Oral Cancer

Epidemiology and Etiology

Epidemiology

• Oral (mouth) cancer accounts for most head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess cancers.
• The majority is squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma (SCC) (SCC).
• Peak incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is in the 6th decade of life.
• Men > women by a 2:1 ratio
• Common in certain countries: Bangladesh, Sri Lanka, India, and Pakistan

Etiology

• Tobacco chewing/ smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
• Alcohol
• HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomavirus (HPV) infection
• Chronic mechanical irritation (badly positioned dentures)
• Low intake of fruits and vegetables
• Betel quid chewing (contains areca nut)
• Presence of precancerous Precancerous Pathological conditions that tend eventually to become malignant. Barrett Esophagus lesions:
  • Erythroplakia (red plaque Plaque Primary Skin Lesions)
  • Leukoplakia Leukoplakia Leukoplakia is a potentially malignant lesion affecting the squamous epithelium usually within the oral cavity. Leukoplakia can be associated with a history of chronic tobacco and alcohol use, both of which can synergistically damage the epithelium. Leukoplakia (white plaque Plaque Primary Skin Lesions)
  • Leukoerythroplakia (speckled plaque Plaque Primary Skin Lesions)
  • Oral lichen planus Oral Lichen planus Oral lesions accompanying cutaneous lichen planus or often occurring alone. The buccal mucosa, lips, gingivae, floor of the mouth, and palate are usually affected (in a descending order of frequency). Typically, oral lesions consist of radiating white or gray, velvety, threadlike lines, arranged in a reticular pattern, at the intersection of which there may be minute, white, elevated dots or streaks (Wickham’s striae). Lichen Planus
  • Oral submucous fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
  • Actinic or solar cheilitis
  • Oral discoid lupus erythematosus Discoid Lupus Erythematosus Alopecia
  • Chronic oral graft-versus-host disease Graft-versus-host disease The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the graft vs host reaction. Transfusion Reactions (GVHD)
• Risk for malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology:
  • ↑ With age
  • ↑ With the age of the lesion
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
  • ↑ With alcohol consumption
  • Depends on the anatomical site of the premalignant lesion

Pathophysiology

• Histopathology:
  • Over 90% of head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess cancer is SCC. 
  • The remainder is adenocarcinoma of the salivary gland Salivary gland Glands that secrete saliva in the mouth. There are three pairs of salivary glands (parotid gland; sublingual gland; submandibular gland). Diseases of the Salivary Glands with tumors mainly arising from the mucosal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology.
• SCC development:
  • Mutations and epigenetic changes accumulate, which affect the expression of oncogenes Oncogenes Genes whose gain-of-function alterations lead to neoplastic cell transformation. They include, for example, genes for activators or stimulators of cell proliferation such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of ‘v-‘ before oncogene symbols indicates oncogenes captured and transmitted by retroviruses; the prefix ‘c-‘ before the gene symbol of an oncogene indicates it is the cellular homolog (proto-oncogenes) of a v-oncogene. Carcinogenesis and tumor Tumor Inflammation suppressor genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
  • Major pathways:
    • Tobacco and alcohol: overexpressed p53 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
    • HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomavirus (HPV): inactivated Rb RB Chlamydia gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, leading to overexpressed p16 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Progression of squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology in response to toxin/ HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomavirus (HPV) exposure → hyperkeratosis Hyperkeratosis Ichthyosis Vulgaris → dysplasia → carcinoma in situ → cancer
• Anatomical sites frequently involved:
  • Lateral and ventrolateral tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy 
  • The floor of the mouth
  • Buccal mucosa
  • Retromolar trigone Trigone Urinary Tract: Anatomy: attached mucosa overlying the ascending ramus of the mandible Mandible The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. Jaw and Temporomandibular Joint: Anatomy (posterior to the last molar tooth) and extending superiorly to the maxillary tuberosity

Clinical Presentation

• Oral features:
  • Red or red-white lesion(s)
  • Persistent oral swelling Swelling Inflammation 
  • Mouth ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers
  • Sore tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy
  • Unexplained tooth mobility 
  • Unusual bleeding in the mouth
• Other related signs and symptoms:
  • Trismus Trismus Spasmodic contraction of the masseter muscle resulting in forceful jaw closure. This may be seen with a variety of diseases, including tetanus, as a complication of radiation therapy, trauma, or in association with neoplastic conditions. Tetanus
  • Difficulty swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility 
  • Halitosis
  • Jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy or facial swelling Swelling Inflammation
  • Painless neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess lump ( lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy)

Mnemonic

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is recommended for suspicious oral lesions lasting 3 or more weeks:

• Red
• Ulcer
• Lump
• Especially indurated (firm on palpation Palpation Application of fingers with light pressure to the surface of the body to determine consistency of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. Dermatologic Examination) lesion(s) or a combination of lesions

Diagnosis

Diagnostic approach

• Established by lesion biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
• Panendoscopy (to determine tumor Tumor Inflammation extent)
• Imaging (to locate metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis):
  • Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests
  • CT and MRI
  • PET-CT scans

Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

• TNM staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis for oropharyngeal cancers:
  • Primary tumor Tumor Inflammation (T):
    • TX: Primary tumor Tumor Inflammation cannot be assessed.
    • T0: no evidence of primary tumor Tumor Inflammation
    • Tis: carcinoma in situ
    • T1: tumor Tumor Inflammation ≤ 2 cm in greatest dimension
    • T2: tumor Tumor Inflammation > 2 cm but ≤ 4 cm
    • T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones: tumor Tumor Inflammation > 4 cm 
    • T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones: Tumor Tumor Inflammation invades adjacent structures (e.g., mandible Mandible The largest and strongest bone of the face constituting the lower jaw. It supports the lower teeth. Jaw and Temporomandibular Joint: Anatomy, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, muscle).
  • Regional lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy (N):
    • NX: Regional lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy cannot be assessed.
    • N0: no regional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
    • N1: metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis in a single, ipsilateral lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node ≤ 3 cm 
    • N2a: metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis in a single, ipsilateral lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node > 3 cm but < than 6 cm
    • N2b: metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis in multiple, ipsilateral lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy all < 6 cm in greatest dimension
    • N2c: metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis in bilateral or contralateral lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy all < 6 cm in greatest dimension
    • N3: metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis in any lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node > 6 cm
  • Distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis (M):
    • M0: no evidence of distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
    • M1: distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
• Spreading of the tumor Tumor Inflammation to a contralateral lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node is prognostically worse than spreading into multiple, ipsilateral lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy.

Management and Prognosis

Management

• Early cancer (stages I and II):
  • Surgical resection: > 3 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma tumor Tumor Inflammation invasion for stage I lesions; neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess dissection for stage II lesions
  • Radiotherapy if surgery is not feasible
• Locoregionally advanced cancer (stage III and IV): aggressive lesions, with a high rate of recurrence even with surgery or radiotherapy:
  • Surgery + neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess dissection:
    • Maxillectomy/mandibulectomy: bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types involvement 
    • Glossectomy: tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy involvement
    • Laryngectomy: larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx: Anatomy involvement
  • Followed by radiotherapy with or without chemotherapy Chemotherapy Osteosarcoma
• Inoperable tumors: radiotherapy or radiotherapy + chemotherapy Chemotherapy Osteosarcoma
• Additional management:
  • Cancer surveillance Surveillance Developmental Milestones and Normal Growth
  • Functional rehabilitation
  • Educate on tobacco cessation, alcohol cessation, and other high-risk factors.

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Five-year survival:
  • Early oral cancer: 82.5%
  • Locally advanced oral cancer: 54.7%
• Recurrence and 2nd primary malignancy Malignancy Hemothorax risk:
  • > 80% of stage III and IV cancers recur within 4-years posttreatment.
  • Frequent surveillance Surveillance Developmental Milestones and Normal Growth needed:
    • In the 1st 4 years
    • For patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with continued high-risk behavior (i.e. smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases, alcohol consumption)
• Most important factor in prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas: involvement of lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node(s)

Differential Diagnosis

• Aphthous stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis: round-to-oval, painful ulcers with a crater-like appearance on a yellow-gray base with erythematous margins. Mucosal ulcers are on nonkeratinized mucosal surfaces only. Recurrence of ulcers is common and does not involve systemic symptoms. Aphthous stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis commonly occurs after minimal trauma (e.g., tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy biting). Management is supportive. 
• Oral candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis: presents as white plaques on the oral mucosa Oral mucosa Lining of the oral cavity, including mucosa on the gums; the palate; the lip; the cheek; floor of the mouth; and other structures. The mucosa is generally a nonkeratinized stratified squamous epithelium covering muscle, bone, or glands but can show varying degree of keratinization at specific locations. Stomatitis, which can be scraped off with a tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy depressor. 90% of cases are due to Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis. Predisposing conditions include ill-fitting dentures, immunosuppression, and corticosteroid inhaler use. Oral candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis is common in pediatrics, particularly in small children. Management is with antifungal Antifungal Azoles mouthwash. 
• Herpetic gingivostomatitis Gingivostomatitis Herpes Simplex Virus 1 and 2: presents as painful, perioral vesicular lesions in clusters. The condition is contagious and caused by herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology type 1 Type 1 Spinal Muscular Atrophy. Herpetic gingivostomatitis Gingivostomatitis Herpes Simplex Virus 1 and 2 is more common in children and at 1st exposure to the herpes virus Herpes Virus Antivirals for Herpes Virus, which is also responsible for cold sores Cold sores Stomatitis caused by herpesvirus hominis. It usually occurs as acute herpetic stomatitis (or gingivostomatitis), an oral manifestation of primary herpes simplex seen primarily in children and adolescents. Labial and Genital Herpes and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever blisters. Management is supportive, but antivirals can be used.
• Herpangina Herpangina Acute types of coxsackievirus infections or echovirus infections that usually affect children during the summer and are characterized by vesiculoulcerative lesions on the mucous membranes of the throat; dysphagia; vomiting, and fever. Coxsackievirus: a common childhood illness often caused by group A coxsackieviruses. The presentation includes oral lesions (usually with a white base and a red border) and a prodrome Prodrome Symptoms that appear 24–48 hours prior to migraine onset. Migraine Headache of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, irritability, malaise Malaise Tick-borne Encephalitis Virus, sleeplessness, and headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess. The lesions typically involve the posterior pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy and may be very painful. Management is supportive.