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The part of the digestive tube which lies behind the nasal cavities, mouth, and larynx is called the Pharynx . It resembles an inverted conical tube lined by a mucous membrane .
Fig1.1: Laryngoscopic view of frontal part of pharynx.
Cavity of the Pharynx extends to a length of about 12.5 cm. It is wide below the base of the skull and is very narrow at its end point in the esophagus. It is posteriorly bound by loose areolar tissue to the cervical part of the vertebral column. Its anterior part is incomplete, and is attached successively to parts like mandible, tongue, hyoid bone and cartilages. It is laterally bound to the styloid processes and their respective muscles. The pharynx is in contact with various arteries, veins and nerves. A total of 7 cavities open into the pharynx, namely the nasal cavities (2), the tympanic cavities (2), esophagus, larynx and mouth. The pharynx is categorized into three main parts namely Nasopharynx, Oropharynx, and Laryngopharynx [1, 4].
The Nasopharynx is the part following the nose and is positioned higher than the soft palate. At the front it is connected to the nasal cavities through the choanae. The auditory tube opens into the nasopharynx on its lateral wall [3, 6]. The mucous membrane folds vertically to form the salpingopharyngeal fold and a smaller fold called the salpingopalatine. There is depression behind the opening of the auditory tube called the pharyngeal recess. The posterior wall contains a mass of lymphoid tissue called the pharyngeal tonsil.
The Oropharynx is the part of pharynx that lies between the soft palate and the hyoid bone. The anterior part of it opens into the mouth. The lateral wall encloses the palatine tonsil placed between the two palatine arches .
The Laryngopharynx extends from the hyoid bone to the lower end of the cricoid cartilage and from there is continuous with the esophagus. It forms the entrance of the larynx and the epiglottis is present at the base .
Fig1.2: Laryngopharynx .
The Pharyngeal muscles (Fig1.2) are categorized as follows
The Constrictor inferior also known as the Inferior constrictor is thickest constrictor muscle in the Pharynx. It originates sidewards of the thyroid cartilage and cricoid cartilage. These muscle fibres spread backward and medially. The inferior muscle fibres are horizontal and are arranged in continuation with the circular fibres of the esophagus.
The Constrictor medius also known as the Middle constrictor is smaller in size compared to the inferior constrictor and its shape resembles a fan. It originates from the upper border of the hyoid bone. The muscle fibres deviate from their origin. The lower fibres slide down below the Constrictor inferior, the middle fibres are arranged transversely, and the upper fibres rise to partly cover the Superior constrictor.
Fig1.3. Muscles of the pharynx and cheek.
The Constrictor superior also known as Superior constrictor is pale and thin in contrast to the rest. Its origin includes the margin of the pterygoid plate located medially, the alveolar process of the mandible and some fibres sidewards of the tongue. The gap amid the basal portion of the skull and the muscle's upper border is blocked by the pharyngeal aponeurosis.
The Stylopharyngeus is a slender and long muscle that is cylindrical on the top and is flattened beneath. It originates from the base of the styloid process and then extends downward between the Superior constrictor and medius, and broadens below the mucous membrane.
The Salpingopharyngeus originates from the lower part of the auditory tube near its opening. It extends downward and combines with the posterior fasciculus part of the Pharyngopalatinus .
The Constrictors and Salpingopharyngeus are enriched by nerves from the pharyngeal plexus. Nerve branches from the external laryngeal nerves and also the recurrent nerves connect the inferior constrictor. The Stylopharyngeus is supplied by the glossopharyngeal nerve .
In the event of deglutition, the pharynx moves upward and dilation occurs in different directions, to allow the food ingested into it from the mouth. The Stylopharyngei aid the upward and lateral pulling of the pharynx thus increasing its transverse diameter. As soon as food enters the pharynx, it slides down as a result of relaxation of the elevator muscles, and the Constrictor muscles shrink upon the bolus, and allow its movement gradually into the esophagus .
The coating of the pharynx includes layers of mucous, fibres, and muscles. The fibrous coat is present between the mucous and muscular layers. The thickness gradually reduces downward. A strong fibrous band provides strength. The mucous layer is continuous with the lining of the auditory tubes and also with the mucous layer of the larynx, mouth and nasal cavities. Columnar ciliated epithelium covers the nasopharynx. The oral and laryngeal parts are covered by stratified squamous epithelium. Racemose mucous glands are present beneath the mucous membrane .
Fig1.4. Pharyngeal muscles along with their blood vessels and nerves.
The human body has three lymphoepithelial structures known as tonsils. There are of three types of tonsils namely the adenoid tonsil, the lingual tonsil and the palatine tonsil. The palatine tonsils are present at the back of the throat. They are ellipsoid in shape and are of the size of an almond. Lingual tonsils on the other hand are present under the tongue. Adenoid tonsils are located upward on the rear wall at the back of oral cavity. The size of adenoids or pharyngeal tonsils is prominent during childhood but the size diminishes in adulthood. The tonsils constitute a part of the lymphatic system and are made up of lymphoid tissue. Tonsils attain their maximum size by puberty and thereafter there may be gradual atrophy. A condition called Tonsillitis may result in obstruction of the upper airway, difficulty in speaking and swallowing. The tonsils are therefore removed by a procedure called tonsillectomy .
Types & Features:
When they are infected, they cause obstruction in the nasopharynx and cause inflammation and may even infect the eustachian tubes resulting in further infection of the middle ear.
Made of pseudo stratified ciliated columnar epithelium.
In the event of chronic infections, surgical removal of tonsils is done.
Lies in pharynx roof.
2. Palatine tonsils:
It lies in right and left sides of the Oropharynx.
They are made of non keratinized stratified squamous epithelium.
They are present in the tissue of mucous membrane located at the rear portion of the mouth.
Inflammation that occurs in these tonsils is known as tonsillitis. This condition is characterized by pain due to swelling in the throat. It may even result in fever and make swallowing difficult.
Long and branched.
3. Lingual tonsils:
Made of non keratinized squamous epithelium.
Long and unbranched.
CANCER OF THE PHARYNX
Most throat cancers are squamous cell carcinomas (cancer that begins in thin, flat cells that look like fish scales) [1, 2]. Cancer that forms in tissues of the pharynx is known as the pharyngeal cancer .
Throat cancer includes cancer of the nasopharynx (the upper part of the throat behind the nose), the oropharynx (the middle part of the pharynx), and the hypopharynx (the bottom part of the pharynx). Cancer of the larynx (voice box) may also be included as a type of throat cancer .
The exact cause of Pharynx Cancer is unknown but it has been subjected that Pharynx Cancer in body is due to [4, 5]:-
Use of tobacco or Smoking.
Excessive drinking of alcohol.
Irritation of the lining of the mouth, due to jagged teeth or ill-fitting dentures.
Human immunodeficiency virus.
Herpes simplex virus.
Epstein barr virus.
Exposure to asbestos .
Exposure to sun over a prolonged period.
Chewing of betel nut.
Inhalation of wood dust.
The signs and the symptoms of the pharyngeal cancer include: Sore throat, Swallowing difficulties, Dysphagia, Lump in throat, Bleeding from mouth, ulcer in throat, Weight loss and Enlarged lymph nodes .
CANCER OF TONSILS
Lymphoma type of tonsil cancer arises from the lymphatic cells present in the tonsillar wall. Smoking is primarily related to this type of cancer and too much of alcohol drinking also causes carcinogenesis. Palatine tonsils are primarily.
Initial symptoms include sore throat and pain radiating to the ear. Crypt like convoluted structures are formed with peaks and valleys covered with mucous.
Microorganisms like bacteria and viruses or sometimes foreign particles cause infection leading to tonsillitis that is chronic along with formation of pus and inflammation. Squamous epithelium covers the outer part of the tonsils. B-cell lymphocytes (WBC's) are present in bulk beneath the epithelial layer.
Cancers that originate from the squamous epithelium account for squamous cell carcinoma (SCC). Lymphoma refers to the cancer of WBC's that occurs from lymphocytes that have different prognosis as compared to SCC. The lymphatics (vessels) drain extra fluid form tonsils to local lymph nodes, sometimes SCC can metastasize through these lymphatics to local lymph nodes. A direct correlation exists - larger the tumour greater the chance of metastasis. The symptoms include sore throat, blood in saliva, difficulty in eating and appearance of large tonsil on one side. Smoking damages the tissues repeatedly that lead to cancer evolution .
Most tonsillar cancer contain between 10 to few hundred copies of HPV per beta-actin.
HPV type 31 was found in one laryngeal cancer with normal p53 and HPV type 16 in two tonsil cancers with aberrant p53 expression.
Squamous cell carcinoma.
Symptoms include Lump formation in the neck, blood in the salivary secretions, sore throat, difficulty in swallowing, excessive swelling of tonsil on one side only and loss of weight .
GENETIC LEVEL UNDERSTANDING OF SMOKING INDUCED PHARYNGEAL CANCER
MGMT is a DNA repair gene and CDKN2A, RASFFI are tumor suppressor genes. Promoter methylation or hypermethylation of the MGMT, CDKN2A and RASFFI genes results in oral and pharyngeal cancer. The normal cells get transformed to cancer cells due to methylation. CpG island cytosine methylation of the particular region of MGMT gene results in gene silencing and that particular gene is not expressed anymore. Promoter methylation of the MGMT, CDKN2A and RASFFI genes leads to 29.6%, 11.5% and 12.1% of the tumor respectively.
Taioli, E., Ragin, C., Wang, X.H., Chen, J., Langevin, S.M., Brown, A.R., Gollin, M., Garte, S. and Sobol, R.W. (2009). "Recurrence in oral and pharyngeal cancer is associated with quantitative MGMT promoter methylation". BMC cancer. 9, 354.
CYP1A1 is also known as cytochrome P450 1A1. The high activity of CYP1A1 in an individual increases the risk of cancer when they are highly exposed to smoke components. It is induced by xenobiotics to produce genetic susceptibility of malignancies. The genotypes CYP1A1m1/m1 and CYP1A1w1/m1 showed higher risk of cancer when compared to CYP1A1w1/w1. Likewise, the genotypes CYP1A1w2/m2 and CYP1A1m2/m2 showed higher risk of cancer when compared to CYP1A1w2/w2. The m1 mutants had the mutation in the m2 site whereas the m2 mutants had the mutations in the m1 site. Individuals carrying either CYP1A1 m1 or m2 allele will have increased risk to the head and neck cancer
Sabitha, K., Reddy, M.V. and Jamil, K. (2010). "Smoking related risk involved in individuals carrying genetic variants of CYP1A1 gene in head and neck cancer". Cancer Epidemiol. 34(5), 587-592.
Polymorphism (T3801C base change in intron 6 that results in the new MspI restriction site and A2455G base change in exon 7 which result in the change of amino acid from Ile to val) of CYP1A1 are interlinked and this polymorphism is associated with the increased risk of the lung cancer. Polymorphism in CYP2D6, CYP2E1 and GSTM1 forms the DNA ducts in persons who smoke cigarettes.
Wu, X., Zhao, H., Suk, R. and Christiani, C.D. (2004). "Genetic susceptibility to tobacco-related cancer". Oncogene. 23, 6500-6523.
Tobacco exposure influences the p53 mutation and deletion of 3p, 5q and 9p21. Even Cyclin D1 expression and amplification is influenced by smoking. Maximum rate of p53 mutation and loss fo heterozygosity was found at 3p, 4q and 11q3q amplification has been reported in many tobacco-associated cancers including the lungs, cervix and esophagus. PIK3CA is a candidate oncogene at 3q for HNSCC and the PI3K pathway plays an important role in modifying the effects of benzopyrene and its metabolites. It was suggested by Racz and colleagues that PAX7 (transcription factor which is carcinogenic) and ENO1 may be the candidate oncogenes.
Singh, B., Wreesmann, B.V., Pfister, D., Poluri, A., Shaha, R.A., Kraus, D., Shah, P.J. and Rao, P.H. (2002). "Chromosomal aberrations in patients with head and neck squamous cell carcinoma do not vary based on severity of tobacco/alcohol exposure". BMC Genet. 3, 22.
mEH otherwise known as the microsomal form of epoxide hydrolase. It is associated with metabolism of exogenous xenobiotics compounds. It causes oral and pharyngeal cancer. It is found in aerodigestive tract. It gets involved in the hydrolysis of the arene, alkene and the aliphatic epoxides from polycyclic aromatic compounds and aromatic compounds. It also involves in the enzymatic hydrolysis of epoxides to trans-dihydrodiols. It has two polymorphism. One is the substitution of the C with T in the exon 3 and the His is replaced with the Tyr in the 113 position of the amino acid. This polymorphism is known as show allele. In the other polymorphism, the G is replaced by C in the exon 4 and the residue His is replaced with Arg in the amino acid position 139. This kind of polymorphism is known as fast allele HYL3. Tyr at the position 113 and the His in the position of 139 are the major amino acids in the Caucasian population.
Lema, L.V., Ravina, A.R., Crespo, M.A., Kelsey, K.T., Loidi, L. and Dios, J.M. (2008). "Cyp1A1, mEH and GSTM1 polymorphisms and risk of oral and pharyngeal cancer: A Spanish case-control study". Journal of Oncology. Volume 2008, Article ID 741310, 11 pages.
mEH is encoded by EPHX1 gene. This gene gets involved in metabolizing carcinogens present in tobacco. Genotypes of EPHX1 involved in high mEH activity were found to increase the risk of smoking-related cancers of the oral cavity, pharynx, and larynx. Polymorphism in EPHX1 gene was found to be a genetic determinant in smoking-induced cancers.
Mironova, J.N., Mitrunen, K., Bouchadry, C., Dayer, P., Benhamou, S. and Hirvonen, A. (2000). "High-activity Microsomal epoxide hydrolase genotypes and the risk of oral, pharynx and larynx cancer", Cancer Research. 60, 534-536.
The frontline chemotherapeutic regimen for NPC was a combination of Cisplatin with 5-fluorouracil. A novel derivate of gossypol called ApoG2 can help kill nasopharyngeal carcinoma (NPC) cells by causing inhibition of the antiapoptotic function of the Bcl-2 proteins.
Hu, Z.Y., Sun, J., Zhu, X.F., Yang, D. and Zeng, Y.X. (2009). "ApoG2 induces cell cycle arrest of nasopharyngeal carcinoma cells by suppressing the c-Myc signaling pathway". J Transl Med. 23, 7-74.
ZD6474 has an anti-proliferative effect on the human nasopharyngeal carcinoma (NPC.
Xiao, X., Wu, J., Zhu, X., Zhao, P., Zhou, J., Liu, Q.Q., Zheng, L., Zeng, M., Liu, R. and Huang, W. (2007). "Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase". Int J Cancer. 121(9):2095-2104.
2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) was found to inhibit human HK-1 proliferation and in vitro and in vivo inhibition of CNE-2 nasopharyngeal carcinoma (NPC).
Nguyen, T.H., Ong, C.K., Wong, E., Leong, C.T., Panasci, L. and Huynh, H. (2005). "2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) exhibits p53-dependent and -independent antiproliferative activity in human nasopharyngeal carcinoma cells in vitro and in vivo". Int J Oncol. 27(4):1131-1140.
The polymorphism of CYP1A1 m1 involves a T-C substitution in the 3' noncoding region of the gene thus creating a MspI restriction enzyme cleavage site. The polymorphism occurs due to an A to G substitution at nucleotide 4889 in exon 7 of the gene. This further leads to the substitution of isoleucine by valine at the amino acid position 462 of the protein. This region is known to encode a CYP1A1 heme-binding domain. The CYP1A1 m3 polymorphism, creating a MspI site, is found only in Africans Americans, so may not be important in association study. The polymorphism of CYP1A1 m4 involves C to A substitution resulting in substitution of threonine by asparagine at 461 amino acid of the protein.
Roy, B. and Sikdar, N. (2003). "Polymorphisms in Drug-metabolizing Genes and Risk of Head and Neck Squamous Cell Carcinoma". Int J Hum Genet. 3(2): 99-108.
Cytochrome P450 2A6 (CYP2A6) is responsible for the metabolism of nicotine.
Sellers, E.M., Tyndale, R.F. and Leona C.F. (2003). "Decreasing smoking behaviour and risk through CYP2A6 inhibition". Drug Discovery Today. 8(11), 487-493.
CYP1A1, CYP1A2, CYP2A6, and CYP1B1 are the main isoforms of cytochrome P450 oxidizing PAH and other xenobiotics. Polymorphism of these genes influences the activity of the enzyme and, respectively, the activity of carcinogen. A significant amount of CYP1A1 is found only in smokers. CYP1A2 is expressed in liver tissue and is induced by the same xenobiotics as CYP1A1. CYP1A2 is necessary for metabolic activation of pro-carcinogen aryl amines and heterocyclic amines formed under thermal treatment of food. CYP1B1 isoform oxidizes estrogens with the formation of 4-oxy-derivative, which can be easily converted to highly active metabolite inducing cell dysfunction and possibly transformation. The level of CYP1B1 isoform is relatively high in estrogen-dependent organs in women. The GST and NAT families are the most studied phase II genes.
Zaridze, D.G. (2008). "Molecular Epidemiology of Cancer". Biochemistry (Moscow). 73(5), 532-542.
In a tumour analytical study the point mutation in the p53 was at codon 117 located in exon 2 of p21 gene which resulted in an amino acid substitution of Cys-->Tyr.
Ibrahim, S.O., Lillehaug, J.R. and Vasstrand, E.N. (2003). "Mutations of the cell cycle regulatory genes p16INK4A and p21WAF1 and the metastasis-inducing gene S100A4 are infrequent and unrelated to p53 tumour suppressor gene status and data on survival in oropharyngeal squamous cell carcinomas". Anticancer Res. 23(6C), 4593-600.
CpG island hypermethylation was found to inactivate the promoter of CDKN2 that is responsible for the coding of a cyclin dependent kinase inhibitor p16INK4a.
Temam, S., Bénard, J., Dugas, C., Trassard, M., Gormally, E., Soria, J.C., Faivre, S., Luboinski, B., Maranda, P., Hainaut, P., Lenoir, G., Mao, L. and Janot, F. (2005). "Molecular Detection of Early-Stage Laryngopharyngeal Squamous Cell Carcinomas". Clin Cancer Res. 11(7), 2547- 2551.
To interact with the cellular macromolecules such as DNA, chemical carcinogens like tobacco-specific polycyclic hydrocarbons and nitrosamines as well as alcohols require activation by phase I oxidative enzymes like cytochrome P450 (CYP1A1, CYP1B1, CYP2E1, CYP2C19, CYP2D6 and CYP2A6).
Ruwali, M. and Parmar, D. (2010). "Association of functionally important polymorphisms in cytochrome P450s with squamous cell carcinoma of head and neck". Indian Journal of Experimental Biology. 48, 651-655.
The NPCA2 gene plays a role in altering the susceptibility to nasopharyngeal carcinoma.