Uppala Divya1, Paynni Padmini P2, Sindhuja Vaddadi1, Nikitha Rangu1

1-Department of Oral Pathology and Microbiology, Gitam Dental College And Hospital, Visakhapatnam

2– Indiana University Purdue University, Indianapolis

Running title – Updates in Oral Premalignancy and Malignancy

Received: 27-10-2023

Revised: 31-10-2023

Accepted: 3-11-2023

Address for correspondence: Dr. Divya Uppala, MDS, Professor and Head Of The Department, Department Of Oral Pathology And Microbiology, Gitam Dental College And Hospital, Q9jh+578, Gandhinagar Campus, Rushikonda, Visakhapatnam.

E mail – uppala.divya@gmail.com

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-Noncommercial ShareAlike 4.0 license, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms

How to cite this article: Uppala D, Paynni P P, Sindhuja V, Nikitha R. Exploring Current Trends in Premalignancy and Malignancies: Diagnostic, Prognostic, and Therapeutic Advancements. J Oral Biomed Sci 2023; 2(3):132-138

Abstract:

Premalignant lesions and malignancies present formidable challenges in contemporary healthcare, necessitating continuous advancements across diagnostic, prognostic, and therapeutic domains. This comprehensive review seeks to delve deeply into recent developments in the field, encompassing terminology evolution, classification systems, clinical determinants, molecular markers, genomic profiling, immunotherapy, and screening strategies. By synthesizing existing knowledge with recent research findings, this article aims to provide a nuanced understanding of the evolving landscape of oral potentially malignant disorders (OPMDs) and oral cancer, offering insights poised to revolutionize patient care paradigms.

Key words – Pre malignancy, malignancy, advances

Introduction:

Premalignant lesions and malignancies constitute a significant burden on global healthcare systems, manifesting in various forms across diverse populations. The introduction underscores the critical imperative of advancing diagnostic accuracy and refining treatment modalities to mitigate the impact of these conditions. Emphasizing the dynamic nature of the field, it highlights the perpetual need to stay abreast of emerging trends and innovations to enhance patient outcomes effectively1.

Evolution of Terminology in Precancerous Lesions: Tracing the Historical Context

The concept of “precancer” emerged in medical parlance in 1875, attributed to the pioneering work of Victor Babes, a distinguished Romanian physician. Initially, the term encompassed a broad spectrum of conditions across various organ systems, including junctional nevi and xeroderma pigmentosa of the skin, leukoplakia, and papillomas of the urinary bladder and larynx, as well as polyps of the colon and solitary adenomas of the thyroid. This conceptual framework evolved, reflecting advances in medical understanding and diagnostic precision2

In 1978, a seminal working group convened by the World Health Organization (WHO) delineated the terminology further, distinguishing between “lesions” and “conditions” within the overarching category of “precancer.” Precancerous lesions were defined as morphologically altered tissues wherein the risk of oral cancer surpassed that of their ostensibly normal counterparts. On the other hand, precancerous conditions denoted a generalized state associated with a significantly heightened predisposition to cancer development. Subsequent deliberations and empirical insights culminated in a pivotal workshop held in London in 2005, heralding a paradigm shift in terminology. Propelled by a desire for greater precision and clinical relevance, the consensus among experts favored the adoption of the term “Oral Potentially Malignant Disorders” (OPMDs), advocating for the retirement of the antiquated label “precancer.” This semantic transition signified a nuanced understanding of the dynamic interplay between epithelial alterations and oncogenic progression within the oral mucosa3.

Additionally, the WHO’s monograph on Head and Neck Tumors in 2005 introduced the term “epithelial precursor lesions,” encapsulating the evolving conceptualization of premalignant oral lesions. Defined as epithelial alterations exhibiting an increased propensity for progression to squamous cell carcinoma, this terminology underscored the progressive nature of malignant transformation inherent in certain oral pathologies. Furthermore, Manne RK proposed the term “potentially malignant disorders/individuals” to denote individuals lacking known predisposing disorders or clinically evident lesions, yet harboring oral mucosal susceptibilities to carcinogenesis. This conceptual refinement reflected a nuanced appreciation of the multifactorial etiology underpinning premalignant conditions, transcending simplistic dichotomies4.

Epidemiological research indicates that approximately 4.47% of the global populace may harbor Oral Potentially Malignant Disorders (OPMDs), with a notable concentration observed within the South Asian demographic. Men appear to be disproportionately affected, likely attributable to their higher rates of tobacco and alcohol consumption relative to women. Studies suggest that the prevalence of OPMDs varies among populations and is closely linked to lifestyle habits. Alarmingly, around 80% of oral cancer cases stem from OPMDs, underscoring the pivotal role of these precancerous conditions in disease pathogenesis. Moreover, the overall malignant transformation (MT) rate of OPMDs stands at 7.9%, highlighting the gravity of this public health challenge5.

Key entities identified as high-risk OPMDs include leukoplakia, proliferative verrucous leukoplakia (PVL), erythroplakia, oral lichen planus (OLP), oral submucous fibrosis (OSMF), actinic cheilitis, palatal lesions of reverse cigar smoking, discoid lupus erythematosus, dyskeratosis congenita, oral lichenoid lesions, and oral graft versus host disease. These entities represent focal points for diagnostic vigilance and therapeutic intervention, embodying the interface between premalignancy and malignant transformation within the oral cavity5.

Classification:

The primary aim of implementing a classification and grading system is to ensure consistent reporting and management practices while also facilitating the evaluation of lesions in epidemiological studies. Over the past two decades, more than 20 classification systems have been proposed to standardize grading systems for Oral Epithelial Dysplasia (OED). For a grading system to be clinically effective, it must be reproducible, and the histological assessment should accurately reflect the lesion’s malignant potential. Many of these systems draw inspiration from the classification of precursor lesions in other anatomical sites, such as Squamous Intraepithelial Neoplasia (SIN) of the cervix and the Ljubljana classification of the larynx6.

In the recently published 2017 WHO grading system, certain features present in the 2005 WHO classification, such as “squamous hyperplasia (acanthosis and basal cell hyperplasia)” and “carcinoma in situ (CIS),” have been omitted from the OED grading. The term CIS has been eliminated from the 2017 WHO classification and is now used interchangeably with severe dysplasia. Additionally, the cytological/cellular feature of “increase in nuclear size” from the 2005 WHO classification has also been removed from the 2017 WHO diagnostic criteria of OED. Instead, the architectural feature of “loss of epithelial cell cohesion” has been incorporated into the 2017 WHO diagnostic criteria6.

Oral squamous cell carcinoma (OSCC), the most prevalent type of head and neck cancer, has garnered significant attention from the scientific community. This is attributed to its exceptionally high incidence and mortality rates across numerous countries, along with its multifaceted social and economic ramifications for patients who survive this debilitating illness. The paradox surrounding OSCC lies in its ease of diagnosis, often prompted by routine oral examinations, juxtaposed with the staggering number of patients diagnosed at advanced stages. The consequences of late-stage diagnosis in OSCC are profound, impacting prognosis, patient quality of life, and imposing significant financial burdens on healthcare systems worldwide7.

Warnakulasuriya et al. (2006) discussed a binary system in their review of the OED classification, highlighting a workshop held in the United Kingdom by the WHO Collaborating Centre for Oral Cancer and Precancer (2005). The workshop emphasized the necessity of a two-tier classification system – categorizing lesions as either low risk (no/questionable/mild) or high risk (moderate/severe) – to enhance reproducibility and clinical applicability. The binary system, incorporating four architectural and cytological features, demonstrated a higher multi-observer kappa compared to the WHO system. However, the authors noted the requirement for further studies before implementing the two-tier system8.

Cancer Genomics and Bio Markers:

The use of molecular markers alongside clinical and histological grading has been proposed to enhance the prediction of disease progression. Changes and mutations in the genetic makeup of oral epithelial cells are fundamental aspects of “premalignancy.” Numerous genes and signaling pathways have been implicated in the genesis of OSCC. Molecular markers associated with OED have been identified to be linked with malignant transformation. However, the practical value of these genetic markers in OPMD/OED requires further clarification9.

Genomic hypomethylation involves a reduction in the extent of DNA methylation, resulting in genomic instability and dysregulation of gene expression, thus playing a role in cancer development. Epigenetic alterations, including DNA methylation and histone modifications, have been scrutinized for their involvement in OSCC. Anomalies in epigenetic processes may lead to tumor suppressor genes’ inactivation and oncogenes’ activation10.

A study by Hsiung and colleagues examined global DNA methylation levels in the DNA extracted from the whole blood of 278 patients diagnosed with head and neck squamous cell carcinoma (HNSCC) and 526 control subjects. They utilized a modified version of the combined bisulfite conversion and restriction enzyme analysis targeting the LRE1 sequence, a long interspersed nuclear element repeat region located on 22q11-q12. Their findings revealed a significant association between elevated HNSCC risk and higher global DNA methylation levels in whole blood, particularly notable among individuals with low folate intake or high alcohol consumption. These results strongly suggest that the global DNA methylation level in whole blood could potentially serve as a biomarker for assessing HNSCC risk11.

Oral infection with human papillomavirus (HPV) is identified as an independent factor contributing to oropharyngeal cancer. While the general population exhibits a low prevalence of oral HPV (4.5%), studies indicate that 95% of HPV-related head and neck cancers are specifically linked to HPV 16. Oropharyngeal cancers associated with HPV tend to emerge in proximity to the base of the tongue and within the tonsils. Approximately 63% of oropharyngeal cancer cases annually are attributed to HPV infection. MicroRNAs (miRNAs) represent a class of small RNA molecules that contain 19-24 nucleotides to regulate gene expression post-transcriptionally. Changes in the expression levels of specific miRNAs have been associated with oral squamous cell carcinoma (OSCC), and ongoing research seeks to elucidate their functional implications. miRNAs, often found associated with exosomes, exhibit enhanced stability in saliva, rendering them promising biomarkers for detecting oral cancer12.

In the 2022 follow-up to the seminal publication “Hallmarks of Cancer” by Hanahan and Weinberg in 2000, a novel hallmark known as “unlocking phenotypic plasticity” has been acknowledged. Feinberg and Levchenko define phenotypic plasticity as the transient ability of isogenic cells to adopt different phenotypic states, closely linked to epithelial-mesenchymal transition (EMT), drug resistance, and heightened cell proliferation13.

DOI, or Depth of Invasion, indicates the extent to which a tumor infiltrates beyond the basement membrane into underlying tissues. This metric holds significance in assigning the T stage (tumor stage) within the TNM (Tumor, Node, Metastasis) staging system for cancer. Two closely related but distinct pathological parameters, tumor thickness (TT) and depth of invasion (DOI), have been delineated in the latest editions of the AJCC staging manuals (7th and 8th editions) for Oral Squamous Cell Carcinoma (OSCC) and Oral Tongue Squamous Cell Carcinoma (OTSCC), holding critical importance for histopathological assessment, staging, prognostic significance, and treatment implications. Tumor thickness (TT) is calculated starting from the surface of the invasive squamous cell carcinoma, whether the tumor is endophytic or exophytic, and from the base of the ulcer for ulcerated tumors, extending to the deepest point of invasion. However, it’s important to note that TT has been omitted from the latest staging manual14.

The tumor microenvironment (TME) is a complex and dynamic structure comprising immune cells, stromal cells, blood vessels, and the extracellular matrix (ECM), actively promoting cancer progression through dynamic interactions with cancer cells. Components of the tumor microenvironment include MDSCs, stimulated to develop in the bone marrow by various cytokines, and tumor-associated macrophages (TAMs), which have distinct functions in immune defense and surveillance15.

In oral premalignant lesions, characterized by M2 tumor-associated macrophages and MDSCs, associated with poor prognosis and disease progression, along with immune-supportive features including infiltration with CD8+ T lymphocytes, helper cells, and B cells. Hydroxy radical species produced by granulocytes and myeloid cells may contribute to the progression of oral premalignant lesions, promoting genetic changes necessary for malignant transformation and directly suppressing cytotoxic T cells. An elevated neutrophil-to-lymphocyte ratio is associated with worse survival outcomes, while increased eosinophil infiltration is observed in cancer compared to dysplasia. Regulation of the immune microenvironment by genomic changes in oral premalignant lesions is depicted, highlighting the intricate interplay between genetic alterations and immune cell infiltration16.

Diagnostic Advancements in Oral Cancer Detection Using Salivary Biomarkers:

In the quest for non-invasive diagnostic tools, saliva has emerged as a promising medium for early detection, diagnosis, and monitoring of oral squamous cell carcinoma (OSCC) and oral premalignant lesions. Babiuch et al. delved into the immunological mechanisms underlying oral carcinogenesis, particularly focusing on changes in proinflammatory NF-kappaB dependent cytokines in premalignant and malignant oral mucosa. Their research pinpointed IL-8 as a primary biomarker associated with malignant transformation in OSCC, with observable alterations in both tumor tissue and salivary samples. Additionally, elevated levels of other proinflammatory cytokines in saliva, such as IL-6 and TNF-alpha, were noted in OSCC patients, underscoring the role of chronic inflammation in OSCC development. Genetic changes in OSCC have also been investigated through saliva analysis, revealing promising predictive factors.17

Oh et al. documented significant mRNA alterations in saliva samples from OSCC patients across six genes, exhibiting notably reduced expression levels. Particularly, the combined assessment of monoamine oxidase B and NGFI-A binding protein 2 emerged as a crucial predictive factor for early OSCC detection in younger individuals. While these findings shed light on OSCC pathogenesis, further research is warranted to validate the biomarker potential of salivary mRNA in OSCC detection. Salivary biomarkers have garnered attention in oral cancer research, notably in OSCC. Saliva offers a non-invasive and readily accessible avenue for identifying molecular alterations linked to cancer progression. Several salivary biomarkers have undergone investigation to OSCC, encompassing proteins, DNA, RNA, metabolites, epigenetic markers, exosomes, inflammatory markers, enzymes, and combination biomarker panels. These biomarkers hold promise for early detection, treatment response monitoring, and prognosis evaluation in OSCC. However, it’s crucial to emphasize the need for additional validation and standardization before these biomarkers can be universally integrated into clinical practice. Validated salivary biomarkers, if established, could revolutionize oral cancer screening and monitoring, offering a patient-centric and non-invasive approach to diagnosis and management7.

Genetic tools:

CRISPR, an acronym for Clustered Regularly Interspaced Short Palindromic Repeats, signifies a revolutionary technology that enables precise and targeted genome editing, marking a significant advancement in the fields of molecular biology and genetic engineering. It equips researchers with a powerful tool for manipulating genes across various organisms, including humans. The Key Characteristics of CRISPR Technology; CRISPR-Cas System: Derived from the natural defense mechanisms of bacteria and archaea against viral intrusions, the CRISPR-Cas system consists of short, partially palindromic repeated DNA sequences (CRISPR) and associated proteins (Cas, or CRISPR-associated proteins). These elements collaborate to identify and cleave specific DNA sequences, facilitating precise DNA editing with exceptional accuracy18.

Genome Editing Procedure: a. Designing Guide RNA (gRNA): Scientists engineer a synthetic RNA molecule known as guide RNA (gRNA), which complements the target DNA sequence slated for editing, b. Cas Protein Binding: The gRNA directs the Cas protein to the designated DNA sequence. Serving as molecular scissors, the Cas protein precisely cuts the DNA at the specified location, c. DNA Repair Mechanism: Upon DNA cleavage, the cell’s intrinsic repair mechanisms are activated. This repair process may induce gene mutations, either through error-prone repair mechanisms or by incorporating a desired DNA sequence19.

Applications Encompass the Genome Editing: CRISPR facilitates precise alterations to genes, enabling researchers to add, remove, or substitute specific DNA sequences with remarkable precision. Functional Genomics: CRISPR is extensively utilized in functional genomics research, allowing scientists to elucidate the functions of particular genes by selectively disrupting or modifying them. Therapeutic Applications: CRISPR holds promise for treating genetic disorders by correcting disease-causing mutations. However, therapeutic applications are still in early stages, facing technical and ethical challenges20.

Various updates on diagnostic tools:

Several advancements have been made in screening and diagnostic strategies, including the implementation of updated techniques. Reflectance confocal microscopy (RCM) serves as a valuable intermediary between dermoscopy and histopathology, facilitating non-invasive, real-time virtual skin biopsies at the bedside. Through fluorescence or reflectance methods, RCM offers imaging capabilities depending on the contrast source. Furthermore, the latest iteration of ex vivo confocal microscopy, incorporating digital staining, has proven effective in guiding Mohs surgery.

The VELscope Enhanced Oral Assessment System revolves around a handheld scope utilized by clinicians to illuminate oral tissues using blue light, revealing natural tissue fluorescence. This fluorescence enhances traditional oral examinations by enabling visualization of abnormal areas that may not be evident to the naked eye. By emitting harmless, bright blue light, the VELscope device detects abnormal tissue changes, causing oral mucosa to fluoresce naturally. Healthy tissues exhibit distinct fluorescence patterns, which may be disrupted in the presence of abnormalities such as oral cancer. Operating as an adjunctive device, the VELscope system complements traditional intra and extraoral head and neck exams without requiring dyes or prolonged testing procedures. A VELscope exam can be seamlessly integrated into routine dental hygiene visits, typically completed within two minutes21.

Chemiluminescence, also known commercially as ViziLite is a screening aid utilized in oral examinations to enhance the identification, assessment, and monitoring of oral mucosal abnormalities, particularly in individuals at heightened risk of oral cancer. The principle of chemiluminescence, previously utilized in Obstetrics and Gynaecology for early cervical cancer and precancer detection, involves the emission of light resulting from a chemical reaction, with minimal heat emission. The rationale behind chemiluminescence lies in the application of acetic acid solution, which aids in removing debris, disrupting the glycoprotein barrier on the surface epithelium, and desiccating the mucosa. This process enhances light penetration, facilitating better visualization of oral mucosal abnormalities due to changes in their refractive properties. The blue-white light generated is absorbed by cells of normal mucosa, characterized by a normal nuclear-cytoplasmic ratio of 1:4, while cells with abnormal nuclei, including dysplastic and neoplastic cells, reflect the light. Also, Microlux DL and Oroscopic DK help in identifying mucosal lesions22.

 Immunotherapy

The field of immunotherapy has witnessed significant advancements in the treatment of oral squamous cell carcinoma (OSCC). The immune system plays a crucial role in preventing tumors through various mechanisms. Firstly, it can defend against virus-induced tumors by eliminating or suppressing viral infections. Secondly, by swiftly resolving inflammation and eliminating pathogens, the immune system creates an environment less conducive to tumor formation. Thirdly, it can target and eradicate tumor cells specifically, based on their expression of tumor-specific antigens or stress-induced molecules. This mechanism, known as tumor immune surveillance, has been further elaborated upon by Schreiber et al. and is now conceptualized as immune editing, encompassing three phases. The first phase involves the control of tumor growth through T-cell activation and antigen presentation, termed immunosurveillance or elimination. The second phase, equilibrium, sees tumor growth in a steady state due to genetic instability, while the third phase, escape, occurs when tumor cells evade or suppress the immune system, leading to tumor progression23.

Immunotherapy approaches can be broadly classified into active and passive categories. Active immunotherapy stimulates the immune system to directly attack tumor cells by harvesting immune cells, such as natural killer (NK), dendritic, and cytotoxic T cells, and reintroducing them into the patient’s body. Passive immunotherapy enhances the immune system by targeting cell surface receptors to trigger antibody-dependent cell-mediated cytotoxicity (ADCC). Agents commonly used in immunotherapy include anti-CTLA-4 and anti-PD-1 antibodies, with the former having broader impacts on T cell function but also higher frequencies of side effects24.

Cancer vaccines utilize patients’ tumor cells to educate T cells to identify and eliminate cancer cells within the tumor. They can include specific antigens sourced from RNA, DNA, or peptides, or utilize pulsed dendritic cells or whole cells. Despite their potential for inducing long-lasting immunity, cancer vaccines have drawbacks including high cost, limited efficacy for rapidly proliferating tumors, and delayed immune response25.

Antigen vaccines consist of specific antigens from patients’ tumors, while dendritic cell vaccines harness dendritic cells’ ability to combat tumor cells. DNA or RNA vaccines formulated from genetic material have shown effectiveness in eliciting tumor regression. Whole-cell vaccines, derived from entire cancer cells, offer another approach to immunotherapy26.

Conclusion:

The knowledge of the trends in oncopathology of the oral aspect is important as this field is rapidly evolving. There are continuous developments in the treatment aspect of carcinomas using various changes in oral microenvironment.

Conflict of interest: None

Source of support: Nil

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