What is the etiology of multiple primary malignant neoplasms (Multiple Primary Malignant Tumors)?

From the Guidelines

The etiology of multiple primary malignant neoplasms (MPMNs) is multifactorial, with genetic predisposition playing a significant role, particularly in inherited cancer syndromes such as Li-Fraumeni syndrome, which is caused by mutations in the TP53 gene and is characterized by an increased risk of developing multiple primary malignancies, including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma, as reported in a study published in the Journal of the National Comprehensive Cancer Network in 2016 1. The development of MPMNs involves several interconnected factors, including:

• Genetic predisposition, with inherited cancer syndromes like Li-Fraumeni syndrome, BRCA mutations, and Lynch syndrome increasing the risk of developing multiple cancers
• Environmental exposures to carcinogens, such as tobacco, alcohol, ultraviolet radiation, and certain chemicals, which can damage DNA in multiple tissues and lead to independent malignancies
• Treatment-related factors, including radiation therapy and certain chemotherapeutic agents, which can induce secondary cancers years after initial treatment
• Age, as the risk of developing cancer increases with time, allowing for multiple malignancies to develop sequentially
• Immune system dysfunction, which may reduce surveillance against cancer cells and permit multiple tumors to develop
• Hormonal influences, which can affect hormone-responsive tissues and potentially lead to multiple cancers in organs like the breast, prostate, or endocrine system
• Field cancerization, where large areas of tissue are exposed to carcinogens, resulting in multiple primary tumors developing in the same region, particularly in the head and neck, lung, or bladder. Understanding these etiological factors is crucial for appropriate screening, prevention strategies, and management of patients with or at risk for multiple primary malignancies, as highlighted in studies published in the Journal of the National Cancer Institute in 2006 1 and the American College of Medical Genetics and Genomics in 2015 1.

From the FDA Drug Label

The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported. A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with tamoxifen in clinical trials.

The etiology of multiple primary malignant neoplasm associated with tamoxifen is unknown, but it may be related to the estrogen-like effect of tamoxifen. The most common types of uterine malignancies associated with tamoxifen are:

• Adenocarcinoma of the endometrium
• Uterine sarcomas, including malignant mixed mullerian tumors (MMMT) There is also a report of second primary tumors at sites other than the endometrium, but the relationship to tamoxifen is still uncertain 2.

From the Research

Etiology of Multiple Primary Malignant Neoplasm

• The etiology of multiple primary malignant neoplasms can be attributed to various factors, including host-related, lifestyle, and environmental influences 3.
• Genetic predisposition syndromes, such as Li-Fraumeni syndrome, can increase the risk of developing multiple primary malignant neoplasms 4.
• Radiation exposure, particularly in patients with cancer predisposition syndromes, can also contribute to the development of multiple primary malignant neoplasms 4.
• The frequency of multiple primary malignant neoplasms is reported to be in the range of 2-17% 3.
• Aetiological factors that may predispose patients to multiple primaries can be grouped into:
  • Host-related factors
  • Lifestyle factors
  • Environmental influences
• The management of multiple primary malignant neoplasms represents an interesting clinical scenario, requiring a multidisciplinary approach to ensure favorable outcomes 5.

Classification and Etiopathogenesis

• Multiple primary malignant neoplasms can be classified as synchronous or metachronous, depending on the timing of their occurrence 5, 6.
• The etiopathogenesis of multiple primary malignant neoplasms is complex and multifactorial, involving genetic and environmental interactions 7.
• Telomere changes and genetic-environmental interactions play a crucial role in the development of cancer, including multiple primary malignant neoplasms 7.

Clinical Implications

• Clinical situations when multiple primaries should be suspected and ruled out in a patient are crucial for early detection and treatment 3.
• General principles and possible treatment strategies for patients with synchronous and metachronous multiple primary tumours should be considered, taking into account individual tumor risk and patient characteristics 5.