In recent years, there has been an increasing trend of MPCs. The diagnostic criteria developed by Warren and Gates(Warren 1932) 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.

MPCs can arise in any combination of organs and systems, and the literature shows inconsistencies regarding the most frequently involved sites. For instance, Gursel et al. (2011) reported that the most common sites for the first primary cancer were the throat, bladder, and breast, while the second primary cancer most frequently involved the lungs, breast, and colon. In contrast, Utada et al. (2014) 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. Conversely,Jin-Hee Kwon et al. reported breast, thyroid, stomach, lung, and colorectal cancers comprised the top five first primary cancers (Kwon et al. 2024).

The etiology of MPCs remains unclear, and is widely considered to be multifactorial, involving elements such as aging, host factors, immune status (Yamamoto et al. 2006), environmental factors (Hanahan and Weinberg 2011), genetic predisposition (Ratajska et al. 2012), and iatrogenic factors (Eggermond, et al. 2014). 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. 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 (Yoshida 2021). Core genes associated with HBOC include BRCA1/2, BARD1, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53 (Speiser and Bick 2023). 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 account for 8.9% (BRCA1: 5.95%; BRCA2: 2.94%), while PVs in other breast and ovarian cancer susceptibility genes (ATM, BARD1, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53) were detected in 8.2%: (Öfverholm et al. 2023). Pathogenic variants in the BRCA1 and BRCA2 genes represent the primary etiological factors for HBOC (Yoshimura et al. 2022). Notably, breast cancers associated with BRCA2 PVs were predominantly lobular tumors, whereas those associated with BRCA1 PVs were predominantly ductal tumors (Agostinetto et al. 2024).

LFS is an autosomal dominant cancer predisposition syndrome characterized by high penetrance and early-onset malignancies. Premenopausal breast cancer develops in 79% of female LFS patients, while osteosarcoma, central nervous system tumors, adrenocortical carcinoma, and soft tissue sarcomas are found in approximately 27% of patients (Prejac et al. 2021). Furthermore, breast cancer, soft tissue sarcomas, adrenocortical tumors, and specific types of brain tumors have been designated as "core" cancers within the LFS spectrum (Barili et al. 2024). Female LFS carriers face a very high risk of breast cancer, which increases significantly with age, exceeding 70% by age 70 (Fortuno et al. 2024).

Notably, TP53 mutations are observed in both HBOC and LFS. However, their distribution differs: 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(Kasper et al. 2025).Pathogenic germline mutations in the TP53 gene cause approximately 70% of LFS cases (Tian et al. 2022). 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) (Andrade et al. 2021). 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 (Sandoval et al. 2022).

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%), and bone (9.3%) (Hosseini 2024). A separate study found that approximately 27% of TP53 mutation carriers develop soft tissue sarcomas, most commonly rhabdomyosarcoma, with liposarcoma or pleomorphic sarcoma also being frequent subtypes (Consul et al. 2021).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 (Frebourg et al. 2020).

This patient exhibited major tumor types associated with both HBOC (breast cancer and ovarian cancer) and hTP53rc (breast cancer and UPS). The presence of relatively characteristic tumor sites suggests that this patient may potentially be a double carrier of germline mutations in both BRCA1 and TP53. 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 (Ea et al. 2024). As a single-case report, the generalizability of our findings is inherently limited. This limitation is compounded by the absence of definitive genetic testing and the lack of a significant family history. These gaps preclude a definitive diagnosis of a hereditary syndrome. Therefore, the association we propose remains hypothetical and is based primarily on the exceptional rarity of the clinical presentation and the distinctive pattern of involved organs.

In this case, she was diagnosed with right breast ductal carcinoma in 2002. However, ten years later, she was diagnosed with ovarian cancer. Consequently, when a left breast nodule and a right thigh mass were subsequently detected, they were highly suspicious for metastatic disease. This highlights a critical clinical challenge: while such lesions raise suspicion for metastasis, clinicians must not hastily classify them as such and should always consider the possibility of MPCs when encountering new masses in other organs. Furthermore, the clinical presentation of MPCs can be obscured by overlapping features of individual tumors, necessitating a high index of suspicion.

A systematic diagnostic approach is therefore essential. Firstly, a thorough clinical examination is imperative. Secondly, imaging modalities such as PET/CT play a crucial role in identifying suspicious lesions. 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 performing genetic testing to identify potential hereditary cancer 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 synchronous resection is not feasible, priority should be given to treating the lesion with the poorest prognosis, most rapid progression, or that poses the most immediate threat to life. When selecting systemic chemotherapy, regimens with broader antitumor activity may be considered, aiming to balance efficacy with toxicity to maximize therapeutic benefit. 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 (Bottosso et al. 2024).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 malignancies. The patient succumbed to her disease 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. Moving forward, clinicians should use advanced diagnostic technologies—including histopathology and genetic testing— to establish correct diagnoses promptly Ultimately, the management of MPCs should be guided by a multidisciplinary team (MDT) approach to formulate timely and effective, tumor-specific strategies. This paradigm is essential to prolonging patient survival and improving their quality of life.