Metastatic Neoplasms to the Oral Cavity 

Updated: Jun 26, 2018
Author: Abraham Hirshberg, MD, DMD; Chief Editor: Jeff Burgess, DDS, MSD 

Overview

Background

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.

Pathophysiology

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]

Etiology

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.

Epidemiology

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.

Prognosis

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]

 

Presentation

History

Symptoms develop in a relatively short period. In the oral soft tissues, most patients report a lump. In the jawbones, swelling, pain, and paresthesia of the affected nerve are the chief reported symptoms.

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.[27]

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 reported symptoms.

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 Examination

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.

An exophytic, sometimes ulcerated lesion is the most common clinical presentation of metastatic lesions in the oral soft tissues.

In its early manifestation, gingival metastasis resembles hyperplastic or reactive lesions (eg, pyogenic granuloma, peripheral giant cell granuloma, fibrous epulis),[28] as shown in the images below.

A large pedunculated mass on the gingiva resembles A large pedunculated mass on the gingiva resembles a pyogenic granuloma and peripheral giant cell granuloma in a 44-year-old woman with metastatic breast carcinoma.
A large soft-tissue mass on the gingiva resembles A large soft-tissue mass on the gingiva resembles pyogenic granuloma and peripheral giant cell granuloma in a 51-year-old man with metastatic renal cell carcinoma.

In other oral soft-tissue locations, especially in the tongue, the metastatic lesion manifests as a submucosal mass.

With progression of the disease, oral metastatic lesions, especially those located in the soft tissues, may cause progressive discomfort, pain, bleeding, superinfection, dysphagia, interference with mastication, and disfigurement.

In the jawbones, the common location of the metastatic lesion is the mandible; the molar area is the most frequently involved site.

A rapidly progressing swelling accompanied by pain and paraesthesia are the classic symptoms of a metastatic tumor in the jawbone.

Mental nerve neuropathy, or the so-called the numb chin syndrome, should raise the suspicion of metastatic disease in the mandible.

In the jawbones, physical examination reveals a bony swelling with tenderness over the affected area.

Sometimes, tooth mobility and trismus are present.

Metastatic disease to the jaws may extend into the overlying soft tissues, appearing to imitate a dental or periodontal infection.

In some cases, especially those of metastatic hepatocellular carcinoma, severe postbiopsy hemorrhagic episodes had been reported.

 

DDx

Diagnostic Considerations

Misdiagnosis of a metastatic lesion as a benign reactive lesion may delay diagnosis and treatment. Metastatic tumors should always be considered in the differential diagnosis of benign-looking lesions in the oral cavity, especially in patients with a previous history of a malignant disease. Biopsy is mandatory to establish an accurate diagnosis.

For oral soft tissues, consider the following:

  • Pyogenic granuloma
  • Peripheral giant cell granuloma (only in the gingiva)
  • Fibrous epulis (only in the gingiva)
  • Malignant primary tumor (oral cancer, including salivary gland tumor)

For the jawbone (differential diagnosis depends on location), consider the following:

  • Malignant tumors (eg, primary intraosseous carcinoma, other malignant odontogenic tumors)
  • Central malignant salivary gland tumors
  • Sarcoma (eg, malignant fibrous histiocytoma, fibrosarcoma)

Bony lesions can mimic benign lesions (some cases), as follows:

  • Periapical pathology
  • Infected odontogenic cyst or tumor
  • Osteomyelitis

For fumb lips or chin,[29]  consider the following:

  • Odontogenic - Dental infection, dental local anesthesia, facial trauma, dental trauma, osteomyelitis, benign local tumors
  • Systemic - Amyloidosis, sarcoidosis, sickle cell anemia, syphilis, vasculitis, aneurysms, multiple sclerosis, HIV disease, diabetes mellitus
  • Nonmetastatic neurological manifestation of malignancy

Differential Diagnoses

 

Workup

Imaging Studies

The balance between the activities of osteoblasts and osteoclasts in general determines the phenotype of metastatic bone lesions, either osteolytic or osteoblastic. Metastases from prostate cancer usually form osteoblastic lesions in bone[22, 30] ; by contrast, bone metastases from kidney, lung, or breast cancers are more often osteolytic.

An oral radiographic survey may be helpful. The most common radiographic presentation is that of a lytic lesion with ill-defined margins. Occasional osteoblastic lesions are observed. In approximately 5% of the patients, the radiographs do not reveal any pathologic changes.

Periapical and panoramic radiographs, CT scans, and MRIs can be obtained to evaluate the extent of the lesion.

Lack of radiographic changes does not exclude the possible presence of a small metastatic deposit in the jawbone.

Procedures

The following steps constitute the diagnostic algorithm for evaluation of oral metastases:

  • Review the clinical history.

  • Review the available radiographic findings.

  • If a history of a previous tumor exists, obtain the slides and reports for review.

  • Perform a biopsy of the lesion.

  • Evaluate the light microscopic features of the neoplasm. On the basis of the histologic features, determine the need for special studies (eg, histochemical staining, immunohistochemical tests, electron microscopy).

  • In cases in which the primary tumor is not found (unknown primary), look for signs and symptoms in an attempt to identify the potential primary. A standard diagnostic evaluation of patients with unknown primary tumor (UPT) should be based on medical history, physical examination, clinical symptoms, laboratory studies, histopathological review with immunohistochemical analyses and imaging evaluations.[31]

Medical history can define areas of concerns, such as the respiratory system in a smoker, cough and hemoptysis, or misdiagnosed breast nodules in a woman. Moreover, personal history of previous biopsies, removed or spontaneously regressed lesions, or family history. The standard battery of laboratory tests includes a complete blood cell count; iron metabolism (eg, iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss); urinalysis (helpful for discovering microscopic hematuria or the presence of proteinuria); liver and renal functional tests, including hepatitis B (HBV) and hepatitis C (HCV) markers; and stool examination for occult blood. In addition, some selected tumor markers should be determined, such as alpha-fetoprotein (αFP) for hepatocellular carcinoma and germ cell tumors, beta-human chorionic gonadotropin (βHCG) for germ cell tumors, and prostate specific antigen (PSA) for prostate carcinoma. Other tumor markers, such as carcinoembryonic antigen (CEA), CA125, CA15.3, and CA19.9, can be useful; however, because of their low specificity, they cannot be used to establish definitive diagnoses. Whole-body CT scanning should be performed in all patients, and mammography should be performed in women. Functional imaging (ie, fludeoxyglucose [FDG] positron emission tomography [PET]/CT) has gained a main role in the detection of the site of origin of unknown primary cancers and is currently recommended by the European Association of Nuclear Medicine.

Cancers of unknown primary origin are defined as histologically confirmed metastatic tumors for which no known primary site has been identified following thorough physical examination and laboratory and imaging diagnostic tests. The proportion of unknown primary origins in oral metastases varies from 5-17%. These variations probably result from a less restricted definition of what is called carcinoma of unknown primary (CUP), and the prevalence is probably much less. CUP may retain the signature of the primary origin, and advancement in molecular technologies may lead to identification of the primary origin.[32] These various tests, using DNA microarrays, quantitative real-time polymerase-chain-reaction (rtPCR), or tissue-of-origin assays based on mRNA or microRNA (miRNA) are based on the premise that in analyzing a large number of genes, the metastatic tumors match their primary tumor. The accuracy of these tests varies from 70% for mRNA- to 90% for DNA-based tests.[33, 34]

Plan the treatment protocol based on the clinical, pathological, and radiographic information.

Histologic Findings

The diagnosis is always based on histologic findings from the biopsy specimen.[35] The clue to the diagnosis is the resemblance of the metastasis to the primary tumor. If a history of a previous tumor exists, compare the current histologic findings with those of the preexisting primary malignant tumor; it is often difficult to determine, for patients with a previous history of malignancy, whether a lesion represents a metastasis or a new primary neoplasm. Histochemical staining, immunohistochemical testing,[36] and sometimes molecular cDNA profiling should be performed to identify the primary source of the metastatic tumor. The accuracy of immunohistochemistry and molecular cDNA profiling (by either RT-PCR or chips) exceeding 80% according to most authors.[31, 32]

Most oral metastatic malignancies appear to be of epithelial origin, mainly adenocarcinomas, and a very useful tool in diagnosing the primary origin is the pattern of expression of cytokeratins 7 and 20.[22] Nonepithelial tumors such as melanoma, sarcoma, lymphoma, and germ cell tumors can be diagnosed using appropriate immunohistochemical testing, and they can be managed even without an identifiable site of origin.

Attend to the differentiation of the primary intraoral malignancies from metastatic tumors. Several primary intraoral malignancies (especially those originating from salivary glands) have histologic features similar to those of tumors in distant organs: for example, primary ductal carcinoma of a salivary gland origin versus metastatic breast carcinoma, primary intraoral clear cell carcinoma versus metastatic renal cell carcinoma, primary intraoral squamous cell carcinoma versus metastatic squamous cell carcinoma from the lung, or primary intraoral malignant melanoma versus metastatic malignant melanoma. Malignant soft tissue tumors may originate intraorally, but, because of their rarity, one should always consider a metastatic origin.

 

Treatment

Medical Care

Oral metastases usually indicate widespread disease. Treatment modalities are limited to palliation. In some cases, surgical treatment, sometimes combined with radiation therapy and/or chemotherapy, can improve the patient's quality of life.

Surgical Care

Adequate surgical treatment can improve the prognosis in some cases in which the oral region is the single metastatic site.