Metastatic Neoplasms to the Oral Cavity 

Cancer is a complex disease in which many basic processes, such as cell division, apoptosis, and cell migration are dysregulated. It is the process of metastasis that results in morbidity and eventual mortality.

Metastatic tumors to the oral region are uncommon and may occur in the oral soft tissues or jawbones. Because of their rarity, metastatic tumors to the oral region are challenging to diagnose. Therefore, they should be considered in the differential diagnosis of inflammatory and reactive lesions that are common to the oral region.

The metastatic process involves sequential steps, including progression of the primary tumor towards invasive carcinoma and dispersion of cancer cells through the lymphatic or blood vessels. Circulating cancer cells that survive settle in the microvasculature of the target organ and extravasate through the vessel wall. Infiltrated cells might proceed towards overt metastasis with or without an intervening period of latency (dormancy). These steps are supported by functions of the cancer cells themselves or of the tumor microenvironment.^[1] Cancer cells must possess traits that will allow them to survive in new environments; thus, a successful metastatic colony depends on the ability of cancer cells to appropriate distinct microenvironments at each step in the metastatic cascade: the primary tumor, systemic circulation, and the final metastatic destination.^{[1, 2]}

One of the most basic features is cell movement through the extracellular matrix, a process known as epithelial-to-mesenchymal transition. This process is marked by a complex and coordinated set of molecular changes leading to the motile behavior of the invading cancer cells, which involves dynamic cytoskeletal changes, cell-matrix interactions, localized proteolysis, actin-myosin contractions, and focal contact disassembly.^[3]

Tumor progression depends on the formation of new blood vessels (angiogenesis) and is a prerequisite for tumor outgrowth.^[4] It is well established that tumor growth beyond the size of 1–2 mm is angiogenesis dependent. The development of the tumor vasculature is dependent on the homeostatic balance between a variety of proangiogenic and antiangiogenic, inflammatory, and coagulation factors.^{[5, 6]} The critical initial stimulus for angiogenesis is hypoxia in the growing tumor. Hypoxia leads to the up-regulation of hypoxia-induced transcription factors (HIF)–a and HIF-2a, which are the master regulators of proangiogenic signals, mainly the vascular endothelial cell growth factors (VEGFs).^{[5, 6, 7, 8]}

Thus, a successful metastatic colony is the result of complex sequential genetic and epigenetic alterations that enable the tumor cells to reach their final destination. Studies provided evidence that predictive profiles of metastasis-associated genes are present at an early stage in tumorigenesis; therefore, metastatic competence may be “hardwired” into tumors from an early stage. Moreover, a subject of some debate is the existence of cancer stem cells, which would be inherently resistant to current therapies and have the ability to repopulate primary or metastatic tumors following treatment.

Considerable evidence indicates that metastasis of various cancers to distant organs is not a random event, but is a regulated, site-specific process.^[2] Gene expression profiling studies indicate that distinct molecular pathways are involved in the lymphatic and hematogenous dissemination of several cancers. The oral region is not a preferred site for metastatic colonization; cancers in this location are usually the result of secondary spread from other metastatic lesions, especially those from the lungs. However, approximately 30% of oral metastases are the first sign of the metastatic disease. In such cases, tumor cells bypass the filtration of the lungs, probably through the valveless vertebral venous plexus; an increase in the intrathoracic pressure directs the blood flow into this system from the caval and azygous venous system and accounts for the increased distribution of axial skeleton and head and neck metastasis.

The pathogenesis of the metastatic process in the jawbones is not clear. In the skeleton, bones with red marrow are the preferred sites for metastatic deposits. Several primary malignancies prefer bone as their metastatic target, especially cancers from the breast, prostate, lungs, and kidneys. Expression of CXC chemokine receptor and its ligand are known to be involved in cancer metastasis.^[9] It has been demonstrated that the ligand is highly expressed in bone marrow.

Jawbones have little active marrow, especially in elderly persons; however, remnants of hematopoietic active marrow can be detected in the posterior areas of the mandible, especially in cases of focal osteoporotic bone marrow defects. These hematopoietically active sites may attract metastatic tumor cells. In the oral soft tissues, the rich capillary network of chronically inflamed gingiva can entrap malignant cells. The proliferating capillaries have a fragmented basement membrane through which tumor cells can more easily penetrate.

Frequency

International

Metastatic tumors to the oral region are uncommon and account for approximately 1-1.5% of all malignant oral tumors.^[10] However, autopsies of patients with carcinoma reveal a higher frequency of metastatic deposits in the jawbones, which are not manifested clinically. Metastatic tumors to the jawbones are more frequently reported than those in the oral mucosa (by a ratio of 2.5:1).^{[11, 12, 13]} The most common primary sources of metastatic tumors to the oral region are cancers in the lung, breast, kidney, bone, and colorectum. The breast is the most common primary site for tumors that metastasize to the jawbones, whereas the lung is the most common source for cancers that metastasize to the oral soft tissues (see Sex).

Mortality/Morbidity

The prognosis is grave for metastatic neoplasms to the oral cavity. The time from the appearance of the metastasis to death is several months.

Race

Race has not been studied as a factor in the metastatic process in the oral region; however, changes can occur in different parts of the world, depending on the local prevalence of a particular malignant tumor. For example, in Japanese women, the uterus rather than the breast is reported to be the most common primary sites of cancers that metastasize to the oral cavity. Metastatic tumors originating in cancers of the lung, thyroid, liver, esophagus, and stomach were encountered more commonly in China than in United States.^[14]

Sex

The male-to-female ratio is almost equal for metastatic neoplasms to the oral cavity; however, sites within the oral cavity differ. For the jawbones, the male-to-female ratio is 1:1.1; for the oral mucosa, the ratio is 2:1. The primary site differs between the sexes.

In male patients, the most common primary cancers that metastasize to the oral region are those in the lungs, followed by those in the kidneys, prostate, bone, and skin.

The origin of metastasis to the oral mucosa in men is as follows:

• Lung - 31%
• Kidney - 14%
• Skin - 12%
• Liver - 7.5%
• Colorectum - 5.2%
• Bone - 5.2%
• Testis - 4.5%
• Esophagus - 4.5%
• Stomach - 3.7%
• Rare tumors - 12.4%

The origin of metastasis to the jawbone in men is as follows:

• Lung - 25%
• Kidney - 10.8%
• Liver - 8.6%^[15]
• Prostate - 7.5%
• Bone - 7.5%
• Adrenal gland (cases of neuroblastoma, including cases from retroperitoneum and mediastinum) - 5.3%
• Colorectum - 4.7%
• Testis - 4.4%
• Esophagus - 3.6%
• Stomach - 2.5%
• Bladder - 2.5%
• Rare tumors - 17.6%

In female patients, the most common primary cancers that metastasize to the oral region are those in the breasts, followed with much lower frequency by those in the female genital organs, colorectum, bone, and kidneys.

The origin of metastasis to the oral mucosa in women is as follows:

• Breast - 24%
• Genital organs (uterus, ovaries, cervix, fallopian tubes) - 14.8%
• Kidney - 12%
• Lung - 9.4%
• Bone - 9.4%
• Skin - 6.8%
• Colorectum - 6.8%
• Rare tumors - 16.8%

The origin of metastasis to the jawbone in men is as follows:

• Breast - 36.6%
• Genital organs (uterus, ovaries, cervix, fallopian tubes) - 9.5%
• Kidney - 8.5%
• Colorectum - 7.1%
• Bone - 6.7%
• Adrenal gland (cases of neuroblastoma, including cases from retroperitoneum and mediastinum) - 5.8%
• Thyroid - 5.4%^[16]
• Rare tumors - 20.4%

Age

Most metastatic tumors to the oral region occur in patients aged 40-70 years. On average, patients with metastases to the jawbones are younger (ie, aged 45 y) than those with metastases to the oral soft tissues (ie, aged 54 y). The mean ages of these 2 groups differ probably because of cases of metastatic neuroblastoma to the jawbones in children; these cancers have a propensity to metastasize to bones.