The thymus gland, located in the upper chest behind the breastbone, is an immune system organ responsible for the maturation of T-cells, white blood cells that defend the body against infection. Thymus cancer, a rare malignancy, is classified into two main types: thymoma and thymic carcinoma. Thymomas are generally slow-growing, while thymic carcinomas are more aggressive and likely to metastasize. The exact cause of thymus cancer remains largely unknown, making the study of its associations and underlying biology the focus of current research.
Specific Autoimmune Conditions Associated with Thymoma
The most recognized association with thymoma is the presence of paraneoplastic syndromes, disorders triggered by the immune system’s response to the tumor. These syndromes occur in about a third of all thymoma patients, often manifesting before or at the same time as the cancer diagnosis. The strongest link is with Myasthenia Gravis (MG), a neuromuscular disorder characterized by fluctuating muscle weakness.
MG occurs when the immune system mistakenly produces antibodies that block communication receptors between nerves and muscles. In thymoma-associated MG, the tumor tissue contains abnormal thymic epithelial cells that express components similar to those found on muscle cells. This leads to the incorrect education of T-cells, triggering a systemic autoimmune reaction. The presence of MG can lead to an earlier diagnosis of the thymoma, as the muscle weakness symptoms prompt medical investigation.
Less common are other paraneoplastic syndromes like pure red cell aplasia (PRCA) and hypogammaglobulinemia. PRCA is a rare blood disorder where the bone marrow fails to produce enough red blood cells, leading to severe anemia. Hypogammaglobulinemia (sometimes called Good’s syndrome) is marked by low levels of antibodies, which severely compromises the body’s ability to fight infection. These conditions highlight the systemic impact a tumor in the immune-regulating thymus gland can have on various parts of the body.
Non-Disease Related Risk Factors
While specific autoimmune conditions are the strongest biological indicators, several non-disease factors are associated with an increased likelihood of developing thymus cancer. The risk for thymoma increases with age, with most diagnoses occurring in middle-aged and older adults between 40 and 70 years old. Thymic carcinoma, however, can occur across a wider age range.
Epidemiological data suggests a variation in incidence based on ethnic background, particularly in the United States. Studies indicate that Asian Americans, Native Hawaiians, Pacific Islanders, and African Americans have a higher incidence of thymoma compared to White and Latino populations. This observation points toward potential, yet undefined, genetic or environmental influences that may be unevenly distributed across these groups.
Another factor involves prior exposure to high-dose radiation to the chest, such as that given as treatment for other cancers like Hodgkin lymphoma. Some studies suggest that individuals who received radiotherapy to the chest area many years earlier may have an elevated risk of developing a thymoma decades later. This risk is thought to stem from the radiation damaging the normal cells of the thymus, which over time could lead to malignant transformation.
Cellular and Genetic Changes Leading to Malignancy
Thymus cancer originates from the epithelial cells that line the thymus gland. The transformation into a malignant tumor is driven by acquired genetic mutations that lead to uncontrolled cell growth and division. Unlike many other cancers that accumulate a large number of DNA changes, thymomas are characterized by a relatively low mutational burden.
A highly specific genetic alteration has been identified in a large percentage of the more indolent thymoma subtypes, specifically Type A and Type AB. This involves a recurrent, single-point mutation in the GTF2I gene. The GTF2I gene codes for a transcription factor called TFII-I, which normally helps regulate cell proliferation and development. The mutation causes the resulting protein to become overactive, driving the abnormal growth of the thymic epithelial cells.
More aggressive forms of the disease, such as thymic carcinoma, show a different pattern of genetic instability. These tumors often have a higher number of mutations overall, including changes in tumor suppressor genes like TP53. The loss of function in tumor suppressor genes removes the normal cellular brakes on growth, allowing cancer cells to divide rapidly and spread more aggressively.