High Risk Of Malignant Transformation Research Articles

An Update on Precancerous Lesions of Oral Cavity

Oral cancer is the most common head and neck cancer, found in 270,000 patients annually worldwide. Some cancers develop from precancerous lesions; however, there is no definitive clinico pathological factor or biomarker that reliably enables malignant transformation to be predicted in an individual patient. Early detection and early treatment of oral cancer are important for improving the survival rate of patients; prevention of oral cancer will clearly contribute most to decreasing its death rate. So correct diagnosis and timely treatment of premalignant lesions with high risk of malignant transformation may help to prevent malignant transformation.

Histomorphometric analysis of nuclear and cellular volumetric alterations in oral lichen planus, lichenoid lesions and normal oral mucosa using image analysis software

Lichen planus is a chronic inflammatory mucocutaneous disease that clinically and histologically resembles lichenoid lesions, although the latter has a different etiology. Though criteria have been suggested for differentiating oral lichen planus from lichenoid lesions, confusion still prevails. To study the cellular and nuclear volumetric features in the epithelium of normal mucosa, lichen planus, and lichenoid lesions to determine variations if any. A retrospective study was done on 25 histologically diagnosed cases each of oral lichen planus, oral lichenoid lesions, and normal oral mucosa. Cellular and nuclear morphometric measurements were assessed on hematoxylin and eosin sections using image analysis software. Analysis of variance test (ANOVA) and Tukey's post-hoc test. The basal cells of oral lichen planus showed a significant increase in the mean nuclear and cellular areas, and in nuclear volume; there was a significant decrease in the nuclear-cytoplasmic ratio as compared to normal mucosa. The suprabasal cells showed a significant increase in nuclear and cellular areas, nuclear diameter, and nuclear and cellular volumes as compared to normal mucosa. The basal cells of oral lichenoid lesions showed significant difference in the mean cellular area and the mean nuclear-cytoplasmic ratio as compared to normal mucosa, whereas the suprabasal cells differed significantly from normal mucosa in the mean nuclear area and the nuclear and cellular volumes. Morphometry can differentiate lesions of oral lichen planus and oral lichenoid lesions from normal oral mucosa. Thus, morphometry may serve to discriminate between normal and premalignant lichen planus and lichenoid lesions. These lesions might have a high risk for malignant transformation and may behave in a similar manner with respect to malignant transformation.

La chirurgie du pancréas

Historically, pancreatic surgery has been considered a "major" procedure, usually consisting of pancreatectomy in old or other high-risk patients. Pancreatic surgery carries a risk of fatal complications, major morbidity, and long-term adverse effects. Recently, both the indications and techniques of pancreatic surgery have diversified, notably with the emergence of parenchyma-preserving resection for benign lesions at high risk of malignant transformation, which are often discovered incidentally. A multidisciplinary approach is needed for accurate decision-making, based on the presumed diagnosis, tumor location, surgical risk, and medical history.

The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers

Germinal centers (GC) are sites of intense B cell proliferation, central for T cell dependent antibody responses. However, the role of MYC, a key cell cycle regulator, in this process has been questioned. Here, we identified MYC positive B cell subpopulations in immature and mature GCs, and show through genetic ablation of Myc that they play indispensable roles in GC formation and maintenance. The identification of these functionally critical cellular subsets has important implications for human B cell lymphomagenesis, which mostly originates from GC B cells and frequently involves MYC chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the MYC positive GC subpopulations may be at a particularly high risk for malignant transformation.

Clinicopathological characteristics of malignant transformation in 85 cases of oral leukoplakia

To investigate the histological features of oral leukoplakia which underwent malignant transformation and its correlation with the clinical manifestation. A total of 1832 cases of oral leukoplakia were reviewed and the clinicopathological characteristics of malignant transformation were analyzed. Malignant transformation occurred in 85 cases (4.6%) of the 1832 cases. Thirty cases (2.1%) of 1404 cases with simple epithelial hyperplasia had malignant transformation. Fifty-five cases (12.9%) in 428 cases with epithelial dysplasia were transformed to malignancy, especially in the cases with moderate or severe dysplasia, in which the ratio of malignant transformation was higher than in the cases with simple epithelial hyperplasia (P < 0.005). Clinical parameters associated with an increased risk of malignant transformation were female gender and epithelial dysplasia was more often seen in non-homogenous leukoplakias than in homogenous (P < 0.005). Non-dysplastic leukoplakia may become malignant. Epithelial dysplasia was associated with an increased risk of malignant transformation. Leukoplakia in female may be at a higher risk for malignant transformation.

An Integrated Approach to Regression Analysis in Multiple Correspondence Analysis and Copula Based Models

In this paper, taking into account the possible development of serious disorders of the proliferation of the plasmatic cells, we focus on a dataset concerning the prediction among a chronic disease which has the higher risk of malignant transformation. The purpose of this paper is to argue in favour of the use of multiple correspondence analysis (MCA) as a powerful exploratory tool for such data. Following usual regression terminology, we refer to the primary variable as the response variable and the others as explanatory or predictive variables. As an alternative, a copula based methodology for prediction modeling and an algorithm to stimulate data are proposed.

Detection of MAGE-A Expression Predicts Malignant Transformation of Oral Leukoplakia

The study aimed at checking if MAGE-A expression in oral leukoplakia (OLP) lesions is related to malignant transformation. The 48 samples of OLP that transformed to oral squamous cell carcinoma (OSCC) (group 1) and 50 samples of OLP that did not transform to OSCC (group 2) were included in the study. The expression of MAGE-A was restricted to group 1. The correlation between malignant transformation and MAGE-A occurrence in OLP was statistically significant (p < .0001). Detection of MAGE-A may allow identifying OLP with a high risk of malignant transformation giving a view to a new approach to prevention of oral cancer.

Human papillomavirus–related genital disease in the immunocompromised host

Human papillomavirus (HPV) is responsible for common condyloma acuminata and a number of premalignant and malignant anogenital lesions. These conditions are of particular concern in immunocompromised individuals who have higher risk of malignant transformation and are more difficult to treat. This is part I of a two-part review that will highlight the cutaneous features of condyloma acuminata and vaginal, vulvar, penile, and anal intraepithelial neoplasias, with an emphasis on presentation of these HPV-mediated diseases in the immunocompromised host. Counseling patients about these conditions requires a thorough understanding of the epidemiology, natural history of HPV, transmission and infectivity, risk of malignancy, and the role of the host immune response in clearing HPV lesions. Part II will provide an updated review of available treatments, with a focus on recent advances and the challenges faced in successfully treating HPV lesions in immunocompromised patients.

Mo1200 Detection of Intraductal Papillary Mucinous Neoplasm (IPMN) With a High Risk of Malignant Transformation From Pancreatic Cyst Fluid Aspirates by the DAS-1 Monoclonal Antibody

Mo1200 Detection of Intraductal Papillary Mucinous Neoplasm (IPMN) With a High Risk of Malignant Transformation From Pancreatic Cyst Fluid Aspirates by the DAS-1 Monoclonal Antibody

Mo1201 Pancreatic Stellate Cells Express Inducible Nitric Oxide Synthase

BACKGROUND: IPMN is a precursor lesion to pancreatic ductal adenocarcinoma consisting of 4 epithelial subtypes with varying grades of dysplasia. Intestinal type (IPMN-I) often involves the main duct and has a higher risk of developing invasive carcinoma in comparison to gastric type (IPMN-G). Differentiation of high-risk/malignant IPMN from low-risk IPMN and other benign/low-grade cystic pancreatic lesions remains a challenge, especially in the preoperative setting. mAb Das-1 reacts specifically to a colonic epithelial phenotype. It is both sensitive and specific in identifying various pre-malignant and malignant lesions of the upper GI tract including Barrett's esophagus and incomplete gastrointestinal metaplasia associated with gastric cancer. We have previously demonstrated that it specifically detects high risk IPMN tissue histologically. AIM: To assess the ability of mAb Das-1 to identify cyst fluid of IPMN with a high risk of malignant transformation. METHODS: Cyst fluid was aspirated during surgical resection of IPMN (n=10), serous cystadenoma (n=1), and cystic low-grade neuroendocrine tumor (n=1). Cyst fluid was also aspirated during EUS-FNA of pancreatic pseudocysts (n=4). Sandwich ELISA was performed on each sample (utilizing mAb Das-1 IgM & IgG isotypes) and results were confirmed by Western Blot analysis. Statistical significance was calculated by T-test. RESULTS: Pancreatic cyst fluid from all benign/low-grade lesions (n=8) demonstrated very little reactivity with mAb Das-1 (OD 0.137±0.181). Specifically, reactivity was low among cyst fluid collected from low-grade IPMN-G (OD 0.088±0.003, n=2), pseudocyst (n=4) (OD 0.088±0.041), and non-pseudocyst, benign/low-grade lesions (n=4) (OD 0.187±0.251). In comparison, high-risk and malignant IPMN lesions (intermediate-grade IPMN-I & all high-grade/invasive IPMNs n=8) expressed a significantly higher amount of reactivity (OD 0.866±0.151) when compared to low-grade IPMN-G (p<0.001), pseudocyst (p<0.001), and all benign/low-grade lesions (p<0.002). When stratified by subtype, low-grade IPMN-G (n=2, OD 0.088±0.003), IPMN-G with highgrade dysplasia or invasive carcinoma (n=2, OD 0.402±0.313), intermediate-grade IPMN-I (n=2, OD 0.6339±0.100), IPMN-I with high-grade dysplasia or invasive carcinoma (n=3, OD 1.232±0.265) and high-grade Oncocytic IPMN (OD 1.161), demonstrated a progressive increase in reactivity to mAb Das-1 among each subtype. All results obtained by ELISA were confirmed by western blot analysis. CONCLUSION: mAb Das-1 demonstrates significantly higher reactivity in cyst fluid from high-risk and malignant IPMN compared to fluid from low-grade IPMN-G, pancreatic pseudocyts, and other low-grade pancreatic cystic lesions. The expression of this marker in preoperative cyst fluid may be a useful tool to identify high-risk IPMN lesions and stratify surgical management.

Dento-osseous anomalies associated to familial adenomatous polyposis mimicking florid cemento-osseous dysplasia

Familial adenomatous polyposis (FAP) is a colorectal cancer syndrome characterized by the development of multiple polyps of the colon and rectum with high risk of malignant transformation. The extraintestinal manifestations such as dento-osseous changes are associated with FAP. This is a case report of a 36-year-old female patient who was referred for dental treatment with the initial diagnosis of florid cemento-osseous dysplasia (FCOD). However, the association of the imaging dento-osseous findings with the medical history confirmed the diagnosis of FAP. The paper illustrates the clinical characteristics and imaging findings associated with FAP, and also discusses misdiagnosis based exclusively on imaging features.

Neurofibromatosis 1 phenotype associated to malignant peripheral nerve sheath tumours: a case‐control study

Malignant peripheral nerve sheath tumours (MPNSTs) are the main cause of death in neurofibromatosis 1 adult patients. To determine the clinical type of neurofibromas associated to MPNSTs. Case-control study. Cases were neurofibromatosis 1 adults with MPNSTs and controls were patients without MPNSTs individually matched by age and sex (1 : 3). Both were recruited from our database. The following variables were studied: clinical presence of cutaneous, subcutaneous or plexiform neurofibromas and of internal neurofibromas. Internal neurofibromas were confirmed by clinical imaging. Multivariate odds ratios (aORs) were estimated with their 95% confidence interval (CI). From January 1995 to December 2007, 52 patients (cases) were identified with a MPNSTs, 155 controls could be recruited. In the multivariate analysis, MPNSTs were significantly associated with the presence of internal NFs (aOR: 7.5; 95% CI: 3.2-17.4), a trend for an association was observed for the presence of subcutaneous neurofibromas (aOR: 2.11; 95% CI: 0.89-5). This study confirms the association between the MPNSTs and the internal neurofibromas. The later are indeed associated with a high risk of malignant transformation.

Rapidly Involuting Congenital Melanocytic Naevi in Two Children

Congenital melanocytic naevi (CMN) are considered to be neural crest-derived hamartomas, which are visible at, or shortly after, birth as pigmented tumours (1). The incidence of any size of CMN of neonates ranges from 0.2 to 2.1% (2, 3). They are categorized according to the maximum diameter that the naevus will achieve; small ( 10–20 cm) and giant (> 20 cm) (4). In addition to the cosmetic concern, CMN pose several problems, such as neurocutaneous melanosis, and risk of malignant transformation (5, 6). In a systematic review the risk of melanoma in CMN was estimated to be 0.7%, with a higher risk of malignant transformation occurring during childhood and adoles-cence for giant CMN (2, 7, 8). CMN have a dynamic course and may change over time. They can increase in size during childhood, be-come darker in colour, become hairy, or show pigmen -tary regression (9). Spontaneous involution is a rare phenomenon with few cases described in the literature and, when it occurs, it is often associated with a hypo- or de-pigmented halo (6, 9, 10). We report here 2 cases of spontaneous rapid involution without the halo pheno-menon, in medium to large CMN in 2 children referred to the Karolinska University Hospital.CASE REPORTS

Fistula between anterior rectum wall and seminal vesicles as a rare complication of low-anterior resection of the rectum.

Laparoscopic surgery has become a frequently used modality for rectal tumour surgery. A fistula between the rectum and lower urinary tract is one of the possible complications, with rectovesical fistulas occurring most frequently. This case report presents a 66-year-old man who underwent a laparoscopic low-anterior resection of the rectum due to the presence of a polyp with a high risk of malignant transformation. At the time of discharge on the eleventh postoperative day, the patient returned to the hospital with a fever, scrotal swelling and pain in the right hemiscrotum. These symptoms began four hours after discharge from the hospital. There was no sign of faecaluria. The presence of gas in the urinary bladder was confirmed after catheter insertion. The patient was diagnosed with a fistula between the anterior wall of the rectum and seminal vesicles. The diagnosis was based on cystoscopy findings, X-ray and computed tomography irrigography. The condition was treated conservatively by suprapubic insertion of a catheter and antibiotics. The total length of the treatment, including management of subsequent complications, was 4 months. Twelve months after the complication developed, the patient is symptom free, without urinary tract infection recurrence, and is under the care of both surgery and urology clinics. We describe the clinical symptoms, possibilities of treatment and the result of treatment of this rare complication of rectum low-anterior resection, which has never been described in the literature before.

Functional FEN1 genetic variants contribute to risk of hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer

As a DNA repair protein, Flap endonuclease 1 (FEN1) plays crucial parts in preventing carcinogenesis. Two functional germ line variants (-69G > A and 4150G > T) in the FEN1 gene have been associated with DNA damage levels in coke oven workers and lung cancer risk in general populations. However, the role of these genetic variants on gastrointestinal cancer susceptibility is unknown. Therefore, we evaluated the association between these polymorphisms and gastrointestinal cancer risk in two independent case-control cohorts consisted of a total of 1850 gastrointestinal cancer (hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer) patients and 2222 healthy controls. The impact of these variations on FEN1 expression was also examined using liver, esophagus, stomach and colon normal tissues. It was found that the FEN1 -69GG genotypes were significantly correlated to increased risk for developing gastrointestinal cancer compared with the -69AA genotype in both cohorts [Jinan cohort: odds ratios (OR) = 2.14, 95% confidence interval (CI) = 1.47-2.80, P = 1.0 × 10(-)(6); Huaian cohort: OR = 1.93, 95% CI = 1.37-2.50, P = 0.5 × 10(-6)]. Similar results were observed for 4150G > T polymorphism. In the combined meta-analyses, OR for -69GG or 4150GG genotype was 2.02 (95% CI = 1.59-2.45) or 1.86 (95% CI = 1.45-2.28) compared with -69AA or 4150TT genotype. In vivo FEN1 messenger RNA expression analyses showed that the -69G or 4150G allele carriers had ∼2-fold decreased FEN1 expression in gastrointestinal tissues compared with -69A or 4150T carriers, indicating that lower FEN1 expression may lead to higher risk for malignant transformation of gastrointestinal cells. Our results highlight FEN1 as an important gene in human gastrointestinal oncogenesis and genetic polymorphisms in FEN1 confer susceptibility to gastrointestinal cancers.

Pathology of polyps detected in the bowel cancer screening programme

The success of the UK Bowel Cancer Screening Programme (BCSP) is dependent on reliable diagnosis and effective clinical management of pre-invasive adenomatous polyps. As the malignant potential of colorectal adenomas is highly variable, the purpose of histological assessment is to identify patients who will require subsequent surgery or regular colonoscopic surveillance. Our review encompasses the histopathology and differential diagnosis of screen-detected polyps, focusing on features which discriminate lesions at highest risk of malignant transformation. We explore some of the diagnostic challenges confronting screening pathology, including the characterization of serrated lesions and common mimics of dysplasia and malignancy.

Reduced BMP signaling due to BMPR1A germline mutations in juvenile polyposis

Introduction Juvenile polyposis (JP) is characterized by the development of hamartomatous polyps that collectively carry a high risk of malignant transformation. Germline mutations in the gene for bone morphogenetic protein receptor 1A (BMPR1A) and the tumor suppressor SMAD4 predispose to JP. We set out to evaluate the effect of JP BMPR1A mutations on downstream signaling through the bone morphogenetic protein (BMP) pathway. Methods Mutations found in JP patients were individually recreated in a wild-type (WT) BMPR1A expression vector using a PCR-based site directed mutagenesis (SDM) approach. SDM vectors were then cotransfected with a BMP responsive element luciferase vector (BRE-Luc) and a Renilla internal control into HEK-293T cells. Light units reflecting downstream signaling strength were then quantified after 48 hours. Student's t-test was used for statistical analysis. Results Twenty-two SDM JP mutants were created (14 nonsense and 8 missense). After adjusting for transfection efficiency, BMP signaling was found to be altered for 19 mutations, 17 of which were lower than WT. Two missense and 1 nonsense mutation did not lead to a significant change in activity. Compared to WT, the mean decrease in luciferase for nonsense mutations was 73.1% (p Conclusions To date, JP BMPR1A mutations have not been systematically studied in an in vitro model or been shown to affect downstream signaling. This study confirms that the BMPR1A mutations found in JP patients lead to loss of BMP signaling, which is the likely mechanism leading to this phenotype.

Spermine Oxidase Mediates the Gastric Cancer Risk Associated With Helicobacter pylori CagA

Helicobacter pylori-induced gastric carcinogenesis has been linked to the microbial oncoprotein cytotoxin-associated gene A (CagA). Spermine oxidase (SMO) metabolizes the polyamine spermine into spermidine and generates H(2)O(2), which causes apoptosis and DNA damage. We determined if pathogenic effects of CagA are attributable to SMO. Levels of SMO, apoptosis, and DNA damage (8-oxoguanosine) were measured in gastric epithelial cell lines infected with cagA(+) or cagA(-)H pylori strains, or transfected with a CagA expression plasmid, in the absence or presence of SMO small interfering RNA, or an SMO inhibitor. The role of CagA in induction of SMO and DNA damage was assessed in H pylori-infected gastritis tissues from humans, gerbils, and both wild-type and hypergastrinemic insulin-gastrin mice, using immunohistochemistry and flow cytometry. cagA(+) strains or ectopic expression of CagA, but not cagA(-) strains, led to increased levels of SMO, apoptosis, and DNA damage in gastric epithelial cells, and knockdown or inhibition of SMO blocked apoptosis and DNA damage. There was increased SMO expression, apoptosis, and DNA damage in gastric tissues from humans infected with cagA(+), but not cagA(-) strains. In gerbils and mice, DNA damage was CagA-dependent and present in cells that expressed SMO. Gastric epithelial cells with DNA damage that were negative for markers of apoptosis accounted for 42%-69% of cells in gerbils and insulin-gastrin mice with dysplasia and carcinoma. By inducing SMO, H pylori CagA generates cells with oxidative DNA damage, and a subpopulation of these cells are resistant to apoptosis and thus at high risk for malignant transformation.

Update on Precursor and Early Lesions of Hepatocellular Carcinomas

There is increasing evidence to support a multistep model of the process of human hepatocarcinogenesis. Precursor lesions are characterized by the appearance of dysplastic lesions in the form of microscopic dysplastic foci and macroscopic dysplastic nodules. There are 2 types of small hepatocellular carcinoma (HCC) (≤2 cm in diameter): (1) early HCC with an indistinct margin and (2) progressed HCC with a distinct margin. Pathologic diagnostic criteria for early HCC have recently been set up based on a consensus between Eastern and Western pathologists. To review the nomenclature, pathology, and biomarkers of precursor and early lesions of HCC. Literature review and illustrations from case materials were used. Dysplastic foci are composed of large and small cell changes. Small cell change is considered to be a more advanced precursor lesion than large cell change, and large cell change is a rather heterogeneous lesion that may represent both reactive change and true dysplasia. Dysplastic nodules can be categorized as low or high grade according to the degree of atypia. High-grade dysplastic nodules have been reported to show molecular changes similar to HCC and have a high risk of malignant transformation. Early HCC, which may correspond to microinvasive carcinomas of other organs, is a well-differentiated HCC, and differential diagnosis between early HCC and high-grade dysplastic nodule is difficult. Identification of stromal invasion and application of a panel of markers (glypican-3, heat shock protein 70, and glutamine synthetase) is helpful for diagnosis of early HCC. Detection of precursor lesions of HCC is important in recognizing patients with higher risk of developing HCC, and diagnosis of early HCC can improve patient survival by allowing for early and adequate treatment.

Glycogen Storage Disease Type Ia and VI Associated With Hepatocellular Carcinoma: Two Case Reports

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism due to intracellular enzyme deficiency resulting in abnormal storage of glycogen in tissues. GSD represents an indication for liver transplantation (OLT) when medical treatment fails to control the metabolic dysfunction and/or there is an high risk of malignant transformation of hepatocellular adenomas (HCA). Herein we have reported two cases of GSD, type Ia and type VI, which were both associated with rapidly growing HCA, and underwent OLT because of suspect changes in their radiological features. Final histological findings in the explanted liver showed the presence of hepatocellular carcinoma (HCC) in both cases. In GSD type Ia and VI, OLT is considered to be the treatment of choice when a liver neoplasm is suspected. While the association of HCC with GSD type Ia is well known, this is the first case of HCC in GSD type VI so far reported to the best of our knowledge.