Multiple primary tumors, according to the definition by IARC are primary malignant tumors of different histological origins in the same person. They can be divided into synchronous and metachronous based on the time interval of their occurrence. Synchronous primary tumors are diagnosed in the interval of 6 months and metachronous tumors arise in a period of more than 6 months.
The risk factors for developing multiple primary tumors can be classified into three main categories: host-related, lifestyle, and environmental factors. [4]
Host-related factors, including genetic syndromes and mutations, play a significant role in amplifying the risk of certain cancers. These factors contribute to an individual's susceptibility to developing specific malignancies over their lifetime. Examples of these include Lynch syndrome, which is associated with a higher risk of colon and endometrial cancer, and BRCA1 and BRCA2 mutations, which are linked to an increased risk of breast cancer. Another genetic syndrome, von Hippel-Lindau disease, predisposes individuals to various malignancies such as clear cell renal cell carcinoma and neuroendocrine tumors. [5] MEN1/MEN2 are genetic disorders characterized by the presence of parathyroid and thyroid adenomas, as well as pancreatic islet cell tumors such as gastrinomas, vipomas, and insulinomas. MEN2 is specifically related to medullary thyroid cancer and pheochromocytoma. [6]
Lifestyle factors play a significant role in increasing the risk of cancer, with certain habits contributing more prominently to this elevated risk. For instance, tobacco and alcohol consumption represent factors known to increase the risk of developing various malignancies. A study conducted by Tabuchi et al. identified the most prevalent locations of synchronous primary tumors in smokers as the oral cavity, pharynx, lung, esophagus, and stomach. [7] Prolonged and excessive alcohol intake is a significant contributing factor to the development of liver cancer, as it leads to liver damage and cirrhosis, and eventually increases the risk of hepatocellular carcinoma.
Environmental factors may include for example increased cancer risk in areas with high radon exposure. Regions with high levels of air pollution have been associated with increased rates of lung cancer. Coastal areas or regions with high levels of ultraviolet (UV) radiation exposure are linked to higher rates of skin cancer, including melanoma. Moreover, certain geographical regions with contaminated water sources may pose a higher risk of developing specific types of cancers, such as bladder cancer due to exposure to arsenic in drinking water. Additionally, areas with high levels of industrial activity or hazardous waste disposal sites may increase the risk of various cancers due to exposure to carcinogenic substances in the environment.
Certain viruses play a significant role in the development of various cancers, acting as critical environmental factors in disease etiology. For instance, Human Papillomavirus (HPV) is a major cause of gynecological cancers, notably cervical cancer, and has also been linked to other types of cancer affecting the genital and oral regions. The Epstein-Barr virus (EBV) is another viral agent associated with a higher risk of developing lymphoma and nasopharyngeal cancer, indicating its broad impact on cancer risk. Additionally, Hepatitis B (HBV) and Hepatitis C (HCV) viruses are well-documented contributors to the development of hepatocellular carcinoma.
Occupational exposure to asbestos increases the risk of developing mesothelioma in workers who already have asbestosis. [2]
The incidence of getting a second primary malignancy varies across different cancer sites, ranging from 1% for primary liver malignancy to 16% for primary bladder cancer.Weir et al discovered that the occurrence of multiple primary tumors was 16.9% in colon cancer patients and 19.9% in individuals with lung cancer. [6]
The incidence of multiple primaries in breast cancer patients has been reported to range from 4.1% (Kim et al., 108 patients) to 16.4% (Weir et al., 301 963 patients; maximum follow-up of 10 years). The interval between 5 and 8 years was the median time to a second cancer. There is a substantial correlation between the breast cancer genes BRCA1 and BRCA2 and a higher chance of developing ovarian or second breast cancer. Moreover, lobular breast cancer and hereditary stomach cancer have a close correlation. [8]
Some cases of patients with multiple cancers are presented in the images below.