Leukoplakia

Leukoplakia is a potentially malignant lesion affecting the 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 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 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. Leukoplakia presents as a white plaque that cannot be scraped off. Diagnosis is confirmed with a biopsy. The lesion can be surgically treated, but close observation is always recommended owing to the risk of malignant transformation.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

  • A white patch or plaque
  • Considered a potentially malignant disorder

Epidemiology

  • Prevalence:
    • Global: 1.5%–4.3%
    • More prevalent in Southeast Asia
  • 80% of patients are > 40 years of age.
  • Affects more men than women
  • Annual malignant transformation rate: 0.6%–20%

Risk factors

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.

  • Tobacco use (most common risk factor)
  • Alcohol consumption 
  • Increasing age
  • Infections: 
    • 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. Papillomaviridae: 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

Pathophysiology

  • Exposure to carcinogens → genetic damage or mutations regulating cell turnover and death
  • Occurrence of cell proliferation and hyperkeratosis
  • Recurrent exposure to carcinogens → dysplasia
    • Dysplasia may progress from mild → moderate → severe
    • Carcinoma in situ (CIS) develops → malignancy

Clinical Presentation

General findings

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

Homogeneous leukoplakia

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

  • Uniformly white plaques 
  • Well-defined margins

Nonhomogenous leukoplakia

Nonhomogenous leukoplakia presents a higher risk of malignant transformation and may appear:

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

Locations

  • Oral cavity (most common):
    • Tongue
    • Buccal mucosa
  • 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 
  • 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
  • Bladder

Diagnosis and Management

Diagnosis

Biopsy is required for a definitive diagnosis, to evaluate for dysplasia, and to rule out other conditions. Findings include:

  • Hyperkeratosis with increased thickness of the stratum corneum
  • Parakeratosis (retention of nuclei in the stratum corneum)
  • Epidermal hyperplasia
  • Atrophy
  • Dysplasia, CIS, or invasive carcinoma may be present.
Histologic images of oral leukoplakia

Histological images of oral leukoplakia demonstrating progressive dysplasia and malignant transformation:
A: Hyperkeratosis with low-grade dysplasia present
B: Moderate dysplasia
C: High-grade dysplasia
D: Leukoplakia in the state of becoming invasive carcinoma
E: Invasive carcinoma

Image: “Representative histological pictures of OPLs and OSCCs” by Yang Yi et al. License: CC BY 2.0

Management

  • Close surveillance is indicated.
  • Elimination of risk factors for all patients, including smoking and alcohol use
  • Medical therapy:
    • Vitamin A
    • Retinoids
    • Carotenoids
    • NSAIDs
  • Surgical management:
    • Options:
      • Surgical excision 
      • Laser ablation
      • Cryosurgery
    • Recommended for:
      • Lesions with moderate-to-severe dysplasia on biopsy 
      • Nonhomogeneous leukoplakia

Differential Diagnosis

  • 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 can commonly occur on the oral mucosa, 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. Structure and Function of the Skin folds. Infection of the oral mucosa presents as white plaques that bleed when scraped. The diagnosis is based on a clinical exam and can be confirmed by the identification of yeast on a KOH wet mount. Candidiasis can be treated with oral antifungal medications.
  • Squamous cell carcinoma: a condition caused by the malignant proliferation of atypical keratinocytes. Squamous cell carcinoma 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. Structure and Function of the Skin malignancy and usually affects the sun-exposed areas of light-skinned patients. Squamous cell carcinoma presents as a firm, erythematous, keratotic plaque or papule. A biopsy is used to confirm the diagnosis. Surgical excision is the mainstay of management.
  • Erythroplakia: a precancerous lesion that is similar to leukoplakia, which develops from chronic tobacco and alcohol use. Patients usually present with granular, red, sharply demarcated lesions. A biopsy can show dysplastic keratinocytes that can progress to invasive carcinoma. Erythroplakia is commonly treated with surgical excision.
  • Hairy leukoplakia: a lesion caused by EBV mostly in patients who are HIV positive. Patients develop a white patch on the oral mucosa. The patch 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. Oral Cavity: Lips and Tongue. Some patients may experience mild pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, dysesthesia, and altered taste. Diagnosis is usually clinical, but biopsy and immunocytopathology may be performed. Management includes antiviral medications, topical retinoids, and cryotherapy. Hairy leukoplakia may resolve spontaneously.

References

  1. Bishop, J.A., Sciubba, J.J., Taube, J.M. (2017). Leukoplakia and erythroplakia – premalignant squamous lesions of the oral cavity. In Anton, R. (Ed.). Medscape. Retrieved April 14, 2021, from https://emedicine.medscape.com/article/1840467-overview
  2. Sciubba, J.J., Narendan, A.R. (2017). Dermatologic manifestations of oral leukoplakia. In James, W.D. (Ed.). Medscape. Retrieved April 14, 2021, from https://emedicine.medscape.com/article/1075448-overview
  3. Harris, C.M. (2021). Oral leukoplakia. In Meyers, A.D. (Ed.). Medscape. Retrieved April 14, 2021, from https://emedicine.medscape.com/article/853864-overview
  4. Lodi, G. (2018). Oral leukoplakia. In Corona, R. (Ed.). UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/oral-leukoplakia
  5. Mohammed, F., Fairozekhan, A.T. (2020). Oral leukoplakia. [online] StatPearls. Retrieved April 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK442013/

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