eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Metastatic Neoplasms to the Oral Cavity

Author: Abraham Hirshberg, MD, DMD, Senior Lecturer, Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Israel
Coauthor(s): Amos Buchner, DMD, MSD, Chairman, Professor, Department of Oral Pathology and Oral Medicine, Tel Aviv University School of Dental Medicine, Israel
Contributor Information and Disclosures

Updated: Mar 28, 2008

Introduction

Background

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 oral region.

The Medscape Head and Neck Cancer Resource Center and the Melanoma Resource Center may be of interest. Additionally, the eMedicine article Metastatic Cancer, Unknown Primary Site might be helpful.

Pathophysiology

The metastatic process is complex and involves sequential steps. Tumor cells must detach from the primary tumor, spread in the tissues, invade blood vessels, and survive their travel in the circulation. Then, the metastatic cells settle in the microvasculature of the target organ, extravasate through the vessel wall, and proliferate within the recipient tissue. Different properties are required for the metastasis of primary tumors to secondary sites than for primary tumorigenicity. The most basic feature is cell movement away from the primary tumor through the extracellular matrix.

Cell motility involves remodeling of the cytoskeleton. During the process of epithelial-mesenchymal transition, cells progressively redistribute their apical and basolateral epithelial-specific tight and adherens junction proteins (including E-cadherin and cytokeratins) and re-express mesenchymal molecules (including vimentin and N-cadherin). These changes lead to the loss of cell-to-cell contacts and the gain of cell motility. Extrinsic factors in the tumor microenvironment can promote the motility of cancer cells; stromal cells have been found to have a role in modulating cancer cell motility by producing growth factors and proteases that support the survival and proliferation of carcinoma cells in a paracrine fashion.

A successful metastatic colony is the result of a complex sequential genetic alteration that enables the tumor cells to reach their final destination. Angiogenesis plays an important role in expanding the tumor mass, and increasing neovascularization is correlated with an increased rate of metastasis.¹ Because small tumors of less than 2 mm in diameter already receive a vascular blood supply, it is likely that cancer cells have spread throughout the body years before they are first detected. However, only a small proportion of metastatic cancer cells survive in the circulation, probably due to intrinsic inhibition of apoptosis.

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 lymphatic and hematogenous dissemination of several cancers. The oral region is not a preferred site for metastatic colonization; cancers here 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.³
 
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% of all malignant oral tumors. 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). The most common primary sources of metastatic tumors to the oral region are cancers in the breast, lung, kidney, bone, or 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. The time from the appearance of the metastasis to death is several months.

Race

To the authors' knowledge, 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.

Sex

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.

Origin and site of metastatic tumors to the oral region in men are as follows:

• Oral mucosa
  • 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%
  Jawbones
  • Lung - 25%
  • Kidney - 10.8%
  • Liver - 8.6%⁴
  • 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.

Origin and site of metastatic tumors to the oral region in women are as follows:

• Oral mucosa
  • Breast - 24%
  • Genital organs (uterus, ovaries, cervix, fallopian tubes) - 14.8%
  • Kidney - 12%
  • Lung - 9.4%
  • Bone - 9.4%
  • Skin - 6.8%
  • Colo-rectum - 6.8% 
  • Rare tumors - 16.8%
• Jawbones
  • 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%⁵
  • 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.

Clinical

History

Symptoms develop in a relatively short period.

• In the oral soft tissues, most patients complain of a lump.
• In the jawbones, swelling, pain, and paresthesia of the affected nerve are the chief complaints.
• Give special attention to patients with numb chin syndrome or mental nerve neuropathy. The numb chin syndrome is the consequence of loss of function of the terminal sensory division of the mandibular branch of the trigeminal nerve. Any pathological process involving the mental nerve, the mandibular nerve, and even the mandibular trunk of the fifth nerve may produce this loss of function. The appearance of a mental nerve neuropathy should always raise the possibility of a metastatic disease in the mandible.⁶
• With the progression of the disease, oral metastatic lesions (especially those in soft tissues) cause progressive discomfort. Pain, bleeding, superinfection, dysphagia, interference with mastication, and disfigurement are some of the main patient complaints.
• In some cases, the metastasis is discovered in a recent extraction site.
  • The main symptom is a soft tissue mass extruding from a recent extraction wound and accompanied by pain.
  • In many of these cases, the metastatic tumor is present in the area before the extraction; it can cause pain, swelling, and loosening of the teeth.
  • These symptoms lead to the extraction of the affected tooth. In some cases, metastasis probably develops after extraction.
  • Tooth extraction can serve as a promoting factor in the metastatic process.

Physical

• The clinical presentation of the metastatic tumors differs among the various oral sites.
  • In the oral soft tissues, the attached gingiva is the most commonly affected site, followed by the tongue and, with much less frequency, the remaining mucosa.
  • The presence of teeth seems to have a crucial effect on the oral site preference of metastases.
    • In the dentulous patient, about 80% have metastasis in the attached gingiva.
    • In the edentulous patient, metastatic lesions are distributed equally between the tongue and alveolar mucosa.
  • In the jawbones, the common location of the metastatic lesion is the mandible; the molar area is the most frequently involved site.
• In its early manifestation, gingival metastasis resembles hyperplastic or reactive lesions (eg, pyogenic granuloma, peripheral giant cell granuloma, fibrous epulis).
• In other oral soft tissue locations, especially in the tongue, the metastatic lesion manifests as a submucosal mass.
• In the jawbones, physical examination reveals a bony swelling with tenderness over the affected area.
• Sometimes, tooth mobility and trismus are present.

Causes

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.

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