**6.1 Leukoplakia**

planus (OLP)

### *6.1.1 Clinical presentations*

White or Grayish Patches: The primary characteristic of leukoplakia is the presence of white or grayish patches or plaques on the oral mucosa. These patches can vary in size, shape, and texture [18].

Non-Removability: Leukoplakia patches cannot be scraped off or wiped away. They are firmly attached to the underlying tissues and persist despite gentle manipulation [45].

Irregular Borders: The borders of leukoplakia patches may appear well-defined or irregular [46].

*Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

Surface Texture: The surface of the patches can be smooth, rough, or fissured [46].

Thickness: Leukoplakia patches may be flat or slightly raised and can have a thickened consistency [46].

Asymptomatic: In many cases, leukoplakia does not cause any symptoms and is discovered during routine oral examinations. However, some individuals may experience a burning sensation or sensitivity to spicy foods [47].

#### *6.1.2 Histopathological findings*

Histopathological examination of leukoplakia is essential for confirming the diagnosis and assessing the degree of dysplasia (abnormal cell changes). The histopathological features of leukoplakia can vary depending on the severity of dysplasia and the specific characteristics of the lesion. Here are the detailed histopathological features commonly observed in leukoplakia [45–47]:

Hyperkeratosis: Hyperkeratosis refers to an excessive accumulation of keratin, the tough, protective protein found in the outermost layer of the skin. In leukoplakia, there is often hyperkeratosis present in the epithelial layer of the lesion. This thickening of the superficial layer contributes to the characteristic white appearance of leukoplakia.

Acanthosis: Acanthosis refers to the thickening of the epithelial layer due to an increase in the number of cell layers. In leukoplakia, acanthosis can be observed in varying degrees. It indicates cellular proliferation and an alteration in the normal architecture of the oral mucosa.

Epithelial Dysplasia: Dysplasia refers to abnormal changes in the size, shape, and organization of cells within the epithelium. In leukoplakia, varying degrees of dysplasia can be observed, ranging from mild to severe. The presence of dysplasia is an important indicator of the potential for malignant transformation.


Inflammatory Infiltrate: Inflammatory cells, such as lymphocytes and plasma cells, may be present within the underlying connective tissue of leukoplakia. The presence and extent of inflammation can vary and may indicate the body's response to dysplastic changes or other underlying factors.

It is important to note that the histopathological features of leukoplakia can vary from case to case. Additionally, the degree of dysplasia observed in the histopathological examination plays a significant role in determining the potential for malignant transformation. Regular histopathological evaluation and close clinical

monitoring are necessary for appropriate management and treatment decisions in individuals with leukoplakia.

#### **6.2 Erythroplakia**

#### *6.2.1 Clinical presentations*

Erythroplakia is a potentially malignant oral lesion characterized by a distinct red patch or plaque on the mucous membranes of the oral cavity. It is present as a clinical entity that requires thorough evaluation and monitoring due to its high risk of malignant transformation. Here is a detailed description of the clinical presentation of erythroplakia [45–47]:

Erythematous Appearance: Erythroplakia appears as a persistent, bright red or deep red patch, or plaque on the oral mucosa. The red coloration is due to various factors, such as increased blood vessel dilation, inflammation, and changes in the epithelial cells.

Smooth or Granular Texture: The surface of erythroplakia can range from smooth and velvety to granular or irregular. It may have a slightly raised or flat appearance.

Non-Removable: Unlike some benign conditions, the red patch of erythroplakia cannot be easily wiped off or scraped away. It is firmly attached to the underlying tissues.

Borders: The borders of erythroplakia lesions are typically irregular or ill-defined. They may blend with the surrounding normal tissue or have a distinct demarcation. The border irregularity is an important characteristic that distinguishes erythroplakia from normal or benign oral mucosa.

Size and Shape: Erythroplakia can range in size from a few millimeters to several centimeters in diameter. The size of the lesion is not indicative of its malignant potential. Erythroplakia can have various shapes, including irregular, oval, or irregularly outlined.

Sites of Involvement: Erythroplakia commonly affects the dorsal surface of the tongue, particularly the posterior and lateral borders. It may also involve the ventral surface or appear as a patch underneath the tongue. The area beneath the tongue, known as the floor of the mouth, is another common site for erythroplakia. Erythroplakia may rarely involve the soft palate at the back of the mouth or the tonsillar area.

Asymptomatic: Erythroplakia is often asymptomatic in its early stages. It may be discovered incidentally during routine dental examinations or self-examinations. As the lesion progresses or becomes more advanced, individuals may experience slight discomfort, including a burning sensation or tenderness at the site of erythroplakia. In some cases, erythroplakia may bleed spontaneously or after minor trauma. However, bleeding is not a consistent feature and may occur in advanced or ulcerated lesions.

#### *6.2.2 Histopathological findings*

Histopathological examination of erythroplakia is crucial for assessing its malignant potential and guiding appropriate management. The histopathological characteristics of erythroplakia reveal cellular and tissue changes that indicate its status and progression toward malignancy. Here is a detailed description of the histopathological features commonly observed in erythroplakia [18, 45–47]:

#### *Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

Epithelial Hyperplasia: Erythroplakia often demonstrates varying degrees of epithelial hyperplasia, characterized by an increase in the number of epithelial layers. The basal layer may show increased cellularity and abnormal cell proliferation. The maturation process of the epithelial cells may be disturbed, leading to a lack of normal differentiation from basal to superficial layers. The epithelium may exhibit a disordered or irregular arrangement of cells with loss of normal cell maturation.

Dysplasia: Dysplastic changes are commonly observed in erythroplakia and indicate a higher risk of malignant transformation. Dysplasia refers to the presence of abnormal cellular and nuclear features within the epithelial layers.

Cellular Atypia: Dysplastic cells exhibit varying degrees of cellular atypia, including increased nuclear-to-cytoplasmic ratio, nuclear pleomorphism (variation in size and shape), hyperchromatism (increased nuclear staining), and increased mitotic activity.

Loss of Architectural Orientation: The dysplastic epithelium may demonstrate loss of normal architectural orientation, with a disorderly arrangement of cells and loss of polarity.

Chronic Inflammation: Inflammatory infiltrates, mainly consisting of lymphocytes and plasma cells, may be present in the connective tissue beneath the dysplastic epithelium. Chronic inflammation is a common feature due to the ongoing tissue reaction to the potentially malignant process.

Vascular Dilatation: Erythroplakia is characterized by a red appearance, indicating increased vascularity. Histopathologically, this is manifested by dilated and congested blood vessels within the lamina propria of epithelial-connective tissue interface.

Epithelial Dysjunction: The junction between the dysplastic epithelium and the underlying connective tissue may show irregularities or epithelial dysjunction. This loss of adhesion between the epithelium and connective tissue is indicative of potential invasive behavior.

Basement Membrane Alterations: Erythroplakia may demonstrate alterations in the basement membrane, which serves as a barrier between the epithelium and connective tissue. These alterations may include thickening, fragmentation, or disruptions in the basement membrane structure.

In advanced cases, erythroplakia may exhibit features of carcinoma *in situ*, where dysplastic changes involve the full thickness of the epithelium without invasion into the underlying connective tissue. Histopathological examination of erythroplakia helps determine the severity of dysplasia, identify any signs of invasive behavior, and guide appropriate management decisions, such as close monitoring, surgical excision, or other interventions.

#### **6.3 Oral submucous fibrosis (OSF)**

#### *6.3.1 Clinical presentations*

Clinical manifestations of oral submucous fibrosis (OSF) involve various changes in the oral cavity, including the mucosa, underlying connective tissue, and associated structures. The severity and progression of these manifestations can vary among individuals. Here are the detailed clinical manifestations and oral involvement commonly observed in OSF [18, 45–47]:

Mucosal Changes: Trismus is one of the hallmark features of OSF. As the fibrosis progresses, the fibrous bands in the oral mucosa cause a gradual reduction in mouth opening. Severe cases may result in significant limitation of jaw movement, making it difficult to eat, speak, or perform oral hygiene procedures. The oral mucosa affected by OSF often appears pale or opaque due to the fibrotic changes and reduced vascularity. The mucosa may have a leathery texture upon palpation. The fibrotic bands in OSF lead to a loss of elasticity in the oral mucosa. The affected tissues feel rigid and less pliable compared to normal mucosa.

Gingival Changes: The gingival tissues may become fibrotic and exhibit a firm leathery consistency. This fibrosis can lead to gingival recession, increased attachment loss, and impaired periodontal health. Fibrotic gingiva may restrict proper tooth brushing and flossing, leading to difficulties in maintaining oral hygiene. This can contribute to the progression of oral diseases, such as dental caries and periodontal disease.

Tongue Involvement: The tongue can be affected by fibrosis in OSF, resulting in reduced tongue mobility and firm consistency. This can lead to difficulties in speaking, swallowing, and articulating certain sounds. The filiform papillae on the dorsum of the tongue may progressively disappear due to fibrotic changes. This can result in a smooth or depapillated appearance of the tongue surface.

Cheek and Lip Changes: The fibrotic changes in OSF can affect the buccal mucosa, leading to a firm, rigid consistency, and reduced flexibility. This can result in difficulty in mouth opening, speaking, and chewing. Fibrosis of the lip mucosa may occur in OSF, causing a tightening or puckering of the lip tissues. This can lead to difficulty in lip movement, affecting functions such as smiling and speaking.

Other Manifestations: Many individuals with OSF experience a burning sensation or discomfort in the affected areas, particularly while consuming spicy or hot foods. In advanced stages of OSF, the fibrotic oral mucosa may become fragile and prone to ulceration. These ulcers can cause pain and increase the risk of secondary infections.

Malignant Transformation: OSF carries a potentially malignant nature, with an increased risk of oral cancer development. Oral leukoplakia, erythroplakia, and other dysplastic changes may be observed in OSF, indicating a higher risk of malignant transformation.

#### *6.3.2 Histopathological findings*

Histopathological examination of tissues affected by oral submucous fibrosis (OSF) reveals characteristic findings that help in confirming the diagnosis. Here are the detailed histopathological findings commonly observed in OSF [18, 45–47]:

Epithelial Changes: The epithelium may show varying degrees of atrophy, characterized by thinning of the epithelial layers. The superficial layers of the epithelium often exhibit hyperkeratosis, with an increased accumulation of keratinized cells. Epithelial dysplasia, characterized by cellular and nuclear atypia, may be observed in some cases of OSF. Dysplasia is considered a premalignant condition and indicates an increased risk of malignant transformation.

Fibrosis and Connective Tissue Changes: One of the key histopathological features of OSF is the presence of dense fibrosis in the subepithelial connective tissue. Fibrosis is mainly composed of collagen fibers and may extend into the deeper connective tissue layers. The collagen fibers in the fibrotic areas appear hyalinized and densely packed. They replace the normal loose connective tissue architecture. Increased numbers of fibroblasts, along with myofibroblasts, can be observed within the fibrotic areas. These cells are responsible for the excessive production and deposition of collagen. Vascular changes, such as hyalinization and obliteration of blood vessels,

*Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

may be seen in the fibrotic regions. These changes contribute to reduced vascularity and impaired tissue nutrition.

Inflammatory Infiltrate: A chronic inflammatory infiltration composed of lymphocytes, plasma cells, and occasionally, eosinophils, is often present in the subepithelial region. This inflammatory infiltrate is believed to contribute to the fibrogenic process in OSF. Various pro-inflammatory cytokines and growth factors, such as transforming growth factor-beta, interleukin-6, and tumor necrosis factoralpha, are upregulated in OSF. These molecules play a role in fibroblast activation and collagen synthesis.

Basement Membrane Changes: The basement membrane underlying the epithelium may show thickening and hyalinization. This alteration is believed to be a result of collagen deposition and fibrotic changes.

It is important to note that the severity and extent of these histopathological findings can vary among different individuals and at different stages of OSF. The presence of subepithelial fibrosis, along with epithelial changes and chronic inflammation, is considered essential for the diagnosis of OSF. However, histopathological examination alone may not be sufficient, and a correlation with clinical findings is necessary for accurate diagnosis and management.

#### **6.4 Oral lichen planus (OLP)**

Oral Lichen Planus (OLP) is a persistent inflammation of the buccal, lingual, palatal, and gingival mucosa of the oral cavity. It occurs when one's natural immunity erroneously assaults the healthy epithelium of the oral cavity, causing inflammation and tissue damage. OLP is a kind of lichen planus that can affect the skin, nails, scalp, and genitalia [48, 49].

#### *6.4.1 Clinical presentations*

Oral lichen planus (OLP) can manifest in a variety of clinical manifestations that differ from person to person. However, OLP has the following clinical representations [50]:

Reticular Pattern: The reticular form of OLP is the most common, and it is distinguished by a white, lacy, or web-like pattern on the oral mucosa. Wickham's striae are patterns that can form on the inner lining of the cheeks, tongue, gums, and other regions. The reticular pattern is usually asymptomatic and can be discovered by chance during a standard dental examination.

Erosive/Ulcerative Lesions: OLP can cause erosions or ulcers on the oral mucosa in some circumstances. These areas may appear red, raw, or eroded and may cause pain, burning sensations, or discomfort, especially when eating spicy or acidic meals. The erosive form of OLP might make it difficult to speak or swallow.

Atrophic Lesions: Atrophic OLP is distinguished by oral mucosa thinning and smoothness. The affected areas may appear glossy or shiny, as well as white or erythematous. Atrophic lesions are frequently related with food or drink sensitivities.

Bullous Lesions: In rare situations, OLP may show blister-like lesions known as bullae, which are fluid-filled sacs that can burst and leave erosions or ulcers behind. Bullous OLP can be unpleasant and cause discomfort or problems with oral function.

Plaque-like Lesions: Plaque-like lesions, which are raised areas of the oral mucosa, may appear in some people with OLP. These lesions may be white or gray in appearance and may cause discomfort or irritation.

Oral Symptoms: OLP can cause a burning or stinging sensation, dryness or changed salivary flow, altered taste sensation (dysgeusia), or the sensation of a foreign body in the mouth.

Gingival Involvement: OLP can damage the gingiva (gums) in some situations, causing redness, irritation, and desquamation (peeling) of the gum tissue.

#### *6.4.2 Histopathological findings*

The histopathological investigation is critical in diagnosing oral lichen planus (OLP) and distinguishing it from other oral diseases. The primary histopathological findings linked with OLP are as follows [18, 45, 50]:

Epithelial Changes: OLP is characterized by different epithelial alterations in the oral mucosa. These changes may include acanthosis (epithelial thickening), hyperkeratosis (epithelial thickening on the outside), and uneven or sawtooth rete ridges (elongation and thickening of the ridges between epithelial rete pegs).

Basal Cell Degeneration: The presence of basal cell degeneration is one of the defining histological markers of OLP. This is caused by liquefaction degeneration of the basal cell layer, which is characterized by basal cell adhesion loss and disruption of the basal cell layer's normal architecture.

Inflammatory Infiltrate: OLP is distinguished by a thick and band-like inflammatory infiltrate in the oral mucosa's underlying connective tissue. T-lymphocytes make up the majority of the infiltration, along with other immune cells such as macrophages and the occasional plasma cell. The inflammatory infiltration is frequently found in the subepithelial region and extends into the connective tissue papillae.

Civatte Bodies: Civatte bodies, also known as colloid bodies or apoptotic bodies, are histological abnormalities that are common in OLP. They are eosinophilic, tiny, spherical formations that reflect degenerated or apoptotic epithelial cells. These entities can be seen distributed throughout the epithelium and the underlying connective tissue.

Hypergranulosis: Hypergranulosis is the thickening and prominence of the granular layer in the epithelium. This feature is seen in OLP and is linked to aberrant keratinization of the oral mucosa.

Subepithelial Fibrosis: Subepithelial fibrosis may be found in more chronic or longterm cases of OLP. This is caused by the deposition of collagen fibers behind the epithelium, resulting in a thicker and fibrotic look.

It is vital to note that the histopathological findings in OLP differ depending on the disease's stage and severity. Furthermore, because some of these characteristics can be seen in other oral illnesses, histological testing is an important tool for correct diagnosis and differentiation from other disorders.

OLP is often diagnosed based on clinical characteristics along with histological results. For an appropriate diagnosis, a qualified pathologist with experience in oral pathology must assess the biopsy material and link the histological findings with the clinical presentation.

Understanding genetic alterations in the malignant transformation of the potentially malignant disorders of the oral and maxillofacial region.

The transformation of potentially malignant disorders into malignancies is heavily influenced by genetic alterations. These disorders, alternatively termed precursor lesions or intraepithelial neoplasia, encompass abnormal changes in tissue that possess the capacity to progress into cancerous conditions if not appropriately addressed and treated.

### *Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

Oral cancer typically develops due to cellular alterations. When multiple epithelial cells undergo genetic changes, it is referred to as field cancerization. The initiation of this process is often triggered by oral lesions, which can be categorized as oral potentially malignant disorders. These potentially malignant lesions exhibit genetic instability, resulting in gains or losses of chromosomal material and alterations in nucleotide sequences. Even the border of malignant lesions, some oral cancer specimens show genetic changes. Over the past decade, research has highlighted the crucial role of aberrant DNA methylation in the development of oral cancer. However, oral carcinoma is influenced by various factors related to genetics [51].

During the progression from a potentially malignant lesion to cancer, several genetic alterations can accumulate, leading to uncontrolled cell growth, impaired cell death, and other hallmarks of malignancy. Here are essential insights concerning genetic alterations in the process of turning potentially malignant disorders into malignancies:

1.Oncogenes: Oncogenes are modified versions of normal genes, known as protooncogenes, responsible for regulating cell growth and division. Genetic changes, such as mutations, amplifications, or translocations, can transform protooncogenes into active oncogenes, leading to continuous activation. This persistent activation drives increased cell proliferation and survival, facilitating the progression of potentially malignant disorders into cancer.

Oncogenes can be classified in accordance with the functions of their normal association (proto-oncogenes) in the biochemical pathways that controls sequestration and growth. These include in the following table (**Table 3**) [13]:


**Table 3.**

*Classification of oncogenes with their function and mutational impact.*

2.Growth Factor Receptors: In human tumors, the activation of growth factor receptors involves gene rearrangements, mutations, and overexpression. The development of cancer and stem cells is influenced by specific signaling pathways such as the MAP-Kinase/ERK pathway, the JAK/STAT pathway, the NOTCH signaling pathway, the PI3K/AKT pathway, the Wnt pathway, and the TGF-β pathways.

Dysregulation of growth factor receptors in oral carcinogenesis occurs due to increased production and autocrine stimulation. Carcinogenesis is characterized by irregular expression of transforming growth factor alpha (TGF-α) and beta (TGF-β) [13].


*Genetic Revelation of the Potentially Malignant Disorders in the Oral and Maxillofacial… DOI: http://dx.doi.org/10.5772/intechopen.112697*

Gene silencing occurs when high-level expression changes due to altered gene transcription, driven by the influence of epimutations. This alteration disrupts the interplay between activators and suppressors on specific promoters within the context of chromatin. Consequently, disruptions in epigenetic mechanisms lead to the development of carcinomas and other epigenetic disorders by causing inappropriate gene expression [51].


This had already been shown in the investigation of Huang et al. that Ras/PI3K/ AKT pathways were turned on in the patient (50%) treated with radiotherapy in corporation with RASSF1A/RASSF2A gene silencing due to methylation. Another study from Imai T et al. investigated that RASSF2 methylated in 26% of OSCC [52, 56].


and programmed cell death ligand (PDL)-1 is evident. Additionally, reduced levels of T cell CD3+ and augmented T helper 1 infiltration play significant roles in the development and progression of cancer associated with OPMDs [52].

18.Microsatellite Instability (MSI): MSI refers to the accumulation of errors in DNA microsatellites, repetitive DNA sequences found throughout the genome. Addition or deletion of microsatellite base pairs, known as microsatellite instability (MSI), is another cytogenetic feature shared by precancerous cells and OSCC [54]. In potentially malignant disorders, MSI can arise due to alterations in DNA mismatch repair genes. MSI can lead to the inactivation of tumor suppressor genes and the activation of oncogenes, contributing to cancer progression [50].
