q6pLZ25MPfnhTZiNP0BYQkADiZGDsNEDZRGqxI07pKBgFo2AUjEgAAMYENNWy+g5fAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":true,"prefix":"","firstName":"Qi","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-09-05 12:53:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7544436/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7544436/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00432-025-06354-z","type":"published","date":"2025-11-11T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96105045,"identity":"892f832c-fa0f-4ed5-abb9-96edadff75c1","added_by":"auto","created_at":"2025-11-17 16:07:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":409331,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7544436/v1/784b663d-3711-4c3c-8614-827c8eeb89ae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A clinical report and analysis of metachronous multiple primary cancers occurred in four sites","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMultiple primary cancers (MPCs) refer to the occurrence of two or more primary malignant tumors in different sites of the same system or different organ systems within the same individual. This concept was first proposed by Billroth in 1889 and later revised by Warren et al[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Based on the time interval between occurrences, MPCs can be further classified into synchronous (interval\u0026thinsp;\u0026lt;\u0026thinsp;6 months) and metachronous (interval\u0026thinsp;\u0026gt;\u0026thinsp;6months) types. In oncogenesis, MPCs are considered a rare phenomenon. A study from South Korea revealed that between 2003 and 2022, only 2.3% of 96,174 cancer patients developed MPCs. Breast cancer was the most common first primary tumor, accounting for 15.7% of cases[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].However, with continuous advancements in cancer diagnosis and treatment, the survival time of patients has significantly increased, leading to a rise in the incidence of MPCs.\u003c/p\u003e\u003cp\u003eBreast cancer is one of the most common malignant tumors in women. The Surveillance, Epidemiology, and End Results (SEER) data from 2015\u0026ndash;2021 indicate a 5-year survival rate of 91.7%[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Increased patient life expectancy consequently raises the probability of detecting a second primary tumor. Studies have found that among female breast cancer patients without metastasis, the most common sites for second primary tumors are the breast (30%), lung and bronchus (13.4%), uterus (5.8%), thyroid (5.6%), and melanoma (4.5%), among other locations[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Following radiotherapy, the overall cumulative incidence of second primary tumors increases in these patients, with significant elevations observed specifically in the cumulative incidence of breast cancer, respiratory system cancers, skin cancers, leukemia, soft tissue sarcomas (including heart), and orbital cancers[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Stage at diagnosis, whether radical surgery was performed, and the tumor interval are significant survival-related factors for patients with MPCs in the breast or reproductive system[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCurrently, there is no specific treatment protocol for MPCs in clinical practice, necessitating further in-depth understanding. This article presents a clinically rare case of primary quadruple cancer and discusses it as follows.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 52-year-old woman presented to Xijing Hospital of the Fourth Military Medical University in 2002 with a right breast mass.After completing relevant examinations and laboratory tests, the patient underwent \"modified radical mastectomy for right breast cancer\". Postoperative pathological examination revealed intraductal carcinoma in the right breast, and immunohistochemistry revealed ER negative and PR negative.The patient underwent 2 cycles of CAF(Cyclophosphamide, Adriamycin and Fluorouracil) regimen chemotherapy and weekly paclitaxel treatment, for a total of 6 cycles. The specific dosage of medication is unknown. Postoperative right chest wall radiotherapy DT 50Gy/25 times, single dose 2.0Gy/f. In 2007, Fluorescence in situ hybridization (FISH) showed HER-2 (++), but the patient did not receive targeted therapy.\u003c/p\u003e\u003cp\u003eThe patient was subsequently maintained on regular follow-up. In 2012, due to ovarian cancer, a total hysterectomy with double adnexa, partial omentum, and appendectomy was performed at Gansu Provincial People's Hospital. Postoperative pathology showed serous papillary cystadenocarcinoma, cervical and intestinal interstitial tissue: metastatic serous papillary cystadenocarcinoma, (right ovary) serous papillary cystadenocarcinoma, with cancer tissue involvement in the right fallopian tube cavity, and no cancer tissue involvement in the left ovary and fallopian tube; Chronic cervical inflammation, chronic appendicitis, and no involvement of cancer in the omentum tissue. After surgery, TC regimen (paclitaxel combined with carboplatin) was given for 3 cycles of chemotherapy, and paclitaxel liposomes combined with nedaplatin for 5 cycles. The chemotherapy-related toxicities were tolerable.\u003c/p\u003e\u003cp\u003eIn April 2016, a recurrence of ovarian cancer was identified during a routine follow-up visit, and the patient presented to Gansu Provincial People's Hospital for PET-CT imaging. The results showed that: 1. After right breast, uterus, and bilateral adnexectomy, 2. Nodular abnormal high metabolism in the lower outer quadrant of the left breast, suggesting malignant lesions; 3. Enlarged lymph nodes in the retroperitoneum, suspected of metastasis. Multiple high metabolic nodules in the lower abdominal wall and pelvic cavity are suspected of metastasis, with no other abnormalities. On May 9, 2016, the patient underwent core needle biopsy of the left breast at the Cancer Hospital of the Chinese Academy of Medical Sciences. Histopathological examination revealed invasive ductal carcinoma, not otherwise specified (Grade II). Immunohistochemistry (IHC) demonstrated: ER(\u0026gt;\u0026thinsp;90% strongly positive),PR(20% moderate-to-strong positive),HER-2(3+),PAX2(-),PAX8(-),GATA 3(3+),GCDFP15(2+),Ki-67(30%+).Pathological consultation at Xijing Hospital of the Fourth Military Medical University confirmed the right breast lesion as intermediate-grade ductal carcinoma in situ with focal intraductal papillary carcinoma. The collective findings support the diagnosis of primary left breast carcinoma, definitively ruling out metastatic disease. Administer 8 cycles of chemotherapy, with specific medication: 270mg intravenous infusion of levonorgestrel and 120mg intravenous infusion of nedaplatin D2, Q3W. The last chemotherapy was administered in October 2016.\u003c/p\u003e\u003cp\u003eOn August 31, 2017, the patient discovered a mass on the inner side of the right thigh that gradually increased in size, accompanied by pain and discomfort. There were no discomforts such as chills, fever, chest tightness, shortness of breath, etc. After admission, relevant examinations and laboratory tests were completed. On November 16, 2017, a puncture biopsy was performed on the inner right thigh mass under local anesthesia. Postoperative pathological examination showed malignant tumor and sarcoma. IHC demonstrated: CKp (-),EMA (-),Vimentin (2+), CD68 (large cell+),CD163 (3+),Actin (-),Desmin(-),CD34(-),Bel-2(-),STAT6 (-),CD45(-),S-100(-),Melanoma(-) and ki-67(60\u0026ndash;70% for large cells and 30\u0026ndash;40% for spindle cells).The histopathological features, combined with immunohistochemical findings, support the diagnosis of pleomorphic malignant fibrous histiocytoma (MFH) / undifferentiated high-grade pleomorphic sarcoma.The patient's diagnosis includes postoperative right breast cancer, postoperative ovarian cancer, left breast cancer, and malignant fibrous histiocytoma of the right femur, all of which have been confirmed by pathology to be primary. Following discharge, the patient was continued on Chinese herbal medicine for palliative care with no further antitumor therapy initiated. Due to the patient's repeated chemotherapy in the early stage and poor physical condition, the family requested only symptomatic supportive treatment and respected the wishes of the patient and family. The patient passed away six months after follow-up.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn recent years, there has been an increasing trend of MPCs, and the diagnostic criteria developed by Warren and Gates[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] are now widely used internationally. (1) Each tumor must be confirmed as malignant by histological examination; (2) Each type of tumor has its unique pathological morphology, and each tumor exists independently of each other; (3) Each tumor must be excluded as a metastatic lesion of other tumors. All four types of tumors in this case have been confirmed by pathology to be primary cancers, and they are metachronous multiple primary cancers.\u003c/p\u003e\u003cp\u003eMPCs can occur in any combination of organs and systems, and there are inconsistent literature reports on their common sites. Gursel et al.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] reported that the first primary cancer is more likely to occur in the throat, bladder, and breast, while the second primary cancer is more likely to occur in the lungs, breast, and colon. Utada et al.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] reported that the first primary cancers are mainly esophageal cancer and laryngeal cancer, followed by ovarian cancer, pharyngeal cancer, oropharyngeal cancer, etc; The second most common sites of primary cancer are the thyroid and esophagus, followed by the breast and colon. Jin-Hee Kwon et al. reported breast, thyroid, stomach, lung, and colorectal cancers comprised the top five first primary cancers. This dominance continued for second primaries, with lung, thyroid, breast, stomach, and colorectal cancers again featuring prominently.\u003c/p\u003e\u003cp\u003eThe etiology of MPCs is not yet clear, and most scholars believe that it is the result of multiple factors working together, mainly related to aging, host factors, immune status[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], environmental factors[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], family genetics[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], iatrogenic factors[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], etc. In this case, the patient presented with bilateral breast cancer, ovarian cancer, and a undifferentiated pleomorphic sarcoma (UPS) of the right femur. A hereditary cancer syndrome, such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome or Li-Fraumeni Syndrome (LFS), cannot be excluded out. Breast cancer and ovarian cancer represent the principal tumor phenotypes of HBOC, while breast cancer and soft tissue sarcoma constitute the core tumor phenotypes of LFS. HBOC is an autosomal dominant inherited syndrome. In addition to increased risks of breast and ovarian cancer, HBOC patients may also face elevated risks of developing other cancer types, including melanoma, pancreatic cancer, and prostate cancer[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].Core genes associated with HBOC include: BRCA1/2, BARD1, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11 and TP53[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].Among women diagnosed with breast and/or ovarian cancer, the proportion carrying at least one pathogenic variant (PV) was found to be 16.6%. BRCA1/2 PVs were identified in 8.9% of these women (BRCA1: 5.95%; BRCA2: 2.94%), while PVs in other breast and ovarian cancer susceptibility genes were detected in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0%) and TP53 (0.56%)[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].Mutations in the BRCA1 and BRCA2 genes represent the primary etiological factors for HBOC[\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].Breast cancers associated with BRCA2 PVs were predominantly lobular tumors, whereas those associated with BRCA1 PVs were predominantly ductal tumors[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eLFS is also an autosomal dominant inherited cancer predisposition syndrome characterized by high penetrance and early onset of malignancies. Premenopausal breast cancer is observed in 79% of female LFS patients, while osteosarcoma, central nervous system tumors, adrenocortical carcinoma, and soft tissue sarcomas are found in 27% of patients[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].Breast cancer, soft tissue sarcomas, adrenocortical tumors, and specific types of brain tumors have been designated as \"core\" cancers within the LFS spectrum[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].Female LFS carriers face a very high risk of breast cancer, which increases significantly with age, exceeding 70% by age 70. Beyond breast cancer, lifetime risks for other major cancers are approximately: brain cancer (~\u0026thinsp;9%), soft tissue sarcoma (~\u0026thinsp;4%), osteosarcoma (~\u0026thinsp;3%), and adrenocortical carcinoma (~\u0026thinsp;2%)[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].TP53 mutations are observed in both HBOC and LFS. Null variants were significantly more frequent among patients with HBOC-associated TP53 variants, while missense variants were significantly more frequent in patients with LFS-associated TP53 variants. TP53-associated breast cancers primarily exhibit triple-positive features (ER+/PR+/HER2+), particularly HER2-positive status. TP53 mutations are enriched in breast cancer patients diagnosed between 31 and 35 years of age[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].Pathogenic germline mutations in the TP53 gene cause approximately 70% of LFS cases[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].The median age at first cancer diagnosis for individuals with TP53 mutations is 36.1 years (33.7 years for females; 45.0 years for males)[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].Another study found that among 163 adult female TP53 mutation carriers, 91 were diagnosed with breast cancer, including 72 carriers of the p.R337H variant. Breast cancer was the first diagnosed malignancy in 90% of these cases; 78.2% of patients were diagnosed\u0026thinsp;\u0026le;\u0026thinsp;45 years of age (11.5% \u0026lt;31 years; 66.7% 31\u0026ndash;45 years; 21.8% \u0026gt;45 years)[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTumor site distribution among TP53 germline mutation carriers is as follows: Breast (31.46%), Soft tissues (12.16%), Brain (11.15%), Adrenal gland (9.53%), Bones (9.3%)[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].Another study found that approximately 27% of TP53 mutation carriers develop soft tissue sarcomas, most commonly rhabdomyosarcoma, but liposarcoma or pleomorphic sarcoma are also frequent[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].Therefore, the clinical diversity associated with germline TP53 mutations suggests that a genetically defined hereditary TP53-related cancer (hTP53rc) syndrome encompasses a broader population at high risk than the clinically defined LFS phenotype. Diagnostic criteria for hTP53rc include:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eFamilial presentation: Proband with a \u003cem\u003eTP53\u003c/em\u003e core tumor (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, or adrenocortical carcinoma) before age 46 AND at least one first- or second-degree relative with a core tumor before age 56; or\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eMultiple primary tumors: Proband with multiple tumors, including two \u003cem\u003eTP53\u003c/em\u003e core tumors, the first occurring before age 46, irrespective of family history; or\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eRare tumors: Patient diagnosed with adrenocortical carcinoma, choroid plexus carcinoma, or embryonal anaplastic rhabdomyosarcoma, irrespective of family history; or\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eVery early-onset breast cancer: Breast cancer diagnosis before age 31, irrespective of family history[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eWas radiotherapy administered during the patient's initial breast cancer treatment a risk factor for the development of MPCs? Studies in the literature have summarized that the impact of radiotherapy on the risk of contralateral second primary breast malignancy in HBOC patients has yielded no consistent conclusion[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].Whether radiation therapy exposure increases the risk of secondary malignancies in LFS patients remains undetermined[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis patient exhibited major tumor types associated with both HBOC (breast cancer and ovarian cancer) and hTP53rc (breast cancer and UPS). The genotypic profile suggested a potential dual BRCA1 and TP53 germline mutation carrier status. A case report described a patient carrying similar BRCA1 and TP53 mutations who presented only with breast cancer and spinal metastasis. A 49-year-old female patient with triple-negative breast cancer, harboring germline pathogenic variants in both BRCA1 and TP53 genes, underwent neoadjuvant chemotherapy followed by total mastectomy and axillary lymph node dissection. She received two months of adjuvant radiotherapy post-surgery, followed by ten months of Poly ADP-ribose polymerase(PARP) inhibitor therapy. Subsequently, a biopsy-confirmed spinal metastasis was discovered. The patient experienced rapid disease progression and died four months after initiating first-line treatment for metastatic disease[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].However, no cancer history was documented in the patient's first- or second-degree relatives, and definitive genetic testing to confirm the presence of dominant hereditary susceptibility genes was not performed due to financial constraints.\u003c/p\u003e\u003cp\u003eIn this case, right breast ductal carcinoma in 2002 was in situ carcinoma, with an early stage and low recurrence and metastasis rate. However, ten years later, ovarian cancer recurred and metastasized after chemotherapy, so the presence of left breast nodules and right femoral masses is highly suspected of metastasis. Clinical doctors cannot arbitrarily judge it as metastasis, so the possibility of MPCs should be considered when combining with other organ masses. Due to the fact that the clinical manifestations of MPCs often conceal each other, which requires us to be vigilant. Diagnosis should start from multiple aspects. Firstly, clinical physicians must carefully examine, and secondly, PET/CT is an important diagnostic method. Finally, multi-site pathological biopsy serves as the definitive diagnostic approach for MPCs. By unequivocally establishing clonal independence through histopathological verification, metastatic misdiagnosis is prevented; by definitively confirming secondary primary malignancies, lesion-specific therapeutic strategies are implemented; and by identifying potential hereditary predisposition syndromes, timely cascade screening for patients and relatives is prompted.\u003c/p\u003e\u003cp\u003eAt present, there is no unified standard for the treatment of MPCs. A comprehensive treatment plan mainly consisting of surgery, radiotherapy, and chemotherapy should be adopted based on the pathological type, primary site, clinical stage, and overall condition. If simultaneous surgery is not suitable, lesions with poor prognosis, rapid progression, and direct life-threatening conditions should be treated first. During systemic chemotherapy, a wider coverage regimen can be chosen, balancing both to minimize patient damage and maximize benefits. The patient was diagnosed with intraductal carcinoma of the right breast in 2002 and received radiotherapy and chemotherapy. FISH indicated HER-2(2+), but trastuzumab was not administered due to prohibitive treatment costs following its initial market approval in China (2007).Additionally,anti-HER2 therapy demonstrates effective pathologic complete response (pCR) rates in HER2-positive LFS patients[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].The patient was diagnosed with left breast cancer when ovarian cancer recurred in 2016, and was treated with a TP chemotherapy regimen that took into account both factors, in an effort to save the patient's life. The patient passed away in October 2018, and in the following years. In our clinical practice, the authors have not yet encountered additional patients with quadruple primary tumors.\u003c/p\u003e\u003cp\u003eMPCs remain a significant challenge for us. Due to the complex etiology and diverse clinical manifestations of MPCs, coupled with insufficient understanding by clinical physicians, they are easily misdiagnosed as metastases or missed diagnoses of the primary tumor, leading to incorrect treatment directions, missed treatment opportunities, and worsening of the condition. Therefore, the importance of accurately identifying MPCs is increasingly being recognized. Clinicians should use high-level technical means to make correct diagnoses, in order to detect and treat them effectively in a timely manner, prolong their survival time, and improve their quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics approval\u003c/h2\u003e\u003cp\u003e Written informed consent was obtained from the patient and the patient\u0026rsquo;s family for publication of this case report and any accompanying data. All data have been anonymized to protect patient identity.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: Qi Li;Writing - Original Draft: Rongze Sun,Hongxia Xie;Writing - Review \u0026amp; Editing: Rongze Sun, Sijia He;Investigation: Sijia He;Supervision: Qi Li;Project Administration: Qi Li.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThank Qi Li for the valuable suggestions in determining the scope of the report. Grateful to Sijia He for her assistance in language modification.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed during this case report are included in this published article. The original data (e.g., medical images) are available from the corresponding author upon reasonable request, subject to privacy and ethical considerations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWarren, S., \u003cem\u003eMultiple primary malignant tumors: a survey of the literature and a statistical study.\u003c/em\u003e Gastroenterology, 1932. \u003cstrong\u003e93\u003c/strong\u003e(4): p. 779.\u003c/li\u003e\n\u003cli\u003eKwon, J.H., et al., \u003cem\u003eIncidence and Characteristics of Multiple Primary Cancers: A 20-Year Retrospective Study of a Single Cancer Center in Korea.\u003c/em\u003e Cancers (Basel), 2024. \u003cstrong\u003e16\u003c/strong\u003e(13).\u003c/li\u003e\n\u003cli\u003eThe Surveillance, E., and End Results (SEER) 2025/8/2; Available from: https://seer.cancer.gov/statfacts/html/breast.html.\u003c/li\u003e\n\u003cli\u003eBao, S., et al., \u003cem\u003eNonmetastatic breast cancer patients subsequently developing second primary malignancy: A population-based study.\u003c/em\u003e Cancer Med, 2021. \u003cstrong\u003e10\u003c/strong\u003e(23): p. 8662-8672.\u003c/li\u003e\n\u003cli\u003eHou, N., et al., \u003cem\u003eRadiotherapy and increased risk of second primary cancers in breast cancer survivors: An epidemiological and large cohort study.\u003c/em\u003e Breast, 2024. \u003cstrong\u003e78\u003c/strong\u003e: p. 103824.\u003c/li\u003e\n\u003cli\u003eXiao, L., et al., \u003cem\u003eClinical characteristics and prognostic analysis of multiple primary malignant neoplasms in female patients with breast cancer or genitalia malignancies.\u003c/em\u003e PeerJ, 2022. \u003cstrong\u003e10\u003c/strong\u003e: p. e13528.\u003c/li\u003e\n\u003cli\u003eGursel, B., et al., \u003cem\u003eMultiple primary malignant neoplasms from the black sea region of Turkey.\u003c/em\u003e J Int Med Res, 2011. \u003cstrong\u003e39\u003c/strong\u003e(2): p. 667-74.\u003c/li\u003e\n\u003cli\u003eUtada, M., et al., \u003cem\u003eIncidence of multiple primary cancers and interval between first and second primary cancers.\u003c/em\u003e Cancer Sci, 2014. \u003cstrong\u003e105\u003c/strong\u003e(7): p. 890-6.\u003c/li\u003e\n\u003cli\u003eYamamoto, S., et al., \u003cem\u003eThe risk of multiple primary malignancies with colorectal carcinoma.\u003c/em\u003e Dis Colon Rectum, 2006. \u003cstrong\u003e49\u003c/strong\u003e(10 Suppl): p. 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Bick, \u003cem\u003ePrimary Prevention and Early Detection of Hereditary Breast Cancer.\u003c/em\u003e Breast Care (Basel), 2023. \u003cstrong\u003e18\u003c/strong\u003e(6): p. 448-454.\u003c/li\u003e\n\u003cli\u003e\u0026Ouml;fverholm, A., et al., \u003cem\u003eExtended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer.\u003c/em\u003e BMC Cancer, 2023. \u003cstrong\u003e23\u003c/strong\u003e(1): p. 738.\u003c/li\u003e\n\u003cli\u003eYoshimura, A., I. Imoto, and H. Iwata, \u003cem\u003eFunctions of Breast Cancer Predisposition Genes: Implications for Clinical Management.\u003c/em\u003e Int J Mol Sci, 2022. \u003cstrong\u003e23\u003c/strong\u003e(13).\u003c/li\u003e\n\u003cli\u003eEl Ansari, F.Z., et al., \u003cem\u003eScreening of BRCA1/2 genes mutations and copy number variations in patients with high risk for hereditary breast and ovarian cancer syndrome (HBOC).\u003c/em\u003e BMC Cancer, 2020. \u003cstrong\u003e20\u003c/strong\u003e(1): p. 747.\u003c/li\u003e\n\u003cli\u003eGon\u0026ccedil;alves, D., et al., \u003cem\u003eAn Overview on Radiation Sensitivity in Hereditary Breast and Ovarian Cancer Syndrome.\u003c/em\u003e Cancers (Basel), 2022. \u003cstrong\u003e14\u003c/strong\u003e(13).\u003c/li\u003e\n\u003cli\u003eAgostinetto, E., et al., \u003cem\u003eCharacteristics and clinical outcomes of breast cancer in young BRCA carriers according to tumor histology.\u003c/em\u003e ESMO Open, 2024. \u003cstrong\u003e9\u003c/strong\u003e(10): p. 103714.\u003c/li\u003e\n\u003cli\u003ePrejac, J., et al., \u003cem\u003eA first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor.\u003c/em\u003e World J Surg Oncol, 2021. \u003cstrong\u003e19\u003c/strong\u003e(1): p. 254.\u003c/li\u003e\n\u003cli\u003eBarili, V., et al., \u003cem\u003eGenetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing.\u003c/em\u003e Genes (Basel), 2024. \u003cstrong\u003e15\u003c/strong\u003e(2).\u003c/li\u003e\n\u003cli\u003eFortuno, C., et al., \u003cem\u003eCancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.\u003c/em\u003e JCO Precis Oncol, 2024. \u003cstrong\u003e8\u003c/strong\u003e: p. e2300453.\u003c/li\u003e\n\u003cli\u003eKasper, E., et al., \u003cem\u003eDeciphering dual clinical entities associated with TP53 pathogenic variants: Insights from 53,085 HBOC panel analyses in French laboratories.\u003c/em\u003e Int J Cancer, 2025. \u003cstrong\u003e157\u003c/strong\u003e(5): p. 897-907.\u003c/li\u003e\n\u003cli\u003eTian, P., et al., \u003cem\u003eCharacteristics of TP53 germline variants and their correlations with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients.\u003c/em\u003e J Genet Genomics, 2022. \u003cstrong\u003e49\u003c/strong\u003e(7): p. 645-653.\u003c/li\u003e\n\u003cli\u003ede Andrade, K.C., et al., \u003cem\u003eCancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.\u003c/em\u003e Lancet Oncol, 2021. \u003cstrong\u003e22\u003c/strong\u003e(12): p. 1787-1798.\u003c/li\u003e\n\u003cli\u003eSandoval, R.L., et al., \u003cem\u003eBreast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers.\u003c/em\u003e Front Oncol, 2022. \u003cstrong\u003e12\u003c/strong\u003e: p. 836937.\u003c/li\u003e\n\u003cli\u003eHosseini, M.S., \u003cem\u003eCurrent insights and future directions of Li-Fraumeni syndrome.\u003c/em\u003e Discov Oncol, 2024. \u003cstrong\u003e15\u003c/strong\u003e(1): p. 561.\u003c/li\u003e\n\u003cli\u003eConsul, N., et al., \u003cem\u003eLi-Fraumeni Syndrome and Whole-Body MRI Screening: Screening Guidelines, Imaging Features, and Impact on Patient Management.\u003c/em\u003e AJR Am J Roentgenol, 2021. \u003cstrong\u003e216\u003c/strong\u003e(1): p. 252-263.\u003c/li\u003e\n\u003cli\u003eFrebourg, T., et al., \u003cem\u003eGuidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes.\u003c/em\u003e Eur J Hum Genet, 2020. \u003cstrong\u003e28\u003c/strong\u003e(10): p. 1379-1386.\u003c/li\u003e\n\u003cli\u003eHendrickson, P.G., et al., \u003cem\u003eRadiation therapy and secondary malignancy in Li-Fraumeni syndrome: A hereditary cancer registry study.\u003c/em\u003e Cancer Med, 2020. \u003cstrong\u003e9\u003c/strong\u003e(21): p. 7954-7963.\u003c/li\u003e\n\u003cli\u003eEa, V., et al., \u003cem\u003eBRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management.\u003c/em\u003e Int J Mol Sci, 2024. \u003cstrong\u003e25\u003c/strong\u003e(11).\u003c/li\u003e\n\u003cli\u003eBottosso, M., et al., \u003cem\u003eHER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome.\u003c/em\u003e Eur J Cancer, 2024. \u003cstrong\u003e211\u003c/strong\u003e: p. 114307.\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":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Multiple primary cancers, Hereditary Breast and Ovarian Cancer, hereditary TP53-related cancer syndrome, breast cancer, ovarian cancer","lastPublishedDoi":"10.21203/rs.3.rs-7544436/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7544436/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eThis case report aims to describe a rare occurrence of quadruple primary malignancies\u0026mdash;bilateral primary breast cancer, ovarian cancer, and pleomorphic malignant fibrous histiocytoma/undifferentiated high-grade pleomorphic sarcoma\u0026mdash;and to explore its potential association with hereditary tumor syndromes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a detailed clinical and histopathological analysis of the case. Repeated imaging and pathological examinations were performed to confirm the diagnosis of each primary malignancy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe patient was diagnosed with four distinct primary tumors, and pathological evaluation confirmed each malignancy.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis case underscores the importance of comprehensive pathological and genetic evaluation in patients with multiple primary malignancies. It highlights the increasing incidence of such tumors among long-term cancer survivors and offers valuable clinical perspectives for diagnosis and management in the context of hereditary cancer syndromes.\u003c/p\u003e","manuscriptTitle":"A clinical report and analysis of metachronous multiple primary cancers occurred in four sites","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 07:48:23","doi":"10.21203/rs.3.rs-7544436/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-17T01:36:59+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"34902819441871429466077408151589410416","date":"2025-09-16T21:23:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-15T06:29:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-13T15:12:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-11T22:34:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-11T15:30:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-10T10:13:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21848487773917373124141874321968478282","date":"2025-09-10T07:33:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12411497472369820807674431898657360693","date":"2025-09-10T02:34:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238240543160763332038155762668794617943","date":"2025-09-09T23:42:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17609975053514672057721024419671386042","date":"2025-09-08T04:56:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2299541199922062164933529011274260517","date":"2025-09-07T21:12:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"126398027973537935380980228620969810375","date":"2025-09-07T19:42:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T12:19:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294274044154645099188494356458167103167","date":"2025-09-07T11:53:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-06T17:28:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-06T04:57:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-06T04:57:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2025-09-05T12:43:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"764ea60b-6977-43f7-95d0-a85ed4358653","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T16:02:09+00:00","versionOfRecord":{"articleIdentity":"rs-7544436","link":"https://doi.org/10.1007/s00432-025-06354-z","journal":{"identity":"journal-of-cancer-research-and-clinical-oncology","isVorOnly":false,"title":"Journal of Cancer Research and Clinical Oncology"},"publishedOn":"2025-11-11 15:58:02","publishedOnDateReadable":"November 11th, 2025"},"versionCreatedAt":"2025-09-12 07:48:23","video":"","vorDoi":"10.1007/s00432-025-06354-z","vorDoiUrl":"https://doi.org/10.1007/s00432-025-06354-z","workflowStages":[]},"version":"v1","identity":"rs-7544436","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7544436","identity":"rs-7544436","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}