Oral Cancerization Research Articles

Oral Field Cancerization: A Narrative Review

Oral Field Cancerization: A Narrative Review

Gene mutation analysis of oral submucous fibrosis cancerization in Hainan Island.

The sequencing panel composed of 61 target genes was used to explore the related mutation genes of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) cancerization, so as to provide a theoretical basis for the early diagnosis of oral submucous fibrosis cancerization, find the most important mutations in OSF cancerization, and more targeted prevention of OSF cancerization. A total of 74 clinically diagnosed samples were included, including 36 cases of OSCC and 38 cases of OSF cancer patients. DNA was extracted, and targeted gene panel sequencing technology was used to analyze the gene frequency of pathogenic mutation sites in clinical samples. Gene panel sequencing analysis showed that there were 69 mutations in 18 genes in OSCC and OSF cancerous specimens. The results of gene panel sequencing were screened, and 18 mutant genes were finally screened out and their mutation frequencies in the samples were analyzed. According to the frequency of gene mutations from high to low, they were TP53, FLT4, PIK3CA, CDKN2A, FGFR4, HRAS, BRCA1, PTPN11, NF1, KMT2A, RB1, PTEN, MSH2, MLH1, KMT2D, FLCN, BRCA2, APC. The mutation frequency of FLT4 gene was significantly higher than that of OSCC group (P < 0.05). FLT4 gene may be related to OSF cancerization and is expected to be an early diagnostic biomarker for OSF cancerization.

Oral field cancerization: Genetic profiling for a prevention strategy for oral potentially malignant disorders

Background: Oral cancer therapy, such as radiation or surgical treatment, has pernicious long-term effects that patients suffer throughout their life, the disability being considerable with delayed diagnosis. It is well known that many oral cancers develop from oral potentially malignant disorders (OPMDs). Patients diagnosed with OPMDs may have an increased risk of developing cancer anywhere in the oral cavity. Early detection and intervention could be essential prevention strategies to inhibit oral cancer progression. OPMDs may not immediately develop into carcinoma. However, this condition provides a “field” of specific abnormalities wherein evolving altered genetic cells can be explained with the “field cancerization” concept. Purpose: This review aims to describe the “field cancerization” concept in oral cancer and OPMD, which is expected to contribute to a better clinical management strategy for oral cancer prevention. Review: “Oral field cancerization” describes oral cancers that develop in multifocal areas of pre-cancerous changes. It can be found as histologically abnormal tissue surrounding the tumor, suggesting that oral cancer often consists of multiple independent lesions. Conclusion: The oral field cancerization concept should prompt healthcare professionals to remind their patients that frequent oral examination with histological studies and molecular testing is mandatory for those at high risk of developing malignancies.

Oral Field Cancerization: A Review with Case Reports

The concept of field cancerization was proposed by Slaughter et al. in 1953. Field cancerization of the mucosa of aerodigestive tract frequently develops on account of tobacco and alcohol usage. The oral cavity is one of the predominant and prevalent sites of development of potential malignancies, therefore, it comes into direct contact with many carcinogens. All of the epithelium beyond the boundaries of tumour can undergo histological changes and may have more than one independent area of malignancy. The mucosa undergoes a change, perhaps due to carcinogen exposure and is therefore more susceptible to the development of many foci of malignant transformation. This explains the high incidence of recurrence of oral cancer, the rate being 32.7%, despite excision of tumour or other therapies. So, diagnosis and treatment of oral cancer should not only be focused on the lesion, but also on the field from which it developed. In this article, we emphasize on the concept of field cancerization, highlight the carcinogenic influence of tobacco and alcohol in the development of multiple primary tumours in the oral cavity by presenting clinical cases. Keywords: Field cancerization; Squamous cell carcinoma; Metastasis; Second primary tumours; Synchronous/ Metachronous tumours3.

Expression of Ki-67, Cyclin D1, P53, and P16 in patients with oral leukoplakia and leukoplakia cancerization with spicy diet in Chengdu.

To investigate the expression of Ki-67, Cyclin D1, P53, and P16 in patients with oral leukoplakia (OLK) and OLK cancerization who have aspicy diet in Chengdu. Thirtypatients with OLK andspicy diet and 15 patients with OLK without spicy diet in Chengdu were divided into three groups: hyperplastic OLK (OLK-), OLK with mild to moderate dysplasia (OLK+), and severe dysplastic OLK or oral squamous cell carcinoma (OSCC) transforming from OLK (OLK++/OSCC). The expression of Ki-67, Cyclin D1, P53, and P16 were detected by immunohistochemistry and statistically analyzed. The expression of Ki-67 and P53 in patients with or without spicy diet in the OLK+and OLK++/OSCC groups were stronger than that of the OLK- group (P<0.05). The OLK++/OSCC group showed a higher expression of Cyclin D1 and lower expression of P16 than the OLK- group (P<0.05). The expression of Ki-67, Cyclin D1, P53, and P16 in patients with spicy diet and without spicy diet had no substantial difference. The expression of Ki-67 and Cyclin D1 showed a positive correlation (r=0.439, P=0.015). Spicy diet did not have an influence on the expression of Ki-67, Cyclin D1, P53, and P16 in patients with OLK and OSCC. The expression of Ki-67, Cyclin D1, and P53 increased with the development of OLK, whereas P16 showed opposite expression trend.

New oral cytodiagnostic criteria predict change to oral epithelial dysplasia (OED) and cancerization

AbstractObjectivesThe purpose of this retrospective observational study was to evaluate the specificity of the new oral cytodiagnostic criteria and whether the new criteria predict change to oral epithelial dysplasia (OED) and cancerization for leukoplakia and oral lichen planus (OLP).Study designFifty‐three cases of leukoplakia without OED and 126 cases of OLP were included in this study. Liquid‐based cytology (LBC) was performed just before biopsy. We evaluated the specificity of the new oral cytodiagnostic criteria and the rates of change to OED and cancerization for each cytodiagnosis in leukoplakia and OLP.ResultsOne hundred and seventy patients were negative for intraepithelial lesion or malignancy (NILM), seven had low‐grade squamous intraepithelial lesions (LSILs), and two were indefinite for neoplasia (IFN). The specificity was 95% and the rates of OED change and cancerization in the observation period were 3.4% and 1.7%. In leukoplakia, there was a significant difference in the rates of change to OED and cancerization between negative for intraepithelial lesion or malignancy (NILM) and LSIL (odds ratio: 12.9; 95% CI: 1.72‐96.73).ConclusionsThe new oral cytodiagnostic criteria have high specificity for oral mucosal lesions. And, it was suggested that the cases diagnosed with LSIL using new criteria have a high possibility of change to OED or cancerization in leukoplakia.

Inactivation of homeodomain-interacting protein kinase 2 promotes oral squamous cell carcinoma metastasis through inhibition of P53-dependent E-cadherin expression.

Homeodomain‐interacting protein kinase 2 (HIPK2), a well‐known tumor suppressor, shows contradictory expression patterns in different cancers. This study was undertaken to clarify HIPK2 expression in oral squamous cell carcinoma (OSCC) and to reveal the potential mechanism of HIPK2 involvement in OSCC metastasis. Two hundred and four OSCC tissues, together with paired adjacent normal epithelia, dysplastic epithelia, and lymph node metastasis specimens, were collected to profile HIPK2 expression by immunohistochemical staining. High throughput RNA‐sequencing was used to detect the dysregulated signaling pathways in HIPK2‐deficient OSCC cells. Transwell assay and lymphatic metastatic orthotopic mouse model assay were undertaken to identify the effect of HIPK2 on tumor invasion. Western blotting and luciferase reporter assay were used to examine the HIPK2/P53/E‐cadherin axis in OSCC. Nuclear delocalization of HIPK2 was observed during oral epithelial cancerization progression and was associated with cervical lymph node metastasis and poor outcome. Depletion of HIPK2 promoted tumor cell invasion in vitro and facilitated cervical lymph node metastasis in vivo. According to mRNA‐sequencing, pathways closely related to tumor invasion were notably activated. Homeodomain‐interacting protein kinase 2 was found to trigger E‐cadherin expression by mediating P53, which directly targets the CDH1 (coding E‐cadherin) promoter. Restoring P53 expression rescued the E‐cadherin suppression induced by HIPK2 deficiency, whereas rescued cytoplasmic HIPK2 expression had no influence on the expression of E‐cadherin and cell mobility. Together, nuclear delocalization of HIPK2 might serve as a valuable negative biomarker for poor prognosis of OSCC and lymph node metastasis. The depletion of HIPK2 expression promoted OSCC metastasis by suppressing the P53/E‐cadherin axis, which might be a promising target for anticancer therapies.

Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy.

The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. "Short" pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.

Cancer stem cell markers ALDH1 and Bmi1 expression in oral erythroplakia revisited: Implication for driving the process of field cancerization.

The correlation of ALDH1 and Bmi1 expression in potentially malignant oral erythroplakia (OE) with oral carcinoma development was reported in our earlier study. Interestingly, a model of field cancerization orchestrated by the cancer stem cells (CSC) was proposed and suggested the identification of CSC-specific markers is useful for prognosis and providing novel targets for prevention and treatment of field cancerization. We revisited the correlation of ALDH1 and Bmi1 expression in OE with the second and multiple carcinomas development. Strikingly, we observed that the expression of ALDH1 and Bmi1 within a single potentially malignant OE lesion significantly correlate with subsequently developing multiple and multifocal carcinomas, which parallels the process of oral field cancerization. Significantly, ALDH1 and Bmi1 are well-defined markers of CSC for head and neck cancer. Consequently, we provided a preliminary evidence for CSC driving the process of field cancerization.

Oral field cancerization: Tracking the invisible

Cancer is one of the most common diseases affecting humans worldwide, despite latest advances made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still questionable. Oral cavity is one of the commonest site for potentially malignant disorders. These pre-malignant pathologies may progress to dysplastic lesions then to invasive carcinomas.The presence of one or more mucosal areas consisting of epithelial cells that have cancer-associated genetic or epigenetic alterations.The prognosis of squamous cell carcinoma patients is adversely influenced by development of a new tumor. This review highlights the pathophysiological changes during field cancerization

"Curette technique" and FISH analysis for the assessment of oral field cancerization

"Curette technique" and FISH analysis for the assessment of oral field cancerization

Concepts in Understanding Oral Field Cancerization: A Brief Review

The concept of ''field effect in cancer'' originated in 1953 from the histopathological observations of Slaughter and colleagues regarding the occurrence of multiple primary oral squamous cell carcinomas and their local recurrences. There are two fundamental theories regarding the development of Oral field cancerization (OFC) which include the 'Classical' and the 'Clonal'mechanism. The classical view hypothesizes that the entire epithelial surface of the upper aerodigestive tract has an increased risk for the development of premalignant disorders because of multiple genetic abnormalities in the whole tissue region; owing to prolonged exposures of susceptible carcinogens as a result of tobacco or alcohol consumption. Whilst the clonal theory believes that there always exists a field with genetically altered cells having a high risk of developing premalignant and malignant disorders. Here, the developing separate tumors, from a genetically individually altered stem cell in the extended field, share the same clonal origin and some degree of genetic similarity. Modern molecular and histological technologies exploring the tissue abnormalities in OFC have been performed. Herein, we have briefly discussed regarding the concepts of field cancerization along with the various diagnostic molecular techniques and the therapeutic aspects.

Oral Field Cancerization and Its Clinical Implications in the Management in Potentially Malignant Disorders.

Oral cancer is one of the common malignancies reported in India. Most of these cancers are preceded by potentially malignant disorders. Despite improvements in the management strategies of these cancers the posttreatment prognosis has remained poor. The 5-year survival rates of oral cancers in most countries are still below 50%. The poor outcomes in oral cancer prevention and treatment can be due to nature of the spread of genetically altered cells as fields within the epithelial compartment. The conventional management protocols need to be modified taking into consideration the field spread of genetically altered cells.

Role of PET-CT scan in synchronous primary cancers of the upper aerodigestive tract: a case report

Oral field cancerization though not a new concept, has time and again, proven to be a challenge to the clinician, in terms of diagnosis and management. Prolonged exposure of the aerodigestive tract to carcinogens causes multifocal cancers. Intraepithelial migration of dysplastic or clonal cells becomes the seed for different primaries in the same field. The probability of synchronous malignancies should be borne in mind while evaluating a patient with head and neck cancer. With the advent of highly specific diagnostic tools like the PET scan, the chances of missing a second primary are eliminated/negligible. This is a case report on a patient who was found to have multiple primaries on clinical and radiological evaluation. Patient underwent multimodality treatment with chemoradiotherapy followed by surgery and is currently under follow-up. We aim to highlight the role of PET scanning in the evaluation of head and neck cancer to prevent missing a second primary.

Field effect in oral cancer: An update

The concept of oral field cancerization (OFC) was first introduced by Slaughter et al. in 1953 in the setting of oral cancer, to propose the field cancerization theory which claims that after repeated exposure, the mucosa accumulates genetic alterations, resulting in the induction of multiple, independent, malignant lesions, thus field cancerization involves the lateral spread of premalignant or malignant disease and contributes to the recurrence of head and neck tumors. The molecular studies regarding OFC have been expanding exponentially since a few years. The need for chemoprevention and the management of OFC with its resultant effects of development of second primary tumors (SPTs) have been challenging till today. Hence, the article tries to explain the conflicting aspects of various mechanisms by which SPTs develop, the molecular techniques and chemoprevention of OFC.

Oral field cancerization: An update of evidences

Patients with head and neck squamous cell carcinoma often develop multiple premalignant lesions; this led to the concept of field-effect in cancer which was originated by Slaughter et al. in the year 1953. Though this was based on histopathological observations, the development of modern molecular technologies has extended the field effect concept by exploring the molecular abnormalities in tissues that appear histologically normal. In this update, we discuss in detail about the origin, principle, various theories used to explain this effect, molecular findings and therapeutic implications related to oral field cancerization.

Oral field cancerization: an update on current concepts.

There always exists a field with genetically altered cells with a high risk of developing premalignant and malignant lesions. It may often happen that an individual stem cell is genetically altered and can cause the formation of a clone or a patch which is likely to turn into a tumor. This explains the higher recurrence rates following tumor resections. It is essential to identify and to treat this field in order to have greater chances to prevent cancer and achieve a better outcome. This article reports concepts, theories and markers for the assessment of field cancerization.

Oral Field Cancerization: An Update

Patients with head and neck squamous cell carcinoma (HNSCC) often develop multiple (pre) malignant lesions. This finding led to the field of the cancerization theory, which hypothesizes that the entire epithelial surface of the upper aerodigestive tract has an increased risk for the development of (pre) malignant lesions, because of multiple genetic abnormalities in the whole tissue region. Cancer begins with multiple cumulative epigenetic and genetic alterations that sequentially transform a cell or a group of cells in a particular organ. These early genetic events may lead to the clonal expansion of preneoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these cells drive them toward the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers, owing to changes in the cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remains in the organ, demonstrating the concept of field cancerization. This review explains the concept of field cancerization and various field theories along with a molecular basis of field formation.

Chromosomal Instability, DNA Index, Dysplasia, and Subsite in Oral Premalignancy as Intermediate Endpoints of Risk of Cancer

Chromosomal instability and aneuploidy may represent biomarkers of oral exposure to damaging agents and early signs of clinical disease according to the theory of "oral field cancerization." The hypothesis was tested that the DNA index (DI) values, obtained by high-resolution DNA flow cytometry (DNA-FCM), may potentially contribute to oral cancer risk prediction. For this purpose, the DI of oral fields of normal-appearing mucosa and oral potentially malignant disorders (OPMDs) in 165 consecutive patients was tested for association with dysplasia and/or the oral subsites of tongue and floor of the mouth taken as high-risk intermediate endpoints surrogate of cancer clinical endpoints. The association was evaluated by logistic regression using patient gender, age, tobacco, cigarette smoking habit, and alcohol abuse as confounding variables. Different DI models provided evidence of statistical significant associations. Subdividing the DI values in diploid, near-diploid aneuploid, and high or multiple aneuploid from both OPMDs and oral normal-appearing mucosa, ORs, respectively, of 1, 4.3 (P = 0.001), and 18.4 (P < 0.0005) were obtained. Routine DI analysis by high-resolution DNA-FCM seems potentially useful to complement dysplasia and subsite analysis for assessment of oral cancer risk prediction and for a better management of the patients with OPMDs. Work is in progress to validate the present findings in a prospective study with clinical endpoints. Identifying DNA abnormalities in oral premalignancy may lead to biomarkers of oral exposure and cancer risk and potentially to more effective prevention measures.

Oral field cancerization: current evidence and future perspectives

Oral field cancerization implies that oral cancer does not arise as an isolated cellular phenomenon but rather as an anaplastic tendency involving many cells at once and results in the multifocal development of cancer at various rates within the entire field in response to a carcinogen especially tobacco. This concept has been frequently used to explain the occurrence of multiple primary cancers and recurrences following complete excision of oral cancer. This review deals in detail with the origin, principle, various theories used to explain this effect and molecular, genetic, as well as cytogenetic findings related to oral field cancerization. Further, the clinical implications and future research directives are also discussed.