Salivary gland cancer (SGC) is a rare malignancy developing in the tissues that produce saliva, accounting for a small fraction of head and neck cancers. The salivary system includes three major pairs of glands: the parotid (in front of the ears), the submandibular (beneath the jaw), and the sublingual (under the tongue). While most tumors in these glands are benign, some are malignant. Research continues to investigate the factors leading to the uncontrolled growth of these cells.
Established Environmental Exposure
The most established environmental risk factor for salivary gland cancer is exposure to ionizing radiation. This risk is highest for individuals who received therapeutic radiation treatments to the head and neck for other medical conditions. The cumulative dose of radiation received by the salivary glands directly correlates with the risk of cancer development.
The time between radiation exposure and diagnosis, known as the latency period, is notably long, often spanning over two decades. Median latent periods are frequently reported between 20 and 25 years, reflecting the slow, multi-step process of radiation-induced cancer development.
Unlike common oral cavity and throat cancers, tobacco and alcohol use are not major drivers of most salivary gland malignancies. Limited data suggests a slight risk increase from certain occupational exposures, such as chronic contact with specific substances like nickel alloy dust, silica dust, or those used in rubber manufacturing. These associations are considered weak due to the overall rarity of the disease.
Inherited Genetic Predisposition
SGC is generally not considered a hereditary disease, but a small fraction of cases can be linked to inherited genetic factors. These inherited mutations are present in a person’s germline cells and predispose the individual to developing various cancers, including SGC.
The best-known example of this inherited predisposition is Li-Fraumeni syndrome, caused by a mutation in the TP53 gene. TP53 normally acts as a tumor suppressor, helping to halt cell division when DNA damage occurs. Inheriting a defective copy significantly impairs the cell’s ability to repair damage, leading to a higher lifetime risk of developing multiple cancer types, including SGC.
Even in families with a history of salivary tumors, the cause is often sporadic, meaning the genetic changes were acquired, not inherited. The vast majority of SGC cases arise in individuals without a predisposing inherited syndrome.
Statistical Risk Factors
Several non-modifiable demographic and health factors are associated with an increased risk of SGC, though they are not direct causes. Age is a strong indicator, as incidence rises significantly after age 50, with most patients diagnosed in their sixties or seventies. This increase is thought to be due to the cumulative effect of cellular damage over time.
Data suggests a slightly higher incidence rate in men compared to women. Certain pre-existing health conditions also influence risk. For example, the aggressive carcinoma ex pleomorphic adenoma arises from a pre-existing benign salivary gland tumor called a pleomorphic adenoma.
The autoimmune disorder Sjögren’s syndrome is relevant because it causes chronic inflammation in the salivary glands. People with Sjögren’s syndrome have an elevated risk of developing non-Hodgkin’s lymphoma, a cancer that can originate in the salivary glands. This link is attributed to the sustained accumulation and overactivity of immune cells within the glands.
The Underlying Cellular Process
Like all cancers, SGC begins with a fundamental change in the cell’s genetic material. This involves the accumulation of acquired, or somatic, mutations in the DNA of salivary gland cells. These mutations disrupt normal regulatory pathways controlling cell growth, division, and programmed cell death.
Genetic alterations typically involve activating genes that promote cell growth (oncogenes) or inactivating genes that suppress tumor formation. For instance, certain SGC subtypes feature specific chromosomal rearrangements. Mucoepidermoid carcinoma frequently involves a fusion oncogene called MECT1-MAML2. Similarly, adenoid cystic carcinoma is often characterized by the presence of the MYB-NFIB fusion oncogene.
These acquired mutations allow affected cells to divide uncontrollably and ignore growth-stopping signals. Despite identifying these specific molecular drivers in certain subtypes, the exact trigger or mechanism responsible for the initial DNA damage remains unknown for the majority of salivary gland cancer patients. Consequently, a large proportion of SGC cases are classified as having an idiopathic, or unknown, etiology.