Leukoplakia (Clinical)

Overview

Definition^[1,4]

• A white patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes or plaque Plaque Primary Skin Lesions
• Considered a potentially malignant disorder

Epidemiology^[1,4,12]

• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency:
  • Global: 1.5%–4.3%
  • More prevalent in Southeast Asia ASIA Spinal Cord Injuries
• 80% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are > 40 years of age.
• Affects more men than women
• Annual 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 rate: 0.6%–20%

Risk factors^[2,4,12]

Risk factors are similar to those for 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).

• Tobacco use (most common risk factor): smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases and, especially, chewing
• Alcohol consumption 
• Increasing age
• Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease:
  • 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)
  • Chronic 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 (insufficient evidence to consider this an “oral potentially malignant disorder”)^[10]

Pathophysiology^[3]

• Exposure to carcinogens Carcinogens Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogenesis → genetic damage or mutations regulating cell turnover and death
  • Variants in cancer driver 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 containing functionally damaging variants have also been identified.
  • Basis for progression to oral cancer Oral cancer Oral cancer includes neoplasms arising from the oral mucosa, tonsils, and salivary glands. More than 90% of oral cancers are squamous cell carcinoma (SCC). Risk factors include premalignant lesions, tobacco chewing/smoking, alcohol consumption, and HPV infection. Oral Cancer^[6]
• Occurrence of cell proliferation and hyperkeratosis Hyperkeratosis Ichthyosis Vulgaris
• Recurrent exposure to carcinogens Carcinogens Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogenesis → dysplasia
  • Dysplasia may progress from mild → moderate → severe
  • Carcinoma in situ Carcinoma in situ A lesion with cytological characteristics associated with invasive carcinoma but the tumor cells are confined to the epithelium of origin, without invasion of the basement membrane. Leukoplakia ( CIS CIS Multiple Sclerosis) develops → malignancy Malignancy Hemothorax
• Fibroblast growth factor Fibroblast growth factor A family of small polypeptide growth factors that share several common features including a strong affinity for heparin, and a central barrel-shaped core region of 140 amino acids that is highly homologous between family members. Although originally studied as proteins that stimulate the growth of fibroblasts this distinction is no longer a requirement for membership in the fibroblast growth factor family. X-linked Hypophosphatemic Rickets receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 1 (FGFR1):^[7]
  • Associated with oral epithelial dysplasia grade
  • FGFR1 expression can be analyzed by immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency and is associated with a higher risk of 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.

Clinical Presentation

General findings^[4]

• Patches Patches Vitiligo or plaques:
  • Affect mucosa
  • Tend to be bright white
  • Cannot be scraped off 
• Lesions are asymptomatic.

Homogeneous leukoplakia Homogeneous Leukoplakia Leukoplakia^[12‒14]

This form is less likely to be malignant and is characterized by:

• Uniformly white plaques 
• Well-defined margins

Nonhomogeneous 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^[12,14]

Nonhomogeneous 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 presents a higher risk of 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 and may appear:

• Irregular
• Speckled (white and red)
• Granular
• Nodular
• Verrucous/ exophytic Exophytic Retinoblastoma

Locations^[4,10]

• Oral cavity (most common):
  • 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
  • Buccal mucosa Buccal mucosa Oral Cancer
• Genitalia 
• Esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: Anatomy 
• 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
• Bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess

Diagnosis and Management

Diagnosis^[12‒14]

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 is a clinical term and diagnosis of exclusion. There are no specific histopathologic characteristics to define 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, but biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is performed to evaluate for dysplasia and to rule out other conditions. Potential findings may include:

• Hyperkeratosis Hyperkeratosis Ichthyosis Vulgaris with increased thickness of the stratum corneum Stratum corneum Skin: Structure and Functions
• Parakeratosis Parakeratosis Persistence of the nuclei of the keratinocytes into the stratum corneum of the skin. This is a normal state only in the epithelium of true mucous membranes in the mouth and vagina. Actinic Keratosis (retention of nuclei in the stratum corneum Stratum corneum Skin: Structure and Functions)
• Epidermal hyperplasia Epidermal Hyperplasia Leukoplakia
• Atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation
• Dysplasia, CIS CIS Multiple Sclerosis, or invasive carcinoma may be present.

General management^[4,14]

• Goal of treatment is to prevent oral SCC:
  • However, there is limited evidence and no expert consensus on the approach.
  • Treatment choice is based on:
    • Lesion size
    • Lesion type
    • Grade of histopathologic dysplasia
    • Patient preference
    • Clinician Clinician A physician, nurse practitioner, physician assistant, or another health professional who is directly involved in patient care and has a professional relationship with patients. Clinician–Patient Relationship experience
• Close surveillance Surveillance Developmental Milestones and Normal Growth is indicated: no specific guidance, but consider follow-up every 3‒6 months (adjusted based on risk, new lesions/recurrence, and patient preference)^[14]
• Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of risk factors for all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship, including smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases and alcohol use

Medical therapy^[9,14]

Medical therapy has very limited evidence available, and no reduction in the risk of SCC has been noted. The following have been used in an effort to heal lesions, but relapse Relapse Relapsing Fever is common:

• Vitamin A Vitamin A Retinol and derivatives of retinol that play an essential role in metabolic functioning of the retina, the growth of and differentiation of epithelial tissue, the growth of bone, reproduction, and the immune response. Dietary vitamin A is derived from a variety of carotenoids found in plants. It is enriched in the liver, egg yolks, and the fat component of dairy products. Fat-soluble Vitamins and their Deficiencies
• Retinoids Retinoids Retinol and derivatives of retinol that play an essential role in metabolic functioning of the retina, the growth of and differentiation of epithelial tissue, the growth of bone, reproduction, and the immune response. Dietary vitamin A is derived from a variety of carotenoids found in plants. It is enriched in the liver, egg yolks, and the fat component of dairy products. Fat-soluble Vitamins and their Deficiencies
• Carotenoids Carotenoids The general name for a group of fat-soluble pigments found in green, yellow, and leafy vegetables, and yellow fruits. They are aliphatic hydrocarbons containing 4 terpene subunits. Leukoplakia
• NSAIDs NSAIDS Primary vs Secondary Headaches
• Chemotherapeutic agents

Surgical management^[8,14]

• Options:
  • Surgical excision
  • Laser ablation
  • Cryosurgery
• “Destructive therapies” do not allow for histopathology of the entire lesion, which may have foci or high-grade dysplasia or occult malignancy Malignancy Hemothorax.
• Recommended for:
  • Lesions with moderate-to-severe dysplasia on biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 
  • Nonhomogeneous 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

Photodynamic therapy Photodynamic Therapy Actinic Keratosis^[8]

• An alternative to other surgical options
• Less invasive
• Combined with laser irradiation: 85% complete remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches

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^[11‒14]

• A minority of cases will resolve spontaneously.
• Lesions with nonhomogeneous clinical features have an almost 5-fold higher chance of recurrence after treatment.
• Features with higher risk of 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:
  • Nonhomogeneous 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 in nonsmokers
  • Location: 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 and floor of the mouth
  • Size > 200 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 Myeloma²

Differential Diagnosis

• 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: a superficial fungal infection caused by 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 species. 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 can commonly occur 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, genitals, and 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 folds. Infection of 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 presents as white plaques that bleed when scraped. The diagnosis is based on a clinical exam and can be confirmed by the identification Identification Defense Mechanisms of yeast Yeast A general term for single-celled rounded fungi that reproduce by budding. Brewers’ and bakers’ yeasts are saccharomyces cerevisiae; therapeutic dried yeast is yeast, dried. Mycology on a KOH wet mount. 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 can be treated with oral antifungal Antifungal Azoles medications.
• 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): a condition caused by the malignant proliferation of atypical keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions. 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) is the 2nd most common 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 malignancy Malignancy Hemothorax and usually affects the sun-exposed areas of light-skinned patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. 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) presents as a firm, erythematous, keratotic plaque Plaque Primary Skin Lesions or papule Papule Elevated lesion < 1 cm in diameter Generalized and Localized Rashes. A biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is used to confirm the diagnosis. Surgical excision is the mainstay of management.
• Erythroplakia Erythroplakia A condition of the mucous membrane characterized by erythematous papular lesions. Oral Cancer: a precancerous Precancerous Pathological conditions that tend eventually to become malignant. Barrett Esophagus lesion that is similar to 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, which develops from chronic tobacco and alcohol use. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship usually present with granular, red, sharply demarcated lesions. A biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma can show dysplastic keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions that can progress to invasive carcinoma. Erythroplakia Erythroplakia A condition of the mucous membrane characterized by erythematous papular lesions. Oral Cancer is commonly treated with surgical excision.
• Hairy leukoplakia Hairy leukoplakia Epithelial hyperplasia of the oral mucosa associated with epstein-barr virus and found almost exclusively in persons with HIV infection. The lesion consists of a white patch that is often corrugated or hairy. Epstein-Barr Virus: a lesion caused by EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus, mostly in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who are HIV HIV Anti-HIV Drugs positive. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship develop a white patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes 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. The patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes is often found on the lateral portion of the 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. Some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may experience mild pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, dysesthesia Dysesthesia Complex Regional Pain Syndrome (CRPS), and altered taste. Diagnosis is usually clinical, but biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma and immunocytopathology may be performed. Management includes antiviral Antiviral Antivirals for Hepatitis B medications, topical retinoids Retinoids Retinol and derivatives of retinol that play an essential role in metabolic functioning of the retina, the growth of and differentiation of epithelial tissue, the growth of bone, reproduction, and the immune response. Dietary vitamin A is derived from a variety of carotenoids found in plants. It is enriched in the liver, egg yolks, and the fat component of dairy products. Fat-soluble Vitamins and their Deficiencies, and cryotherapy Cryotherapy A form of therapy consisting in the local or general use of cold. The selective destruction of tissue by extreme cold or freezing is cryosurgery. Chondrosarcoma. Hairy leukoplakia Hairy leukoplakia Epithelial hyperplasia of the oral mucosa associated with epstein-barr virus and found almost exclusively in persons with HIV infection. The lesion consists of a white patch that is often corrugated or hairy. Epstein-Barr Virus may resolve spontaneously, and it is not premalignant..