Tongue cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3] Roukoz A. Karam, M.D.[4]

Tongue cancer is cancer that begins in the cells of the tongue. Approximately 25-30% of all oral cavity cancers begin in the tongue. If cancer begins in the proximal two-thirds of the tongue it is described as oral cancer and if it begins on the distal third of the tongue it is described as throat cancer. Squamous cell carcinoma of the tongue usually arises from the ventrolateral aspect of the mid and posterior tongue, probably due to adjacent pooling of carcinogens. More than 90% of oral cavity cancers are squamous cell carcinomas. The majority of the other lesions are of minor salivary gland origin. Nonsquamous cell cancers comprise fewer than 3% of all lingual malignancies. Genes involved in the pathogenesis of tongue cancer include TP53, c-myc, and erb-b1. On gross pathology, exophytic, ulcerative, and infiltrative growth patterns are characteristic findings of tongue cancer. Tongue cancer must be differentiated from other diseases that cause malignant lesions of the oral cavity and from few non-neoplastic lesions of the oral cavity, such as lymphoma, adenoid cystic carcinoma, adenocarcinoma, mucoepidermoid carcinoma, rhabdomyosarcoma, liposarcoma, infections at the floor of mouth and mandible, and normal adenoid tissue for lesions at the base of tongue. In 2009, the incidence of tongue cancer was estimated to be 10,530 cases per 100,000 individuals in the United States. Males are more commonly affected by tongue cancer than females. The incidence of tongue cancer increases with age. The most potent risk factor in the development of oral cancer is alcohol intake, tobacco use and human papillomavirus transmitted through sexual contact. Head and neck MRI scan is diagnostic of tongue cancer. The predominant therapy for tongue cancer is surgical resection. Adjunctive chemotherapy, radiation, chemoradiation, or brachytherapy may be required.

Hayes Martin was the first to focus on improving cure rates by treating the primary tumor with X-rays. By 1928, V. P. Blair of St Louis was the first to advocate surgery as the best management for oral cancers. A major initiative of the 1970s and 1980s was cytotoxic chemotherapy for patients unfit for surgery.

There is no specific established system for the classification of tongue cancer; however, it’s classified as part of the oral cancers. Oral cancer can be classified into three types based on the potential to spread to other parts of the body such as malignant tumors,precancerous conditions, and benign tumors. Most common type of malignant tumor of the mouth is squamous cell carcinoma. Squamous cell carcinoma is further classified based on macroscopic and microscopic features. About 5% of oral cavity cancers are rare malignant tumors that start in different types of cells in the oral cavity. These include salivary gland cancer, melanoma, bone and soft tissue sarcomas, Lymphomas and extramedullary plasmacytomas, Hodgkin lymphoma, and non-Hodgkin lymphoma metastatic cancer.

Leukoplakia and erythroplakia have the greatest potential for malignant transformation in tongue cancer. World Health Organization classified oral cancer into mild, moderate, and severe dysplasia. Genes involved in the pathogenesis of tongue cancer include TP53, c-myc, and erb-b1. On gross pathology, exophytic, ulcerative, and infiltarative growth patterns are characteristic findings of tongue cancer. Tongue cancer constitutes of highly differentiated squamous cells lacking frank cytologic criteria of malignancywith rare mitoses. The surface of the lesion is covered with compressed invaginating folds of keratin layers. A stroma-like inflammatory reaction and a blunt pushing margin may be seen.

Tongue cancer is caused by a point mutation in the tumor suppressor gene (TP53). The other oncogenes associated with oral squamous cell cancers of tongue include c-mycand erb -b1.

Tongue cancer must be differentiated from other diseases that cause malignant lesions of the oral cavity and from non-neoplastic lesions of the oral cavity, such as lymphoma, sarcoma,, metastatic tumor, malignant salivary gland tumors, tuberculosis, scarlet fever, syphilis, papilloma, lipoma, leiomyoma, neurofibroma, schwannoma, granular cell tumor, benign migratory glossitis, Hairy tongue, pemphigus, erythema multiforme, mucous membrane pemphigoid, vitamin B deficiency, amyloidosis, diabetes mellitus, hypothyroidism, acromegaly.

In 2009, the incidence of tongue cancer was estimated to be 10,530 cases per 100,000 individuals in the United States. Males are more commonly affected with tongue cancer than females. The male to female ratio is approximately 2 to 1. The incidence of tongue cancer increases with age; the median age at diagnosis is 61 years. Approximately one-third of all diagnoses occurred in patients under the age of 55. There is no racial predilection to the tongue cancer.

The most potent risk factors in the development of oral cancer are alcohol intake, tobacco use and human papillomavirus transmitted through sexual contact. The other risk factors include history of betel quid intake, male gender, age over 55 years, ultraviolet light, Fanconi anemia, dyskeratosis congenita, lichen planus, graft-versus-host disease (GVHD), immune system suppression, mouthwash and irritation from dentures.

According to the United States Preventive Services Task Force, screening for tongue cancer is not recommended in the United States. Outside the US, multiple screening programs have been tried in high-risk patients. Screening subjects are tobacco or alcohol consumers.

If left untreated, patients with tongue cancer may progress to develop metastasis. Common complications of treatment of tongue cancer include neurotoxicity, bleeding, radiation caries, trismus, osteonecrosis, oral mucositis, chronic dysphagia, anemia, pharyngocutaneous fistula, aspiration, infections, xerostomia, taste alterations, nutritional compromise, and abnormal tooth development. Prognosis is generally good, and the five-year mortality rate of patients with stage I and II tongue cancer is approximately 89 and 95 percent respectively. The five- year disease specific survival rate of patients with stage III and IV cancers is 39 and 27 percent respectively.

According to the TNM staging system by the American Joint Committee on Cancer, there are four stages of oral cancer based on the tumor size, lymph nodes involved, and metastasis.

Symptoms of tongue cancer include a red or white patch on the tongue, a sore throat, an ulcer or lump on the tongue, pain on swallowing, speaking, or moving the tongue, numbness in the mouth, bleeding from the tongue, pain in the ear, and pain in the mouth or tongue.

Common physical examination findings of tongue cancer include otalgia, submandibular gland asymmetry, and cervical lymphadenopathy.

Laboratory findings consistent with the diagnosis of tongue cancer include reduced CBC levels, abnormal prothrombin time (PT), abnormal activated partial thromboplastin time (aPTT), and abnormal international normalized ratio (INR).

There are no x-ray findings associated with tongue cancer. However, an x-ray may be helpful in the evaluation of metastases to the lungs and mandible.

Head and neck CT scan may be helpful in the diagnosis of tongue cancer. Findings on CT scan suggestive of tongue cancer include soft tissue attenuation of lesions, bony erosions, and increased attenuation of involved nodes.

Head and neck MRI scan is diagnostic of tongue cancer. On head and neck MRI, tongue cancer is characterized by isointense to hypointense mass on T1-weighted MRI and isotense to hyperintense mass on T2-weighted MRI.

Ultrasound may be performed to detect metastases of tongue cancer to cervical lymph nodes and to aid in FNAC of suspicious nodes.

There are no other imaging findings associated with tongue cancer.

Other diagnostic studies for tongue cancer include tumor biopsy and panendoscopy. Tumor biopsy helps to evaluate viable tumor cells. The majority of biopsy findings reflect the presence of squamous cell carcinoma. Panendoscopy is highly accurate for evaluation of smaller or more superficial second primary mucosal lesions.

The predominant therapy for tongue cancer is surgical resection. It is indicated for patients who have positive resection margins, patients with bone invasion, patients with positive lymph nodes, tumor thickness >4 mm, patients with regional recurrence. For patients who are not surgical candidates but can tolerate chemotherapy, a combined chemotherapy and radiotherapy is appropriate. For patients who are not surgical candidates with bad medical condition and can not tolerate the chemotherapy, radiotherapy without chemotherapy is more appropriate. Chemotherapy is used in patients who present with extensive primary lesions, in patients with distant metastasis or with poor prognosis. Targeted therapy may be used in combination with chemotherapy or radiation therapy. Targeted therapy drugs, such as monoclonal antibodies, interrupt the spread and growth of specific tongue cancer cells.

Surgery is the mainstay of treatment for tongue cancer. Radical approach is required in larger lesions, impaired tongue mobility, deep tongue infiltration, floor-of-mouth extension. A partial glossectomy with negative margins can preserve speech and swallowing for most stage I and II lesions of the oral tongue. Partial glossectomy is commonly required for advanced disease.Total glossectomy is required in cases where bilateral lingual arteries are involved by cancer. In these cases, postoperative radiotherapy or chemoradiotherapy, appears to improve disease control compared with surgery alone. Elective treatment of the neck in patients with stage I and II oral cavitycancer is not well established. Studies recommend a tumor thickness cutoff of 4 mm as a threshold for elective neck dissection.

Effective measures for the primary prevention of tongue cancer include avoiding the use of tobacco and excessive use of alcohol. Main methods for prevention are natural components such as: vitamin A, vitamin E, and beta-carotene because they are rich in trace elements and antioxidants. There is a protective effect of diets rich in fresh fruits and vegetables to reduce the incidence of leukoplakia. There is no effective oral cancer screening program either a general or a selected high-risk population for oral cancer in the United States. Screening high-risk individuals in developing countries could be an effective prevention strategy that lowered the stage of oral cancer at diagnosis and improved 5-year survival.

Secondary prevention strategies following tongue cancer include monthly follow-ups for the first 12-18 months following therapy. Drugs such as synthetic retinoids, non-steroidal antiinflammatory drugs, EGFR inhibition, and human papilloma virus related oropharyngeal carcinoma vaccine can be used as a secondary chemopreventiveagents.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3]

Hayes Martin was the first to focus on improving cure rates by treating the primary tumor with X-rays. By 1928, V. P. Blair of St Louis was the first to advocate surgery as the best management for oral cancers. A major initiative of the 1970s and 1980s was cytotoxic chemotherapy for patients unfit for surgery.

• In 1928, V. P. Blair of St Louis was the first to advocate surgery as the best management for oral cancers.

• Billroth appreciated the importance of good access and took the procedure a stage further, removing a section of the mandibular body to reach the tongue and oropharynx.
• In 1875, Bernard von Langenbeck resected the ramus of the mandible in continuity with the primary tumor.^[1]
• In 1917, Esser was the first to describe an axial pattern flap based on the temporal artery.^[2]

• By 1923, radiotherapy was used to treat neck metastases.
• By 1930s, Hayes Martin was the first to focus on improving cure rates by treating the primary tumor with X-rays by the Coutard method supplemented with gold radium seeds.
• By 1950, development of bleeding control techniques, antibiotics, and blood transfusion made it possible to do advanced surgeries for cancers.
• A major initiative of the 1970s and 1980s was cytotoxic chemotherapy for patients unfit for surgeries.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sargun Singh Walia M.B.B.S.[2] Roukoz A. Karam, M.D.[3]

There is no specific established system for the classification of tongue cancer; however, it’s classified as part of the oral cancers. Oral cancer can be classified into three types based on the potential to spread to other parts of the body such as malignant tumors,precancerous conditions, and benign tumors. Most common type of malignant tumor of the mouth is squamous cell carcinoma. Squamous cell carcinoma is further classified based on macroscopic and microscopic features. About 5% of oral cavity cancers are rare malignant tumors that start in different types of cells in the oral cavity. These include salivary gland cancer, melanoma, bone and soft tissue sarcomas, Lymphomas and extramedullary plasmacytomas, Hodgkin lymphoma, and non-Hodgkin lymphoma metastatic cancer.

There is no specific established system for the classification of tongue cancer; however, it’s classified as part of oral cancer:

• Malignant tumours of the oral cavity are cancerous growths that have the potential to spread (metastasize) to other parts of the body.
• The oral cavity is lined with squamous epithelium, which is formed by flat, scale-like cells called squamous cells.
• The most common oral cavity cancer starts in these cells and is called squamous cell carcinoma (SCC).

• Squamous cell carcinomas (SCC) make up 95% of all oral cavity cancers. They are classified based on macroscopic or microscopic features.
  • Macroscopic features:
  • Can be seen without a microscope
  • Squamous cell carcinomas are described as following based on macroscopic features:

• Infiltrative – Cancer is growing into deep layers of the oral cavity
• Exophytic – Cancer is growing outwards from the surface of the oral cavity
• Verrucous– Cancer has a wart-like appearance
• Ulcerated– Cancer appears as an open sore
• Flat – Cancer appears as an abnormal area in the lining of the oral cavity

• Microscopic features:
• Squamous cell carcinomas (SCC) are further divided into the following types based on microscopic features:

• Classical or conventional SCC: Most cancers of the oral cavity are classical or conventional squamous cell carcinoma. This type of SCC starts in the squamous epithelium that lines the oral cavity and occurs most often on the lower lip, tongue and floor of the mouth.
• Variants of SCC: These squamous cell carcinomas have distinct microscopic features that make them look and behave differently from classical SCC.

• Verrucous carcinoma
• Basaloid SCC
• Papillary SCC
• Spindle cell carcinoma (SpCC)
• Acantholytic SCC
• Adenosquamous carcinoma
• Lymphoepithelial carcinoma

• About 5% of oral cavity cancers are rare malignant tumors that start in different types of cells in the oral cavity.
  • Salivary gland cancer
  • Melanoma
  • Bone and soft tissue sarcomas
  • Lymphomas and extramedullary plasmacytomas
  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma
  • Metastatic cancer

• Several types of non-cancerous tumors and tumor-like conditions can arise in the oral cavity and oropharynx.
• A premalignant (or precancerous) lesion is defined as a benign, morphologically altered tissue that has a greater than normal risk of malignant transformation.
• There are several different types of premalignant lesion that occur in the mouth.
• Some oral cancers begin as white patches (leukoplakia), red patches (erythroplakia) or mixed red and white patches (erythroleukoplakia or “speckled leukoplakia”).
• The most common precancerous conditions of the oral cavity are:
  • Leukoplakia
  • Erythroplakia
  • Erythroleukoplakia
  • Proliferative verrucous leukoplakia (PVL)
  • Oral submucous fibrosis

• Benign tumors: There are many different types of benign oral cavity tumors.
  • Hyperplasia
  • Papillomas
  • Pleomorphic adenoma
  • Soft tissue tumors
    • Lymphangioma
    • Hemangioma
    • Neurofibroma
    • Lipoma
• Benign odontogenic tumors and cysts
  • Osteoma
  • Ossifying fibroma
• Benign conditions
  • Candidiasis (thrush)
  • Aphthous ulcers (canker sores)
  • Recurrent herpes labialis (cold sores)
  • Erythema migrans (geographic tongue)
  • Hairy tongue
  • Lichen planus
  • Frictional hyperkeratosis
  • Mucocele

The TNM classification of oral cavity carcinoma is as follows:^[1]

TNM Staging for Oral Cavity Cancers
Tumor
TX	Primary tumor cannot be assessed.
T0	Primary tumor cannot be assessed.
Tis	Carcinoma in situ
T1	Tumor <2 cm or less in greatest dimension
T2	Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3	Tumor more than 4 cm in greatest dimension
T4 (lip)	Tumor invades through cortical bone, inferior alveolar nerve, floor of the mouth, or skin of the face (e.g., chin or nose).
T4a (oral cavity)	Tumor invades adjacent structures (e.g., through cortical bone into deep [extrinsic] muscle of the tongue [[[genioglossus]], hyoglossus, palatoglossus, and styloglossus], maxillary sinus, or skin of the face).
T4b	Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid canal.
Regional Lymph Nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2a	Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b	Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c	Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3	Metastasis in a lymph node more than 6 cm in greatest dimension
Distant Metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
M = Distant metastasis; N = regional lymph nodes; T= primary tumor; Tis = carcinoma in situ. # = Staging system of the American Joint Committee on Cancer.

Staging of Oral Squamous Cell Carcinoma
Stage	Description
0	Tis, N0, M0
I	T1, N0, M0
II	T2, N0, M0
III	T3, N0, M0 T1, N1, M0 T2, N1, M0 T3, N1, M0
IVA	T4a, N0, M0 T4a, N1, M0 T1, N2, M0 T2, N2, M0 T3, N2, M0 T4a, N2, M0
IVB	Any T, N3, M0 T4b, any N, M0
IVC	Any T, any N, M1
M = Distant metastasis; N = regional lymph nodes; T = primary tumor; Tis = carcinoma in situ.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3]

Leukoplakia and erythroplakia have the greatest potential for malignant transformation in tongue cancer. World Health Organization classified oral cancer into mild, moderate, and severe dysplasia. Genes involved in the pathogenesis of tongue cancer include TP53, c-myc, and erb-b1. On gross pathology, exophytic, ulcerative, and infiltarative growth patterns are characteristic findings of tongue cancer. Tongue cancer constitutes of highly differentiated squamous cells lacking frank cytologic criteria of malignancy with rare mitoses. The surface of the lesion is covered with compressed invaginating folds of keratin layers. A stroma-like inflammatory reaction and a blunt pushing margin may be seen.

• The two most common types of precancerous conditions on the tongue are called leukoplakia and erythroplakia and they can usually be easily spotted by a dentist.
• Leukoplakia and erythroplakia have the greatest potential for malignant transformation into tongue cancer.^[1]
• Leukoplakia is defined as a white patch of the mucosa that cannot be characterized clinically or pathologically as any other disease.
• Leukoplakia is considered a premalignant condition from the chronic irritation of the mucous membranes, resulting in increased rates of epithelial and connective tissue proliferation.
• Leukoplakia usually occurs after the age of 40 years, with the peak incidence before age 50 years.
• Leukoplakia is 2-3 times more common in men than in women.
• The rates of malignant transformation of leukoplakia lesions range from less than 1% to as high as 17.5%, averaging 4.5-6%.
• Erythroleukoplakia and nodular leukoplakia exhibit the highest rate of malignant transformation.
• Erythroplakia is defined as a red, velvety plaque found on the oral mucosa that cannot be ascribed to any other predetermined condition.
• No sex predilection is recognized in erythroplakia and it is rarely found on the tongue compared with other sites in the oral cavity.
• Erythroplakia is considered as the earliest sign of asymptomatic cancer by Mashberg.^[2]

• Mild dysplasia: Abnormal cytological features largely confined to the lower third of the epithelium.^[3]
• Moderate dysplasia: The dysplastic process extends into the middle third of the epithelium.
• Severe dysplasia: Extension of the dysplasia into the upper third of the epithelium.
• Carcinoma in-situ: Full thickness involvement is present in the absence of invasion.

• Floor of mouth SCC spreads superficially without invading into the mylohyoid muscle or the sublingual gland until a late stage.
• Tumor involving the lateral margin of tongue tends to spread in depth.
• The intrinsic muscles of tongue run in all directions.
• Tumors of palate spread superficially rather than in depth.

• The mechanism of spread from the primary site to lymph nodes is almost always by embolism or by permeation.
• Spread to local lymph nodes worsens the prognosis in oral and oropharyngeal cancer.
• The lymph nodes in the neck are divided into levels. Levels at high risk for metastasis from oral cavity SCC are Levels I, II and III, and to a lesser extent Level IV.

• Hematogenous spread is less important than local and lymphatic spread.
• The best predictor of the likelihood of this spread is involvement of the neck at multiple levels.
• This suggests that the route of entry of tumors into the circulation is most often via the large veins in the neck and that hematogenous spread is in effect tertiary spread following extracapsular spread from neck lymph nodes.

• Genes involved in the pathogenesis of tongue cancer include TP53, which is located on chromosome 17.^[4]
• The carcinogens in tobacco smoke, for example, increase the prevalence and spectrum of TP53 mutations.^[5]
• Other oncogenes associated with squamous cell cancers of the tongue include c-myc and erb -b1.
• More than 50% of oropharyngeal carcinomas harbour integrated HPV DNA.
• The E6 and E7 viral oncoproteins bind and inactivate the TP53 and retinoblastoma gene products respectively, disengaging two of the more critical pathways involved in cell cycle regulation.
• Local tumor recurrence reflects extension of genetically damaged cells beyond the clinical and microscopic boundaries of carcinoma to the margins of surgical resection.^[6]
• Head and neck SCC have been identified by circulating plasma or serum changes which can be used for follow-up and screening.

• Squamous cell carcinoma is the most common malignancy of the tongue.
• It typically has three gross morphologic growth patterns: exophytic, ulcerative, and infiltrative.
• The infiltrative and ulcerative are the types most commonly observed on the tongue.
• The macroscopic appearance of tongue cancer depends on the following:

• • Duration of the lesion
  • The amount of keratinization
  • The changes in the adjoining mucosa
  • A fully developed tongue lesion appears as an exophytic bulky lesion that is gray to grayish-red and has a rough, shaggy, or papillomatous surface.

• Microscopically, tongue cancers are broadly based and invasive through papillary fronds.
• Tongue cancer constitutes of highly differentiated squamous cells lacking frank cytologic criteria of malignancy with rare mitoses.
• The surface of the lesion is covered with compressed invaginating folds of keratin layers. A stroma-like inflammatory reaction and a blunt pushing margin may be seen.

• SCC is subdivided by the WHO into:^[7]
  • Keratinizing type: Worst prognosis.
  • Undifferentiated type: Intermediate prognosis, EBV association.^[8]
  • Nonkeratinizing type: Good prognosis, EBV association.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3]

Tongue cancer is caused by a point mutation in the tumor suppressor gene (TP53). The other oncogenes associated with oral squamous cell cancers of tongue include c-myc and erb -b1.

The main cause of tongue cancer is genetic mutations due to precancerous lesions or chronic inflammation as follows:^[1]

• The mutations in tumor suppressor genes has been reported in patients with cancers of the oral cavity.
• The most abundant carcinogens in tobacco constitute nitrosamines. Nitrosamines can damage DNA, leading to point mutations.
• These point mutations lead to deregulation of tumor suppressor genes (TP53), which is located on chromosome 17.
• The other oncogenes associated with oral squamous cell cancers of tongue include c-myc and erb -b1.
• Tobacco exposure causes progressive sequential histological changes to the oral mucosa.
• Prolonged period of exposure eventually leads to neoplastic transformation, in particular changes in the expression of p53 mutations.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3]

Tongue cancer must be differentiated from other diseases that cause malignant lesions of the oral cavity and from non-neoplastic lesions of the oral cavity, such as lymphoma, sarcoma,, metastatic tumor, malignant salivary gland tumors, tuberculosis, scarlet fever, syphilis, papilloma, lipoma, leiomyoma, neurofibroma, schwannoma, granular cell tumor, benign migratory glossitis, Hairy tongue, pemphigus, erythema multiforme, mucous membrane pemphigoid, vitamin B deficiency, amyloidosis, diabetes mellitus, hypothyroidism, acromegaly.

The differential diagnosis for a squamous cell carcinoma of the tongue is essentially that of other malignant lesions of the oral cavity as well as a few non-neoplastic lesions. It includes the following:

Other malignancies:

• Lymphoma
• Sarcoma
• Metastatic tumor
• Malignant salivary gland tumors

Infections:

• Tuberculosis
• Scarlet fever
• Syphilis

Benign neoplasm:

• Papilloma
• Lipoma
• Leiomyoma
• Neurofibroma
• Schwannoma
• Granular cell tumor

Idiopathic:

• Benign migratory glossitis
• Hairy tongue
• Pemphigus
• Erythema multiforme
• Benign mucous membrane pemphigoid

Metabolic causes:

• Vitamin B deficiency
• Amyloidosis
• Diabetes mellitus
• Hypothyroidism
• Acromegaly

		Location	Clinical presentation		Investigations	Others
			Symptoms	Signs
Infections	Tuberculosis (TB)[1]	Dorsum	Primary TB symptoms: night fever, sweating, bloody cough, and loss of weight Painful tongue ulcers	Ulcer: irregular outline, undulated borders, and covered with a yellowish-gray, and fibrinous layer	Culture and biopsy Chest x-ray for primary infection Tuberculin skin test
	Scarlet fever[2]	Dorsum	Fever, malaise, headache, pharyngitis Red skin rash Swelling of tongue, white and red coating	Heavy gray-white coating Enlargement of the fungiform papillae, which appear as multiple red dots Dots disappear with time	Throat swab and culture Rapid streptococcal antigen tests	Mainly in children due to group A streptococcal infection
	Syphilis[3]	Dorsum	Single or multiple painless masses or ulcers according to the stage White patches of leukoplakia Symptoms of generalized syphilis in secondary and tertiary stages especially generalized lymphadenopathy	The primary stage The lingual chancre is a solitary, painless, slightly raised, well-demarcated ulcer Enlarged, painless, regional lymph nodes The secondary stage: The mucous patches are slightly raised, grayish-white, and usually surrounded by a red halo If the lesion is scraped, it leaves a raw, bleeding surface The third stage: The gumma appears as a painless, elastic mass that subsequently undergoes central necrosis and ulceration Atrophy of the papillae Frequently associated with leukoplakia, which has a tendency to undergo malignant transformation	Dark-field illumination reveal the causative organism Rapid plasma reagin Venereal Disease Research Laboratory
Benign neoplasms	Papilloma	Dorsum and lateral borders	Painless slowly growing mass	Warty surface or consist of hyperkeratotic finger-like projections Sessile or pedunculated, pink to white color	Biopsy
	Lipoma[4]	Dorsum and lateral borders	Painless slowly growing mass	Soft, sessile, and yellowish	Biopsy
	Leiomyoma[5]	Dorsum	Painless slowly growing mass	Small, single or multiple, circumscribed mass	Biopsy
	Schwannoma[6]	Dorsum and lateral borders	Painless slowly growing lesions, may be painful	Firm, submucosal mass	Biopsy
	Neurofibroma[7]	Dorsum and lateral borders	Slowly growing multiple nodules Unilateral macroglossia	Tongue may show multiple nodules or there may be a more diffuse involvement causing unilateral macroglossia	Biopsy
	Granular cell tumor	Dorsum	Painless, firm, slwoly growing nodules	Submucosal nodules with a yellowish or pinkish color	Biopsy
Malignant neoplasms	Squamous cell carcinoma	Lateral borders	Painless ulcer or exophytic mass. History of heavy use of alcohol and tobacco	The lesion has an ulcerated appearance with rolled borders around a necrotic center It frequently resembles a traumatic ulcer	Biopsy Computed tomography
	Malignant salivary gland tumors[8]	Ventral and dorsum	Slow-growing, painless mass		Submueosal mass May ulcerate in the later stages
	Metastatic tumor	Base of tongue	Painful mass Dysphagia Symptoms of primary tumor	Mass in tongue base Cachexia and loss of appetite Signs of primary tumor	Mass in tongue base Cachexia and loss of appetite Signs of primary tumor	Subtypes: Mucoepidemoid tumors Acinic cell tumors Adenocarcinomas
	Sarcoma[9]	Palate and tongue	Painless slowly growing mass Dysphagia and weight loss	Reddish or bluisb macules that then coalesce to form purplish nodules and may get ulcerated	Biopsy	Subtypes:  Fibrosarcoma Alveolar soft-part sarcoma Rbabdomyosarcoma Leiomyosarcoma Synovial sarcoma Chondrosarcoma Neurogenic sarcoma Kaposi’s sarcoma
Idiopathic	Benign migratory glossitis[10]	Dorsum	Painless redish ulcerative lesions	The lesions appear as one or more irregularly shaped, reddish areas of depapillation surrounded by a narrow, whitish zone of regenerating papillae
	Hairy tongue[11]		Tongue color changes	Hypertrophy of the filiform papillae Tongue color will vary from yellowish-white to brown or black		Risk factors: Tobacco Radiation therapy
Metabolic	Diabetes mellitus	Dorsum	Burning and dryness White plaques on the dorsum of tongue due to Candidal infection in uncontrolled cases	Lingual papillary atrophy	Throat swab Blood glucose level HBA1C
	Hypothyroidism		Dry mouth Difficulties in eating and speaking Tongue swelling	Tongue protrusion Macroglossia	TSH level T3 and T4 levels
	Acromegaly[12]	Generalized	Swollen tongue Lingual indentations	Hyperplasia of the epithelium and connective tissue Macroglossia Spacing and labial tilting of the teeth	Serum IGF-1 concentration Oral glucose tolerance test
	Vitamin B deficiency[13]	Dorsum	Redness in the tip and margins of the tongue Swelling of the tongue Indentations of the teeth Associated neurological symptoms due to niacin and B12 deficiency	Atrophy of both the filliform and fungiform papillae	Serum vitamin B12 and folate levels CBC and blood smear
	Amyloidosis[14]	Lateral borders	Enlarged tongue Decrease in lingual mobility Difficulty in chewing, swallowing and speaking	Generalized induration Yellowish nodules	Tongue biopsy Abdominal fat pad biopsy  Monoclonal pattern on serum protein electrophoresis (SPEP)
Immunologic disorders	Benign mucous membrane pemphigoid[15]	Generalized	Women over the age of 50 Painful bullae or ulcerations	Yellow or hemorrhagic bullae on an erythematous background Bullae rupture leaving a fibrin-covered ulceration	Biopsy Indirect immunofluorescence Autoantibodies against BP180, BP230, laminin 332
	Erythema multiforme[16]	Generalized	It occurs primarily in young men	Small, erythematous plaque that then becomes a vesicle, quickly rupture and become confluent, shallow erosions covered by a pseudomembrane of necrotic tissue	The cause of this disorder is an infectious disease such as Herpes simplex, Coxsackie virus, or drug therapy
	Pemphigus[17]	Generalized		Bullae rupture soon after formation to produce ulcers (pemphigus vulgaris) Fungoid vegetations develop on the base of these ulcers (pemphigus vegetans)	ELISA for antibodies to the BP180 NC16A Biopsy

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3]

In 2009, the incidence of tongue cancer was estimated to be 10,530 cases per 100,000 individuals in the United States. Males are more commonly affected with tongue cancer than females. The male to female ratio is approximately 2 to 1. The incidence of tongue cancer increases with age; the median age at diagnosis is 61 years. Approximately one-third of all diagnoses occurred in patients under the age of 55. There is no racial predilection to the tongue cancer.

In the United States, cancers of the oral cavity represent 2% of all cancers diagnosed annually. In Australia and Europe, the incidence of oral cavity cancer is very low, accounting for less than 5% of all cancers. In France, oral cavity cancer is the third most common cancer in males and the second most common cause of death from cancer.^[1][2]

In 2009, the incidence of tongue cancer was estimated to be 10,530 cases per 100,000 individuals in the United States. Approximately one in 324 men and women will be diagnosed with tongue cancer in their lifetime. According to the National Cancer Institute in the year 2011, the incidence of tongue cancer was estimated to be approximately 12,060 cases per 100, 000 individuals. Out of those approximately 71% ( i.e, 8,560) were men and 29% ( i.e, 3,500) were women.^[2]

Males are more commonly affected with tongue cancer than females. The male to female ratio is approximately 2 to 1.^[3]

There is no racial predilection to the tongue cancer.^[4]

The incidence of tongue cancer increases with age; the median age at diagnosis is 61 years. Approximately one-third of all diagnoses occurred in patients under the age of 55. According to the National Cancer Institute from 2004-2008, the age at diagnosis and percentage of people diagnosed with tongue cancer are shown below:^[2]

Age at diagnosis	percentage of people diagnosed with tongue cancer
Under the age of 20	0.2% of all tongue cancer diagnosis
Between the ages of 20- 34	2.0% of all tongue cancer diagnosis
Between the ages of 35- 44	6.0% of all tongue cancer diagnosis
Between the ages of 45- 54	20.8% of all tongue cancer diagnosis
Between the ages of 55- 64	31% of all tongue cancer diagnosis
Between the ages of 65- 74	21.9% of all tongue cancer diagnosis
Between the ages of 75- 84	13.5% of all tongue cancer diagnosis
The age of 85 years and above	4.6% of all tongue cancer diagnosis

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3] Roukoz A. Karam, M.D.[4]

The most potent risk factor in the development of oral cancer is alcohol intake, tobacco use and human papillomavirus transmitted through sexual contact. The other risk factors include history of betel quid intake, male gender, age over 55 year, ultraviolet light, Fanconi anemia, dyskeratosis congenita, lichen planus, graft-versus-host disease (GVHD), immune system suppression, mouthwash and irritation from dentures.

The major risk factors in the development of tongue cancer include the following:^{[1] [2] [3]}

• Tobacco smoking
  • Cancer of the tongue is correlated the closest with the use of tobacco products.
  • Approximately 90% of patients with oral cavity cancers use tobacco products and that the relative risk of oral cavity cancers increases with the amount smoked and the duration of the smoking.
  • In persons who smoke the incidence of oral cavity cancers is approximately six times that of those who do not smoke.
  • Tobacco exposure causes progressive sequential histological changes to the oral mucosa. A prolonged period of exposure eventually leads to neoplastic transformation, in particular, changes in the expression of p53 mutations. If the tobacco exposure is discontinued, these changes may be reversible.
  • There is compelling evidence supporting the benefit for head and neck cancer patients to cease smoking after treatment for their cancer. Approximately 40% of patients who continued to smoke after definitive treatment for an oral cavity malignancy developed recurrence or developed a second head and neck malignancy. In patients who stopped smoking after treatment, approximately 6% went on to develop a recurrence.
  • There has been a recent increase in the incidence of oral cavity cancer in young adults in the recent years. The explosive use of smokeless tobacco, or snuff, in certain regions of the United States has lead to increased numbers of mandibular alveolus, buccal mucosa, and tongue cancers.
• Alcohol ingestion
  • The correlation between alcohol consumption, particularly hard liquor, and oral cavity cancer is significant, especially in patients taking more than four consumptions per day.
  • Approximately 75% of patients who develop oral cavity cancers consume alcohol, and cancer occurs six times more often in persons who drink than in those who do not drink. The role of alcohol consumption in the development of tongue cancer appears to be independent of smoking.
  • The use of alcohol has a synergistic effect on the risk of carcinogenesis rather than cumulative effect. The risk for a person who drinks alcohol and smokes tobacco is fifteen times that of an individual with neither of these habits.
• Human papillomavirus
  • The human papillomavirus, is an etiologic agent for carcinogenesis in the tongue cancer. Human papillomavirus (HPV) has been detected in various amounts in persons with leukoplakia, oral dysplasia, and malignancy. In the subset of patients without other risk factors, HPV should be considered as an etiologic factor. Human papillomavirus (HPV), especially HPV type 16.^[4]
• Plummer-Vinson syndrome
  • Plummer-Vinson syndrome (Fe deficiency anemia; achlorhydria; and mucosal atrophy of the mouth, pharynx, and esophagus) has been associated with an increased risk of cancer of the tongue. Studies have suggested that vitamins A and C, along with the carotenoids, may be protective against epithelial cancers. Iron and riboflavin deficiencies are known to produce dysplastic changes to the oral mucosa.

• Leukoplakia is a white plaque on surface of tongue
• It often occurs in individuals under the age of 40^[5]
• Leukoplakia can be divided into:^[6]
  • Homogenous lesions: flat, thin, and white^[7]
  • Nonhomogenous lesions: white and red lesion
• Oral leukoplakia should be confirmed by biopsy
• Surgical excision should be recommended in the presence of moderate and severe epithelial dysplasia
• In case of using topical retinoic acid, recurrence rates are 50% after withdrawal^[8]

Risk factors of malignant transformation^[6]

• Female gender
• Long duration of leukoplakia
• Leukoplakia in non-smokers
• Location on the tongue and floor of the mouth
• Size > 200 mm
• Non-homogenous type
• Presence of epithelial dysplasia

• Erythroplakia is a red patch on the tongue surface^[9]
• It occurs in middle aged and elderly patients and affects the soft palate, the floor of the mouth, and the buccal mucosa mainly^[10]
• Tobacco and alcohol consuming are the most common risk factors
• Lesion is usually less than 1.5 cm in diameter, but its size may range between 1-4 cm
• Early effective treatment is mandatory as malignant transformation rates are very high

• Lichen planus is chronic inflammatory disease which may affect oral mucosa between other areas of body^[11]
• It mainly occurs in females between third and sixth decade
• It may be multifocal, papular, bullous, erosive, reticular, and atrophic forms
• Atrophic and erosive pattern are associated with a burning sensation and pain
• Increased malignant transformation risk occurs greater in erosive and atrophic types

• Histologically, lesions show liquefactive necrosis of the basal cells, infiltrative lymphocytes of superficial dermis, sawtooth rete ridges, and hyperkeratosis

• Malignant transformation ratio has been reported in 10% of patients

• After stem cell transplantation, the risk for oral squamous cell carcinoma significantly increase.
• Oral cancer in these patients may have more aggressive behavior with poorer prognosis.
• This effect is due to the continuous lifelong immune suppression and chronic oral graft-versus-host disease.
• The mutations in tumor suppressor genes has been reported in patients with cancers of the oral cavity.
• The most abundant carcinogens in tobacco constitute nitrosamines.
• Nitrosamines damage DNA, leading to point mutations.
• These point mutations lead to deregulation of tumor suppressor genes (TP53), which is located on chromosome 17.
• The other oncogenes associated with oral squamous cell cancers of tongue include c-myc and erb -b1.

Other less potent risk factors includes the following:

• Lifestyle
  • Betel quid
• Genetics
  • Fanconi anemia
  • Dyskeratosis congenita
  • Family history of squamous cell carcinoma
• General
  • Male gender
  • Ultraviolet light
  • Age over 55 year
  • Graft-versus-host disease(GVHD)
  • Immune system suppression
  • Lichen planus
• Unproven risk factors
  • Mouthwash
  • Irritation from dentures

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3]

According to the United States Preventive Services Task Force, screening for tongue cancer is not recommended in the United States. Outside the US, multiple screening programs have been tried in high-risk patients. Screening subjects are tobacco or alcohol consumers.

• Tongue cancer screening is not standard procedure for a health assessment. There is no effective oral cancer screening program either a general or a selected high-risk population for oral cancer in the United States.^[1]
• Screening high-risk individuals in developing countries could be an effective prevention strategy that lowered the stage of oral cancer at diagnosis and improved 5-year survival.^[2]
• Screening subjects in the subgroup who used tobacco or alcohol reduced the mortality rate from oral cancer.^[3]
• The US Preventive Services Task Force (USPSTF) in 2013 stated evidence was insufficient to determine the balance of benefits and harms of screening for oral cancer in adults without symptoms by primary care providers. 
• The American Academy of Family Physicians comes to similar conclusions while the American Cancer Society recommends that adults over 20 years who have periodic health examinations should have the oral cavity examined for cancer. 
• The American Dental Association recommends that providers remain alert for signs of cancer during routine examinations.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2] Mohammed Abdelwahed M.D[3] Roukoz A. Karam, M.D.[4]

If left untreated, patients with tongue cancer may progress to develop metastasis. Common complications of treatment of tongue cancer include neurotoxicity, bleeding, radiation caries, trismus, osteonecrosis, oral mucositis, chronic dysphagia, anemia, pharyngocutaneous fistula, aspiration, infections, xerostomia, taste alterations, nutritional compromise, and abnormal tooth development. Prognosis is generally good, and the five-year mortality rate of patients with stage I and II tongue cancer is approximately 89 and 95 percent respectively. The five- year disease specific survival rate of patients with stage III and IV cancers is 39 and 27 percent respectively.

• Carcinomas of the tongue base are clinically silent until they deeply infiltrate the tongue musculature.
• Tongue cancers usually present late, as they are usually painless and often ignored by the patient. Eventually they present as a non-healing ulcer which demonstrates growth over time.
• Due to the extensive lymphatic drainage of the tongue, nodal metastases are common at the time of diagnosis.
• A neck mass may be the presenting complaint. Because of the difficulties with direct visualization, they may extend into the oral tongue or have clinical lymph metastases before the diagnosis is established.
• Tongue cancer often begins as a white patch, small lump, or sore on the tongue.
• Tongue cancer is often not diagnosed until it has grown and spread to other areas of the mouth, but if caught early it can be easily treatable.
• As the tumors enlarge, they may cause a mass effect which can lead to respiratory compromise when the patient presents late in their illness.^[1]

• Direct surgical complications include infection, bleeding, aspiration, wound breakdown, flap loss, and fistula.

• Complications of chemotherapy includes the following:^[2]
  • Neurotoxicity– This complication is a side effect of certain classes of drugs, such as the vinca alkaloids.
  • Bleeding
• Complications of radiation therapy includes the following:^[3]
  • Radiation caries
  • Trismus
  • Osteonecrosis
• Complications common to both chemotherapy and radiation include the following:^[4]
  • Oral mucositis
  • Chronic dysphagia
  • Anemia
  • Pharyngocutaneous fistula
  • Aspiration
  • Infections such as viral, bacterial, and fungal that results from myelosuppression, xerostomia, and damage to the mucosa from radiotherapy or chemotherapy
  • Xerostomia
  • Functional disabilities such as impaired ability to swallow, eat, taste and speak because of trismus, dry mouth, mucositis, and infection
  • Nutritional compromise such as poor nutrition from eating difficulties caused by dry mouth, mucositis, dysphagia, and loss of taste.
  • Abnormal dental development
    • Altered tooth development, craniofacial growth, or skeletal development in children secondary to high doses of chemotherapy and radiotherapy before age 9.

• Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as good.
• The five-year survival rate was 70% for patients with early oral cavity cancer.^[5]
• Neck dissection was associated with an improved prognosis.
• A five-year relative survival for locally advanced oral cavity of 54.7%.^[6]

• Lymph node involvement is the single most important prognostic factor for outcome in oral cavity cancer^[7]
• The number and size of positive lymph nodes
• The presence of extracapsular extension^[8]
• The ratio of positive lymph nodes to total number of excised lymph nodes^[9]
• In younger patients less than 40 years, tongue cancer is found to have a more aggressive course.^[10]

• The five-year mortality rate of patients with stage I and II cancers is 89 and 95 percent.^[11]
• The five-year survival rate calculated from a population-based database is reported as 67 and 51 percent respectively.^[12]

• The five-year disease specific survival rate of patients with stage III and IV cancers is 39 and 27 percent respectively.^[13]
• Tongue cancer has been associated with a worse prognosis compared with other oral cavity subsites in some series.^[14][15]
• The five year survival rate for individuals diagnosed with Stage I, II, III, and IV is shown below:

Stage of the tongue cancer	Five-year survival rate
Stage I	71%
Stage II	59%
Stage III	47%
Stage IV	37%

• In 2011, approximately 25.69% of all oral cancer deaths were from tongue cancer. According to National Cancer Institute, from 2004-2008 the average age of death from tongue cancer was 66.

• Approximate age of diagnosis of tongue cancer and percentage of deaths from tongue cancer are shown below in this table:

Age of diagnosis of tongue cancer	Percentage of deaths from tongue cancer
≤20	0.1%
Age 20- 34	1.1%
Age 35- 44	3.9%
Age 45- 54	15.4%
Age 55- 64	24.8%
Age 65- 74	23.8%
Age 75- 84	20.3%
≥85	10.7%

Template:WH Template:WS