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. ^[1] 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.

Metastases represent the end products of a multistep cell-biological process termed the invasion metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites. ^{[2, 3]}

The metastatic process involves sequential steps, including invasion through the surrounding extracellular matrix (ECM) and stromal cell layers, intravasation into the lumina of blood vessels, and survival in the circulation. 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). Cancer cells reinitiate their proliferative programs at metastatic sites, thereby generating macroscopic, clinically detectable neoplastic growths (the step often referred to as ‘‘metastatic colonization’’). ^{[2, 3, 4, 5]}

These steps are supported by functions of the cancer cells themselves or of the tumor microenvironment. ^[5] 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. ^{[2, 3, 4, 6]}

One of the most basic features is cell invasion and movement through the extracellular matrix. This is achieved via a process known as epithelial-to-mesenchymal transition (EMT). The EMT program dissociates the cells within epithelial cell sheets into individual cells that exhibit multiple mesenchymal attributes. 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. ^[6] EMT programs are orchestrated by a set of pleiotropically acting transcription factors, including Slug, Snail, Twist, ZEB1, and ZEB2, which organize entrance into a mesenchymal state by suppressing expression of epithelial markers (E-cadherin) and inducing expression of other markers associated with the mesenchymal state. ^[7]

Direct invasion by carcinoma cells of the stromal compartment involves active proteolysis effected principally by matrix metalloproteinases (MMPs), while degrading the BM and other ECM that lie in the path of invading tumor cells, MMP-expressing cells also liberate growth factors that are sequestered there, thereby fostering cancer cell proliferation. ^[8]

Tumor progression depends on the formation of new blood vessels (angiogenesis) and is a prerequisite for tumor outgrowth. ^[9] It is well established that tumor growth beyond the size of 1–2 mm is angiogenesis dependent. Although tumor-associated angiogenesis has traditionally been defined as the sprouting of new vessels from preexisting vessels, it is becoming clear that the blood vessels that support tumor growth can also originate from cells recruited from the bone marrow or can even differentiate from tumor stem cells (vascular mimicry). The development of the tumor vasculature is dependent on the homeostatic balance between a variety of proangiogenic and antiangiogenic (vascular endothelial growth factor and thrombospondin, respectively), inflammatory, and coagulation factors. ^{[10, 11]}

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). ^{[12, 9, 10, 11, 13]} The new blood vessels formed are largely immature leaky and tortuous, allowing tumor cells to intravasate easily into the vasculature.

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.

In the circulation, cancer tumor cells (CTCs) can be entrapped passively in the capillary network of the nearest organ, the liver, or the lungs, which are highly perfused organs, or as a regulated, site-specific process. CTCs actively adhere to the endothelial cells at a specific site, extravasate, and adapt to the new microenvironment to establish a metastatic colony. ^[4] This nonrandom process was first described by Paget in his “seed and soil” hypothesis; the metastatic seed grows preferentially in an organ environment that, in some way, provides a suitable soil. ^[14] It is currently accepted that a successful metastasis requires a "premetastatic niche" to allow invading cancer cells to survive, colonize, and expand to form a macrometastasis. ^{[15, 16]}

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. ^{[17, 18, 19, 20, 21, 22]} 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.

In addition, some cancer cells may elude the trapping in the microvasculature of the lung because of their unusual plasticity or chance passage through arteriovenous shunts, thereby enabling them to become lodged in the microvessels of more distal organs. ^[2]

The pathogenesis of the metastatic process in the jawbones is not clear. ^[19] 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. ^[23] Bone marrow stromal cells provide a niche for MTCs through various interactions mediated by integrins, chemokines, bone morphogenetic proteins (BMPs), Notch signaling, nestin, and osteopontin. Tumor cells find bone microenvironment favorable for invasion and growth, and they recruit resident cells, mainly osteoclasts and osteoblasts, to promote the “vicious cycle” of bone. ^[22] Expression of CXC chemokine receptor and its ligand are known to be involved in cancer metastasis. ^[24] 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 gingiva is the most common site for metastases with strong association to the presence of teeth. ^[21] 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. The inflammatory environment present in the gingiva may provide a permissive niche for metastatic cells, allowing them to perform the essential tasks of angiogenesis, formation of supportive stroma, and immune evasion. ^[21] Nevertheless, the relative low incidence of gingival metastases can argue against the assumption that inflammation is the primary cause for tumor cell attraction to the gingiva. Therefore, it can be assumed that gingival inflammation acts as a cofactor in the attraction of metastatic tumor cells. ^[21]

The oral region is an uncommon site for metastatic lesions. However, several factors can enhance metastatic colonization in the oral region.

In dentulous patients, 80% of the metastatic tumors to the oral soft mucosa are found in the attached gingiva, whereas in edentulous patients, metastatic lesions are equally distributed between the tongue and the alveolar mucosa. The rich capillary network of chronically inflamed gingiva has been suggested as a mechanism that entraps malignant cells.

The jawbones have little active marrow, which is a preferred site for metastatic deposits in the skeleton. However, in some cases, active marrow can be found in the posterior area of the mandible. In addition, remnants of hematopoietic marrow can be found in an edentulous jaw in cases of focal osteoporotic bone marrow defects. These hematopoietically active sites may attract metastatic tumor cells.

Frequency

Metastatic tumors to the oral region are uncommon and account for approximately 1-1.5% of all malignant oral tumors. ^[20] 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). ^{[18, 19, 20, 22]} 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, below).

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. ^{[25, 26]}

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%

• 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 women 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%

• 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 two groups differ probably because of cases of metastatic neuroblastoma to the jawbones in children; these cancers have a propensity to metastasize to bones.

The prognosis is grave for metastatic neoplasms to the oral cavity. The time from the appearance of the metastasis to death is several months. ^[20]