Generative Adversarial Networks in Digital Histopathology: Current Applications, Limitations, Ethical Considerations, and Future Directions.

Generative adversarial networks (GANs) have gained significant attention in the field of image synthesis, particularly in computer vision. GANs consist of a generative model and a discriminative model trained in an adversarial setting to generate realistic and novel data. In the context of image synthesis, the generator produces synthetic images, whereas the discriminator determines their authenticity by comparing them with real examples. Through iterative training, the generator allows the creation of images that are indistinguishable from real ones, leading to high-quality image generation. Considering their success in computer vision, GANs hold great potential for medical diagnostic applications. In the medical field, GANs can generate images of rare diseases, aid in learning, and be used as visualization tools. GANs can leverage unlabeled medical images, which are large in size, numerous in quantity, and challenging to annotate manually. GANs have demonstrated remarkable capabilities in image synthesis and have the potential to significantly impact digital histopathology. This review article focuses on the emerging use of GANs in digital histopathology, examining their applications and potential challenges. Histopathology plays a crucial role in disease diagnosis, and GANs can contribute by generating realistic microscopic images. However, ethical considerations arise because of the reliance on synthetic or pseudogenerated images. Therefore, the manuscript also explores the current limitations and highlights the ethical considerations associated with the use of this technology. In conclusion, digital histopathology has seen an emerging use of GANs for image enhancement, such as color (stain) normalization, virtual staining, and ink/marker removal. GANs offer significant potential in transforming digital pathology when applied to specific and narrow tasks (preprocessing enhancements). Evaluating data quality, addressing biases, protecting privacy, ensuring accountability and transparency, and developing regulation are imperative to ensure the ethical application of GANs.

Constitutive Hedgehog/GLI2 signaling drives extracutaneous basaloid squamous cell carcinoma development and bone remodeling.

Uncontrolled activation of the Hedgehog (Hh) signaling pathway, operating through GLI transcription factors, plays a central role in the pathogenesis of cutaneous basal cell carcinoma and contributes to the development of several malignancies arising in extracutaneous sites. We now report that K5-tTA;tetO-Gli2 bitransgenic mice develop distinctive epithelial tumors within their jaws. These tumors consist of large masses of highly proliferative, monomorphous, basaloid cells with scattered foci of keratinization and central necrosis, mimicking human basaloid squamous cell carcinoma (BSCC), an aggressive upper aerodigestive tract tumor. Like human BSCC, these tumors express epidermal basal keratins and differentiation-specific keratins within squamous foci. Mouse BSCCs express high levels of Gli2 and Hh target genes, including Gli1 and Ptch1, which we show are also upregulated in a subset of human BSCCs. Mouse BSCCs appear to arise from distinct epithelial sites, including the gingival junctional epithelium and epithelial rests of Malassez, a proposed stem cell compartment. Although Gli2 transgene expression is restricted to epithelial cells, we also detect striking alterations in bone adjacent to BSCCs, with activated osteoblasts, osteoclasts and osteal macrophages, indicative of active bone remodeling. Gli2 transgene inactivation resulted in rapid BSCC regression and reversal of the bone remodeling phenotype. This first-reported mouse model of BSCC supports the concept that uncontrolled Hh signaling plays a central role in the pathogenesis of a subset of human BSCCs, points to Hh/GLI2 signaling as a potential therapeutic target and provides a powerful new tool for probing the mechanistic underpinnings of tumor-associated bone remodeling.

Utility of Transfacial Dental Ultrasonography in Evaluation of Cystic Jaw Lesions.

OBJECTIVES: Plain radiography has been widely used in dentistry. Because of the variability of the quality of equipment, radiographic technique, accuracy of interpretation, and radiation risk to the patients, the field is ripe for the introduction of other newer diagnostic modalities. In this report, we demonstrate the utility of ultrasonography in the diagnostic workup of cystic or cystlike lesions of the jaw. METHODS: We used a transfacial ultrasonographic scanning approach to examine 32 patients with clinical or radiographic presentation of a jaw cyst. Computed tomography and histopathologic analysis were used as the reference standards to confirm the findings. RESULTS: Ultrasonography could establish the presence or absence of a lesion, erosion of the buccal cortical plate, and identification of associated soft tissue involvement in all cases (sensitivity and specificity, 100% and 100%, respectively; area under the receiver operating characteristic curve, 1.0; P < .001). CONCLUSIONS: Our observations revealed the usefulness of ultrasonography and demonstrated its potential value when introduced as a routine office-based imaging method for dentistry.

Oral squamous cell carcinoma: early detection and improved 5-year survival in 102 patients.

The 5-year survival rate for oral cancer remains poor, as a significant number of patients present with advanced disease at the time of diagnosis. The need remains for early detection within the context of routine oral examinations and evaluation of any noted clinical abnormalities. This retrospective study analyzed patient demographics, lesion characteristics, and 5-year survival rates associated with oral squamous cell carcinoma (OSCC) that was initially assessed using computer-assisted, 3-dimensional analysis of a transepithelial oral brush biopsy. Patients with oral lesions were initially assessed by community-based dentists and physicians using an oral brush biopsy. In 102 patients, OSCC was subsequently confirmed by incisional biopsy and histopathologic analysis. The majority of patients were without traditional risk factors. Almost half of the cancers presented as white lesions, and one-third presented as lesions smaller than 5 mm. In about three-fourths of all cases, OSCC initially presented without pain or bleeding. The overall 5-year survival rate for all patients was approximately 94%. Despite barriers to early detection, identification of early, asymptomatic OSCC with innocuous-appearing clinical features is achievable. This earlier detection can be expected to lead to a marked improvement in overall survival patterns.

Oral mucosal precancer and cancer: A helpful discriminating clinical tool.

The authors have collaborated with many colleagues in several countries in formulating a useful and practical clinical tool for evaluating oral mucosal findings on routine examination. Consideration of several factors including history, evolution of positive findings and clinical information allows placement of examination results into one of three categories which are graded by a color scheme along a spectrum of concerns (green to red, or no concern to serious concern). Afforded to the clinician is a straightforward grading system as a starting point for office end clinic use for all patients.

An Update on the Use of Artificial Intelligence in Digital Pathology for Oral Epithelial Dysplasia Research.

INTRODUCTION: Oral epithelial dysplasia (OED) is a precancerous histopathological finding which is considered the most important prognostic indicator for determining the risk of malignant transformation into oral squamous cell carcinoma (OSCC). The gold standard for diagnosis and grading of OED is through histopathological examination, which is subject to inter- and intra-observer variability, impacting accurate diagnosis and prognosis. The aim of this review article is to examine the current advances in digital pathology for artificial intelligence (AI) applications used for OED diagnosis. MATERIALS AND METHODS: We included studies that used AI for diagnosis, grading, or prognosis of OED on histopathology images or intraoral clinical images. Studies utilizing imaging modalities other than routine light microscopy (e.g., scanning electron microscopy), or immunohistochemistry-stained histology slides, or immunofluorescence were excluded from the study. Studies not focusing on oral dysplasia grading and diagnosis, e.g., to discriminate OSCC from normal epithelial tissue were also excluded. RESULTS: A total of 24 studies were included in this review. Nineteen studies utilized deep learning (DL) convolutional neural networks for histopathological OED analysis, and 4 used machine learning (ML) models. Studies were summarized by AI method, main study outcomes, predictive value for malignant transformation, strengths, and limitations. CONCLUSION: ML/DL studies for OED grading and prediction of malignant transformation are emerging as promising adjunctive tools in the field of digital pathology. These adjunctive objective tools can ultimately aid the pathologist in more accurate diagnosis and prognosis prediction. However, further supportive studies that focus on generalization, explainable decisions, and prognosis prediction are needed.

Performance of AI chatbots on controversial topics in oral medicine, pathology, and radiology.

OBJECTIVES: In this study, we assessed 6 different artificial intelligence (AI) chatbots (Bing, GPT-3.5, GPT-4, Google Bard, Claude, Sage) responses to controversial and difficult questions in oral pathology, oral medicine, and oral radiology. STUDY DESIGN: The chatbots' answers were evaluated by board-certified specialists using a modified version of the global quality score on a 5-point Likert scale. The quality and validity of chatbot citations were evaluated. RESULTS: Claude had the highest mean score of 4.341 ± 0.582 for oral pathology and medicine. Bing had the lowest scores of 3.447 ± 0.566. In oral radiology, GPT-4 had the highest mean score of 3.621 ± 1.009 and Bing the lowest score of 2.379 ± 0.978. GPT-4 achieved the highest mean score of 4.066 ± 0.825 for performance across all disciplines. 82 out of 349 (23.50%) of generated citations from chatbots were fake. CONCLUSIONS: The most superior chatbot in providing high-quality information for controversial topics in various dental disciplines was GPT-4. Although the majority of chatbots performed well, it is suggested that developers of AI medical chatbots incorporate scientific citation authenticators to validate the outputted citations given the relatively high number of fabricated citations.

Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas.

BACKGROUND: This article presents evidence-based clinical recommendations developed by a panel convened by the American Dental Association Council on Scientific Affairs. This report addresses the potential benefits and potential risks of screening for oral squamous cell carcinomas and the use of adjunctive screening aids to visualize and detect potentially malignant and malignant oral lesions. TYPES OF STUDIES REVIEWED: The panel members conducted a systematic search of MEDLINE, identifying 332 systematic reviews and 1,499 recent clinical studies. They selected 5 systematic reviews and 4 clinical studies to use as a basis for developing recommendations. RESULTS: The panel concluded that screening by means of visual and tactile examination to detect potentially malignant and malignant lesions may result in detection of oral cancers at early stages of development, but that there is insufficient evidence to determine if screening alters disease-specific mortality in asymptomatic people seeking dental care. CLINICAL IMPLICATIONS: The panel suggested that clinicians remain alert for signs of potentially malignant lesions or early-stage cancers while performing routine visual and tactile examinations in all patients, but particularly in those who use tobacco or who consume alcohol heavily. Additional research regarding oral cancer screening and the use of adjuncts is needed.

Corrigendum to "The Role of Medications in Causing Dry Eye".

[This corrects the article DOI: 10.1155/2012/285851.].

Microsecretory Adenocarcinoma: A Novel Salivary Gland Tumor Characterized by a Recurrent MEF2C-SS18 Fusion.

Salivary gland adenocarcinoma not otherwise specified (NOS) is a heterogenous group, likely containing distinct tumors not yet characterized. A growing number of low to intermediate-grade salivary carcinomas are now known to harbor tumor-specific gene fusions. On occasion, identifying a novel fusion allows for recognition of a new salivary tumor type, in addition to representing a potential diagnostic tool. We sought to characterize a distinctive salivary gland adenocarcinoma that would previously have been regarded as adenocarcinoma NOS. On the basis of the recognition of 5 morphologically identical, distinct low-grade salivary adenocarcinomas, we used targeted RNA sequencing (RNA-Seq) to determine whether these could be differentiated from other fusion-associated salivary gland tumors. RNA-Seq was performed on all 5 low-intermediate grade adenocarcinomas NOS with near-identical histologic appearances, as well as 23 low-intermediate grade control adenocarcinoma NOS cases that did not resemble the index cases. All 5 index cases harbored a novel MEF2C-SS18 gene fusion, which was independently confirmed by reverse transcriptase-polymerase chain reaction. The MEF2C-SS18-positive cases arose in the oral cavity (4/5) and parotid gland (1/5) of 3 women and 2 men ranging from 21 to 80 years (mean: 46) and shared near-identical histologic features: intercalated duct-like cells with eosinophilic to clear cytoplasm and small, uniform oval nuclei, infiltrative microcysts and cords, abundant intraluminal secretions, and cellular fibromyxoid stroma. Mitotic rates were low; necrosis was absent. All MEF2C-SS18-positive tumors were positive for S100 and p63 and negative for p40, smooth muscle actin, calponin, and mammaglobin. One of the 23 control cases, a parotid tumor, was found to contain a SS18-ZBTB7A gene fusion; it demonstrated similar, but not identical histologic and immunophenotypic features compared with the MEF2C-SS18 cases. The remaining control cases were negative for SS18 and MEF2C rearrangements. A novel MEF2C-SS18 gene fusion and unique histologic and immunophenotypic features characterize a heretofore undefined low-grade salivary adenocarcinoma for which we propose the term "microsecretory adenocarcinoma." RNA-Seq helped establish this entity as a distinct tumor type, and identified one possibly related case with a different SS18-related fusion. The recognition of microsecretory adenocarcinoma and its separation from other adenocarcinomas NOS will facilitate a more complete understanding of the clinical and pathologic characteristics of this previously unrecognized neoplasm.

Oral mucosal diseases in the office setting--part I: Aphthous stomatitis and herpes simplex infections.

This article is an update and review of the most common nontraumatic ulcerative and vesicular lesions of the oral cavity. Details concerning their etiology, pathogenesis, clinical presentation, differential diagnosis, and management are included. Comparisons are made between the various forms of aphthous ulcerations and their viral counterparts. Lesions of herpes simplex origin are described for both primary and recurrent or secondary forms and differentiation from aphthous ulcerations is made. Treatment options for both the chronic and more acute forms of this condition are discussed.

Oral mucosal diseases in the office setting--Part II: oral lichen planus, pemphigus vulgaris, and mucosal pemphigoid.

Oral lichen planus, pemphigus vulgaris, and mucosal pemphigoid represent a triad of oral mucosal diseases that may be first evaluated or examined by a dental practitioner. This article examines the clinical features, etiology, pathogenesis, diagnostic considerations, and therapeutic options of these three conditions. Treatment considerations and the dentist's role in the overall scheme of management or referral are discussed.

Mitochondrial DNA content increase in response to cigarette smoking.

An increase in mitochondrial DNA (mtDNA) content and decline in mitochondrial function occurs with aging and in response to DNA-damaging agents, including tobacco smoke. We did a cross-sectional study and quantified changes in mtDNA content in a population of individuals with varied smoking and alcohol exposure. Age, smoking history, ethanol intake, and other demographic data were characterized for 604 individuals participating in a screening study for smoking-related upper aerodigestive malignancy. Total DNA was extracted from exfoliated cells in saliva. DNA from a nuclear gene, beta-actin, and two mitochondrial genes, cytochrome c oxidase I and II (Cox I and Cox II), were quantified by real-time PCR. mtDNA content was correlated with age, exposure history, and other variables using multivariate regression analyses. A significant increase (P<0.001) in mtDNA content was noted in smokers (31% and 29% increase for Cox I and Cox II, respectively) and former smokers (31% and 34%) when compared with never smokers. This association persisted after adjustment for other significant factors including age, alcohol drinking, and income (P<0.001). Increased mtDNA content was positively associated with pack-years of smoking (P=0.02). Despite an average smoking cessation interval of 21 years in former smokers, tobacco cessation interval was not statistically significantly associated with mtDNA content. Smoking is associated with increased mtDNA content in a dose-dependent fashion. Mitochondrial DNA alterations in response to smoking persist for several decades after smoking cessation, consistent with long-term, smoking-related damage.

Importance of routine evaluation of the thyroid gland prior to open partial laryngectomy.

OBJECTIVES: To determine the incidence and presentation of synchronous thyroid lesions in a patient population undergoing open partial laryngectomy (OPL), and to determine whether routine preoperative evaluation of the thyroid gland prior to OPL is useful to identify synchronous thyroid lesions in order to reduce the need for reoperation in this complex patient population. DESIGN: Retrospective medical chart review. SETTING: Academic institution. PATIENTS: Sixty-seven consecutive patients with laryngeal tumors who had undergone OPL from 1996 to 2005. INTERVENTIONS: Charts of 67 consecutive patients with laryngeal tumors who underwent OPL in 1996 to 2005 have been reviewed for synchronous thyroid lesions. For all patients, reports of (1) complete preoperative examination findings, (2) inpatient course, (3) postoperative follow-up, and (4) postoperative final histopathologic findings were reviewed. For patients with synchronous thyroid lesions, reports of (1) thyroid evaluation and imaging and (2) preoperative (fine-needle aspiration), (3) intraoperative (frozen section), and (4) postoperative (final) histopathologic results for the thyroid lesions were reviewed. MAIN OUTCOME MEASURES: Incidence of synchronous thyroid lesions and laryngeal cancer in patients undergoing OPL. RESULTS: Eight (11.9%) of 67 (95% confidence interval, 5.3%-22.2%) patients with laryngeal tumors who underwent OPL had evidence of synchronous thyroid lesions. All 8 patients had squamous cell carcinoma of the larynx and underwent either supracricoid or supraglottic laryngectomy. In these 8 patients, synchronous thyroid lesions were incidentally detected. Four patients had papillary thyroid carcinoma, 1 had squamous metaplasia, and 3 had follicular thyroid tissue that was negative for malignancy on final pathologic examination. In 2 patients, the thyroid lesions were detected preoperatively (prior to OPL); in another 2 patients, thyroid masses were detected intraoperatively; and in 4 patients, the thyroid disease was identified postoperatively on histopathologic examination of excised cervical lymph nodes. In 2 patients, thyroidectomy was performed as a second operation after the OPL, and 1 of them had transient vocal fold paralysis for 2 months. Thyroid ultrasonography was performed in 4 patients. In 3 patients, the ultrasonography was performed after the OPL final pathologic findings indicated the presence of metastatic thyroid disease in cervical lymph nodes. Ultrasonography revealed intrathyroidal lesions in all 3 patients. CONCLUSIONS: Patients with laryngeal tumors who will be undergoing OPL might have occult synchronous thyroid lesions. Thyroid surgery in patients with previous OPL may have an increased potential for complication owing to postsurgical changes in the central neck region. Routine preoperative evaluation of the thyroid gland, especially with ultrasonography, to screen for occult synchronous thyroid lesions is recommended for all patients with laryngeal tumors who will be undergoing OPL. Eradication of any thyroid cancer detected preoperatively by fine-needle aspiration should be performed at the same time as OPL. Pros and cons of total thyroidectomy for indeterminate thyroid nodules should be discussed with this patient population.

Lower-extremity liposarcoma metastatic to the larynx: case report.

Distant metastases to the larynx are rare. We describe the case of a 46-year-old man who was referred to our head and neck surgery clinic with a 6-week history of sore throat and otalgia. He was found to have a laryngeal lesion that was consistent with a primary myxoid liposarcoma that had been extirpated from a lower extremity earlier To the best of our knowledge, no case of myxoid liposarcoma metastatic to the larynx has been previously reported in the English-language literature.

Follicular dendritic cell sarcoma of the head and neck: Case report, literature review, and pooled analysis of 97 cases.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare lymphoid neoplasm presenting in the head and neck. There are no pooled analyses of head and neck FDCS cases in the English language literature. METHODS: A MEDLINE and PubMed review of cases from 1978 to February 2014 was performed. Demographics, clinicopathologic data, and outcomes were summarized. RESULTS: We presented 2 patients and analyzed 97 cases. The mean age was 42.7 years (SD = 16.3 years). Outcomes were available for 76 patients. Tumors ≤4 cm had better disease-free survival (63% vs 28% at 5 years; p = .0282). Locoregional recurrence was significantly less likely with surgery and radiation compared to surgery alone (15% vs 45%; p = .019) and in patients receiving a neck dissection (10% vs 43%; p = .046). CONCLUSION: This pooled analysis provides the largest sample size of FDCS of the head and neck to date and suggests that radiation and neck dissection may be beneficial to locoregional oncologic control. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2241-E2249, 2016.

Clinical practice guidelines for oral management of Sjögren disease: Dental caries prevention.

BACKGROUND: Salivary dysfunction in Sjögren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjögren disease were developed to improve quality and consistency of care. METHODS: A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. At least 2 members extracted the data, and the panel rated the strength of the recommendations by using a variation of grading of recommendations, assessment, development, and evaluation. After a Delphi consensus panel was conducted, the experts finalized the recommendations, with a minimum of 75% agreement required. RESULTS: Final recommendations for patients with Sjögren disease with dry mouth were as follows: topical fluoride should be used in all patients (strong); although no study results link improved salivary flow to caries prevention, the oral health community generally accepts that increasing saliva may contribute to decreased caries incidence, so increasing saliva through gustatory, masticatory, or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be considered (weak); and nonfluoride remineralizing agents may be considered as an adjunct therapy (moderate). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The incidence of caries in patients with Sjögren disease can be reduced with the use of topical fluoride and other preventive strategies.

Cetuximab activity in dysplastic lesions of the upper aerodigestive tract.

BACKGROUND: High risk head and neck mucosal premalignancy has a malignant conversion rate of up to 40%, despite adequate surgical therapy. Epidermal Growth Factor Receptor (EGFR) blocking agents, including cetuximab, have shown activity in head and neck squamous cell carcinoma (HNSCC) and have potential for therapy in high risk premalignancy. METHODS: We conducted a randomized, prospective, phase II clinical trial to determine the effects of cetuximab on patients with high risk premalignancy. Patients were randomized to treatment with cetuximab 400mg/m(2) on week one followed by 250mg/m(2) on week 2-8 or observation, with the option for crossover to cetuximab therapy for patients originally randomized to the observation arm. RESULTS: Two of 19 enrolled patients did not complete therapy due to treatment toxicity. Analysis of 17 patients who completed the trial regimen show a trend toward a larger mean decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2) (P=0.082, one-sided exact Wilcoxon rank sum test). However, in the observation group, none of the 5 patients (0%) achieved complete resolution of dysplasia; while 4 of 12 (33.3%) cetuximab treated patients had no remaining dysplasia after therapy. CONCLUSIONS: Treatment of high risk premalignancy of the upper aerodigestive tract with cetuximab alone may result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients. These results warrant further investigation in larger studies with increased statistical power.

Oral medicine (stomatology) across the globe: birth, growth, and future.

Oral medicine (stomatology) is a recognized and increasingly important dental specialty in many parts of the world that recognizes and fosters the interplay between medical health and oral health. Its dental activities rely greatly on the underlying biology of disease and evidence-based outcomes. However, full recognition of the importance of oral medicine to patient care, research, and education is not yet totally universally acknowledged. To address these shortcomings, we outline the birth, growth, and future of oral medicine globally, and record identifiable past contributions to the development of the specialty, providing an accurate, unique, and valuable resource on oral medicine. Although it was challenging to gather the data, we present this information as a review that endeavors to summarize the salient points about oral medicine, based on MEDLINE, other internet searches, communication with oral medicine and stomatological societies across the world, the web page http://en.wikipedia.org/wiki/List_of_dental_organizations, and discussions with a wide range of key senior persons in the specialty.

A transcriptional progression model for head and neck cancer.

PURPOSE: A genetic progression model for head and neck squamous cell carcinoma (HNSC) has been established and implies the presence of transcriptional dysregulation as a consequence of accumulation of genetic alterations. Although expression array data have been provided for HNSC, the timing of transcriptional dysregulation in the progression from normal mucosa to dyplastic epithelium to invasive HNSC has not been described. Here, we describe a transcriptional progression model of HNSC. EXPERIMENTAL DESIGN: Expression arrays representing >12,000 genes and expressed sequence tags were used to examine malignant lesions (M), premalignant lesions (PM), distant, histopathologically normal mucosa from patients with premalignant or malignant lesions (MN), and normal mucosa from the upper aerodigestive tract of patients with noncancer diagnoses (N). Significance analysis of microarrays, hierarchical clustering, and principal components analysis was used to identify genes with differential expression patterns. RESULTS: Using a false discovery rate of <5% for significance analysis of microarray, the M group revealed 965 up-regulated and 1106 down-regulated genes relative to the N group. The PM group demonstrated 108 up-regulated and 226 down-regulated genes relative to the N group, whereas the M group demonstrated only 5 up-regulated and 13 down-regulated genes relative to the PM group. Both hierarchical cluster analysis and principal components analysis revealed a consistent separation between the N, PM, and M groups, with a closer association between the PM and M groups. To provide independent validation of the microarray data, quantitative reverse transcription-PCR was performed for a significantly up-regulated gene, integrin alpha 6, correlating well with microarray data (linear regression analysis, P < 0.0001). CONCLUSIONS: Similarly to the genetic progression model of HNSC, this transcriptional model shows that the majority of alterations occurs before the development of malignancy and identifies key targets of transcriptional dysregulation during progression from a normal to a premalignant state and from a premalignant to a malignant state.