Mucoepidermoid carcinoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Mucoepidermoid carcinoma (also known as “Salivary gland mucoepidermoid carcinoma”) is a malignant salivary gland tumor that consists of epidermoid and mucin producing cells. Mucoepidermoid carcinomas arise from mucous cells, which is normally involved in the secretion of mucous and the protection of surrounding tissue.^[1] Mucoepidermoid carcinoma is the most common malignant salivary gland tumor, and usually occurs in the parotid and submandibular salivary glands. Mucoepidermoid carcinomas may be classified according to location into 2 subtypes: salivary gland confined carcinomas and other organ mucoepidermoid tumors.^[2] The majority of these tumors present as parotid gland mucoepidermoid carcincoma lesions (65%). Development of mucoepidermoid carcinoma is the result of an abnormal production of mucin by mucus-secreting cells.^[3] Genes involved in the pathogenesis of mucoepidermoid carcinoma include MECT1 and MAML2 fusion genes.^[1] Mucoepidermoid carcinomas are usually found in middle aged adults between the second and sixth decade of life. Males are slightly more affected with mucoepidermoid carcinoma than females. The incidence of mucoepidermoid carcinoma is approximately 2.5 to 3.0 cases per 100,000 individuals a year.^[4] If left untreated, progression occurs slow and is then followed by sentinel lymph node metastasis. The treatment choice for mucoepidermoid carcinoma is surgical removal.^[1]

Mucoepidermoid carcinoma was first described by Masson and Berger, two American pathologists, in 1924.^[5]

Mucoepidermoid carcinoma may be classified according to location into 2 subtypes: salivary gland-confined carcinomas and other organ mucoepidermoid carcinomas.

Mucoepidermoid carcinomas arise from mucous cells, which are normally involved in the secretion of mucous and the protection of the surrounding tissue. The pathogenesis of mucoepidermoid carcinoma consists of abnormal production of mucin from mucous cells, associated with the aberrant overgrowth of squamous and epidermoid cells. Genes involved in the pathogenesis of mucoepidermoid carcinoma include the MECT1 and MAML2 fusion genes. On gross pathology, mucoepidermoid carcinomas have a cystic, solid or mixed appearance, are normally located on the parotid or submandibular gland, and range in size from 1 to 8 cm.^[6] On microscopic histopathological analysis, mucoepidermoid carcinomas are characterized by mucous cells with abundant fluffy cytoplasm and large mucin vacuoles.^[6]

There are no established direct causes for mucoepidermoid carcinoma. The development of mucoepidermoid carcinoma has been associated with the result of multiple genetic mutations in the MECT1 and MAML2 fusion genes.

Mucoepidermoid carcinoma must be differentiated from other diseases that cause painless swelling, facial deformity, and facial numbness, such as Warthin tumour, adenoid cystic carcinoma, benign mixed tumor, and metastasis.

Mucoepidermoid carcinoma is the most common malignant salivary gland tumor among general population. The incidence of mucoepidermoid carcinoma is approximately 2.5 to 3.0 cases per 100,000 individuals a year.^[2] The incidence of mucoepidermoid carcinoma increases with age. The median age at diagnosis is between 20 to 50 years.^[7] Males are slightly more affected with mucoepidermoid carcinoma than females. There is no racial predilection for mucoepidermoid carcinoma.^[4]

Common risk factors in the development of salivary gland tumors include: ionizing radiation and occupations associated with an increased risk such as rubber products manufacturing, asbestos mining, plumbing, and some types of woodworking.^[8]

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for mucoepidermoid carcinoma.^[8]

If left untreated, patients with mucoepidermoid carcinoma may progress to develop sentinel metastasis to adjacent lymph nodes. Common complications of mucoepidermoid carcinoma include facial deformity, difficulty swallowing, and local lymph node metastasis. Prognosis will generally depend on the clinical stage, tumor size, and histological grade. The overall recurrence rate will depend on the stage.^[9] Low grade tumors have a 90-98% survival rate and a low rate of local recurrence.^[10]

According to the American Joint Committee on Cancer (AJCC) 7th edition, there are 6 stages of mucoepidermoid carcinoma based on the tumor size and node invasion. Each stage is assigned a letter and a number that designate the tumoral size and node invasion.^[11]

The hallmark symptom of mucoepidermoid carcinoma is painless swelling. A positive history of cancer may be suggestive of mucoepidermoid carcinoma. Symptoms related with mucoepidermoid carcinoma will vary depending on the size and location of the tumor. Common symptoms of mucoepidermoid carcinoma may include facial numbness, adjacent muscle soreness, mandible claudication, otorrhea, dysphagia, and trismus.^[12]

Physical examination findings of mucoepidermoid carcinoma depend on the size and location of the tumor. Physical examination of patients with mucoepidermoid carcinoma is usually remarkable for tenderness and intraoral bluish-red mucosa.^[7]

There are no diagnostic laboratory findings associated with mucoepidermoid carcinoma.

On conventional radiography, there are no characteristic findings of mucoepidermoid carcinoma.^[2]

On CT scan, characteristic findings of mucoepidermoid carcinoma include: well-circumscribed masses, usually with cystic components (low-grade tumors), enhancements of solid components, and calcification. High-grade tumors have poorly defined margins, infiltrate locally, and appear solid.^[2]

On MRI, characteristic findings of mucoepidermoid carcinoma will depend on the stage. Common findings include: low signal cystic spaces in T1 and high signal in cystic areas on T2.^[2]

On ultrasound, characteristic findings of mucoepidermoid carcinoma include: a well-circumscribed hypoechoic lesion with a partial or completely cystic appearance, in contrast to the relatively hyperechoeic normal parotid gland.^[2]

There are no other imaging findings associated with mucoepidermoid carcinoma.^[2]

Other diagnostic studies associated with mucoepidermoid carcinoma may include: fine needle aspiration biopsy and incisional biopsy.^[2]

There is no medical treatment for mucoepidermoid carcinoma. Radiotherapy can be neoadyuvant treatment in some lesions (dependent on the tumor stage and size).

Surgery is the mainstay of therapy for mucoepidermoid carcinoma.^[11]

There is no primary prevention for mucoepidermoid carcinoma.

There is no secondary prevention for mucoepidermoid carcinoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Mucoepidermoid carcinoma was first described by Masson and Berger, two American pathologists, in 1924.

• In 1802, the first surgical excision of a parotid tumor was performed by Bertrandi.
• in 1895, Volkmann described mucoepidermoid carcinoma as the most common malignant epithelial tumour of the salivary glands.^[1]
• In 1924, mucoepidermoid carcinoma was described by Mason and Berger.^[2]
• In 1945, Stewart and his associates, recognized mucoepidermoid of the salivary gland as a separate neoplasm and described its histopathology.^[2]
• In 1958, Beahrs and Adson first described the surgical technique for parotid surgery.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] Maria Fernanda Villarreal, M.D. [3]

Mucoepidermoid carcinoma may be classified according to location into 2 subtypes: salivary gland-confined carcinomas and other organ mucoepidermoid carcinomas. Based on histological features, it is divided into low, intermediate and high grade tumors.

Mucoepidermoid carcinoma may be classified according to location into 2 subtypes:^[1]

• Mucoepidermoid carcinoma are graded into three sub types based on histopathological features:
  • Low
  • Intermediate
  • High grade
• The three most popular grading systems are:
  • The AFIP grading system ^[2]
  • Modified Healey system^[3]
  • The Brandwein system^[4]
• All categories are based on similar set of parameters which include both cytomorphologic and architectural, particularly perineural and angiolymphatic invasion.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Maria Fernanda Villarreal, M.D. [3]

Mucoepidermoid carcinomas arise from mucous cells, which are normally involved in the secretion of mucous and the protection of the surrounding tissue. The pathogenesis of mucoepidermoid carcinoma consists of abnormal production of mucin from mucous cells, associated with the aberrant overgrowth of squamous and epidermoid cells. Genes involved in the pathogenesis of mucoepidermoid carcinoma include the MECT1 and MAML2 fusion genes. On gross pathology, mucoepidermoid carcinomas have a cystic, solid or mixed appearance, are normally located on the parotid or submandibular gland, and range in size from 1 to 8 cm.

• Mucoepidermoid carcinoma originates from pluripotent cells of the excretory ducts of glandular structures.^[1]
• The tumor primarily comprises of mucous, intermediate and epidermoid cells.^[2][3]
• Mucous cells, which are normally involved in the secretion of mucous and protection of the surrounding tissue.
• The pathogenesis of mucoepidermoid carcinoma consists of abnormal production of mucin from mucous cells, associated with the aberrant overgrowth of squamous and epidermoid cells.

• Development of mucoepidermoid carcinoma may be the result of multiple genetic mutations.
• Mucoepidermoid carcinoma is specifically associated with t(11;19)(q21;p13) translocation.^[4][5]

• CRTC1–MAML2 fusion is a primary driver for mucoepidermoid carcinoma initiation and maintenance.^[6][7]

• This translocation creates a MECT1-MAML2 fusion protein that disrupts the Notch signaling pathway.
• This fusion protein is expressed by all cell types of mucoepidermoid when the translocation is present.^[8]
• Genes involved in the pathogenesis of include:

• MECT1 fusion gene
• MAML2 fusion gene

• The CRTC1–MAML2 fusion protein induces the upregulation of the epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) by co-activating the transcription factor CREB.
• AREG subsequently activates EGFR signaling in an autocrine manner that promotes mucoepidermoid carcinoma cell growth and survival.^[9]
• Aberrantly activated AREG–EGFR signaling is essential for CRTC1–MAML2positive mucoepidermoid carcinoma cell growth and survival.^[10]

Human cytomegalovirus (hCMV) infection is commonly seen associated with development of mucoepidermoid carcinoma.

• As HCMV is commonly resides in salivary gland ductal epithelium, It is hypothesized that HCMV could be integral part of pathogenesis of mucopidermoid carcinoma.
• Following results were noted when they tested implication of HCMV in development
  • Protein markers for active HCMV
  • HCMV-specific proteins are present in specific cell types and expression is positive
  • HCMV correlates with upregulation and activation oncogenic signaling pathways (COX/AREG/EGFR/ERK). ^[11]

• On gross pathology, mucoepidermoid carcinoma has a cystic, solid, or mixed appearance.
• Mucoepidermoid carcinoma usually occurs in the parotid or submandibular gland.
• Low grade mucoepidermoid carcinoma are small and partially encapsulated.
• It appears as fluctuant light blue or purplish submucosal lumps. ^[12]
• Other findings on gross pathology include:

• Tumor size ranging from 1 to 8 cm
• Gray or white in color, with mucin filled cysts

The characteristic findings of mucoepidermoid carcinoma on microscopic histopathological analysis are listed below.^{[13][9][14][1][15][16]}

• Mucus secreting cells
• Composed of three cell types:
  • Epidermoid
  • Intermediate
  • Columnar
  • Clear cells

• They all demonstrates prominent cystic growth. ^[9]

• Mucin vacuoles may be rare; however they are integral part of histological features of mucoepidermoid carcinoma.

• Hallmark of these tumors are:
  • Prominent cystic structures lined by mature mucous, intermediate, or epidermoid cells
  • Solid areas are not evident
  • Prominent fibrous stroma
  • It grows in a well-circumscribed manner

• Mucoepidermoid tumors are graded histologically into:

• • Low grade
  • Intermediate grade
  • High grade.

• Low grade is characterized by well-differentiated cells with little cellular atypia, high proportion of mucous cells, and prominent cyst formation.
• Intermediate grade is characterized by intermediate features
• High grade is characterized by poorly differentiated with cellular pleomorphism, high proportion of squamous cells, and solid with few if any cysts

• 
  Histopathologic image of mucoepidermoid carcinoma of the major salivary gland. H & E stain.^[17]
• 
  Histopathologic image of mucoepidermoid carcinoma of the major salivary gland.^[17]
• 
  Histopathologic image of mucoepidermoid carcinoma. Postoperative recurrence of the submandibular tumor. Alcian blue-PAS stain.^[17]
• 
  Gross pathology mucoepidermoid carcinoma.^[17]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Maria Fernanda Villarreal, M.D. [3]

There are no established direct causes for mucoepidermoid carcinoma. The development of mucoepidermoid carcinoma has been associated with the result of multiple genetic mutations.

• There are no established direct causes for mucoepidermoid carcinoma.

• The development of mucoepidermoid carcinoma may be the result of multiple genetic mutations.^[1]
• Common genetic mutations for the development of mucoepidermoid carcinoma can be found here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Maria Fernanda Villarreal, M.D. [3]

Mucoepidermoid carcinoma must be differentiated from other diseases that cause painless swelling, facial deformity, and facial numbness, such as Warthin’s tumor, adenoid cystic carcinoma, benign mixed tumor (salivary glands), and metastasis.

• The table below summarizes the findings that differentiate mucoepidermoid carcinoma from other conditions that cause painless swelling, facial deformity, and facial numbness or weakness.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Maria Fernanda Villarreal, M.D. [3]

Mucoepidermoid carcinoma is the most common malignant salivary gland tumor among general population. The incidence of mucoepidermoid carcinoma is approximately 2.5 to 3.0 cases per 100,000 individuals a year. The incidence of mucoepidermoid carcinoma increases with age. The median age at diagnosis is between 20 to 50 years. Females are slightly more affected with mucoepidermoid carcinoma than males. There is no racial predilection for mucoepidermoid carcinoma.

• The overall adjusted incidence rate of mucoepidermoid carcinoma is approximately 2.5 to 3.0 cases per 100,000 individuals a year.^[1]

• Mucoepidermoid carcinoma is the most common malignant salivary gland tumor among the general population.^[2]
• Mucoepidermoid carcinoma is considered an uncommon tumor among adults.
• Mucoepidermoid carcinoma represents less than 5% of malignancies in the head and neck region, among the adult population.
• Mucoepidermoid carcinoma represents about 16% of all salivary gland tumors among the pediatric population.

• The median age at diagnosis is between 20 to 60 years.^[2][2]

• Females are slightly more affected with mucoepidermoid carcinoma than males.^[3]
• The male to female ratio is approximately 3:2.^[4]
• In mucoepidermoid carcinoma, males are more commonly affected by the aggressive tumor form than females.

• There is no racial predilection for mucoepidermoid carcinoma.^[2][5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2] , Maria Fernanda Villarreal, M.D. [3]

Common risk factors in the development of salivary gland tumors include: ionizing radiation and occupations associated with an increased risk such as rubber products manufacturing, asbestos mining, plumbing, and some types of woodworking.

Common risk factors in the development of salivary gland tumors, include:^[1][1][2][3]

• Ionizing radiation
• Previous history of cancers^[4]
• Occupations associated with an increased risk, such as:
  • Rubber products manufacturing
  • Asbestos mining
  • Plumbing
  • Some types of woodworking
• Occupational exposure to silica dust and nitrosamines

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: , Badria Munir M.B.B.S.[2] , Maria Fernanda Villarreal, M.D. [3]

If left untreated, patients with mucoepidermoid carcinoma may progress to develop sentinel metastasis to adjacent lymph nodes. Common complications of mucoepidermoid carcinoma include facial deformity, dysphagia, and local lymph node metastasis. Prognosis will generally depend on the clinical stage, tumor size, and histological grade. The overall recurrence rate will depend on the stage. Low grade tumors have a 90-98% survival rate and a low rate of local recurrence.

• The majority of patients with mucoepidermoid carcinoma are initially asymptomatic.
• Symptoms usually develop in the second or fifth decade of life, and initially patients complain of swallowing problems that are increased upon mastication.
• If left untreated, patients with mucoepidermoid carcinoma may progress to develop sentinel lymph node metastasis.
• Mode of metastasis may be^[1]

• • Lymphatic (cervical lymph node)
  • Hematogenous
• Most common site for the metastasis is:
  • Lungs
  • Liver
  • Brain
  • Skin
  • Ovary
  • Peritoneum

• Common complications of mucoepidermoid carcinoma include:^[2]

• Facial deformity
• Facial nerve palsy
• Otorrhea
• Lymph node metastasis
• Temporomandibular malocclusion

• Cosmetic concerns leading to severe emotional stress
• Ulceration
• Bleeding from the tumor
• Compression of adjacent tissues which causes:
  • Dysphagia
  • Odynophagia
  • Recurrence of the tumor after surgery
  • Bones may undergo demineralization
  • Submandibular tumors commonly spread to the lymphatic system
  • Intraoral mucoepidermoid carcinoma tumors tend to metastasize to the submandibular glands, post-auricular and neck lymph nodes
  • Palate tumors may metastasize to the skull base and respiratory tract
• Surgical complications:
  • Facial nerve palsy
  • Gustatory sweating (Frey’s syndrome)
  • Post-surgical wound infection
  • Side effects from chemotherapy and radiation therapy

• Prognosis will generally depend on the clinical stage, tumor size, and histological grade.^[2]
• The overall recurrence rate depends on the stage of the tumor.^[2][3]

• Low grade tumors have a 90-98% survival rate and a low rate of local recurrence.
• High grade tumors have a 30-54% survival rate, and a high local recurrence rate.^[3]
• The 5-year survival rate of patients with mucoepidermoid carcinoma is:^[4]

• Stage I 75%
• Stage II 59%
• Stage III 57%
• Stage IV 28%

• Overall incidence of lymph node involvement ranges from 18–28%.
• When distant metastases develop in patients with minor salivary gland tumours the average survival is 2.3 years
• Tumours of the major salivary glands is 2.6 years.^[5][6][7]

^[8][9]

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