Malignant Transformation of Oral Leukoplakia

[Anonymous]

Santosh Patil, Nitin Kalla, Harshwardhan Singh have published an article.

“Malignant Transformation of Oral Leukoplakia in a young Indian female: A case report” as case of month in http://www.waent.org

view the article online at:
(http://www.waent.org/picture_of_the_month/20091122-leukoplakia/oral-leukoplakia.htm)

        

[drmithila]

Background
Oral hairy leukoplakia (OHL) is a disease of the mucosa first described in 1984. This pathology is associated with Epstein-Barr virus (EBV) and occurs mostly in people with HIV, both immunocompromised and immunocompetent, albeit it can affect patients who are HIV negative. The first case in an HIV-negative patient was reported in 1999 in a 56-year-old patient with acute lymphocytic leukemia. Later, many cases have been reported in heart, kidney, and bone marrow transplant recipients and patients with hematological malignancies.[1]

Pathophysiology
The Epstein-Barr virus (EBV), a ubiquitous herpesvirus estimated to infect 90% of the world’s population, has been linked to a growing number of diseases, especially in immunocompromised hosts. Like all herpesviruses, EBV establishes a life-long, persistent infection of its host. The pathogenesis of hairy leukoplakia is clearly complex, potentially requiring a convergence of factors including EBV co-infection, productive EBV replication, EBV genetic evolution, expression of specific EBV "latent" genes, and immune escape. All of these factors are likely facilitated by local and systemic host immunodeficiency.

EBV initially infects basal epithelial cells in the pharynx, where it enters a replicative state leading to the release of infectious virus into the saliva throughout the life of the infected person. In the pharynx, the virus also enters B cells, where it persists indefinitely in a latent state. Cytotoxic T lymphocytes cannot eliminate EBV from the body, but they are essential in maintaining the latent state of the infection. In states of immune dysfunction in which the number of EBV-specific cytotoxic T lymphocytes is decreased, there is an increase in the number of circulating EBV-infected B cells.

In addition, a marked decrease or an absence of Langerhans cells occurs in hairy leukoplakia biopsy tissues.[2, 3] Langerhans cells are the antigen-presenting immune cells that are required for an immune system response to the viral infection and their deficiency may permit EBV to persistently replicate and escape immune recognition.

Epidemiology
Frequency
United States
Hairy leukoplakia is one of the most common virally induced, oral diseases of HIV infected individuals with a point prevalence as high as 25-53%.[4] The 6-year incidence of oral hairy leukoplakia in this patient population was reported to be around 32%. A significant trend to a lower prevalence of oral hairy leukoplakia was observed in the group of patients who were already taking antiretroviral therapy, non–highly active antiretroviral therapy (HAART) and HAART (P < .001 and P = .004, respectively).[5]

Fewer cases of oral hairy leukoplakia have been reported in non-HIV patients. This is probably due to underdiagnosis and underreporting of this disease in patients with hematological malignancies or solid organ transplantation. Some studies have shown the prevalence of oral hairy leukoplakia in renal transplant recipients to be more than 11%.

International
The incidence of oral hairy leukoplakia is similar to that in the United States and thereby reflects the prevalence of HIV. In populations where the prevalence of HIV is low, oral mucosal lesions alone are poor predictors of HIV infection.[6]

A cross-sectional study from Brazil reported on data collected from clinical examinations, interviews, and medical records for adult patients treated an HIV/AIDS clinic at the University Hospital of the Federal University in Rio Grande. Three hundred persons were observed (April 2006 to January 2007). Of these patients, 51% were male and the mean age was 40 years. Thirty-nine percent presented with oral lesions. The most common was candidiasis (59.1%), followed by hairy leukoplakia (19.5%).[7]

A study from Saudi Arabia reported that compared with age and sex-matched healthy control subjects (N = 52), 8.6% of stable renal transplantation patients (N = 58) had oral leukoplakia. Other oral lesions reported were gingival hyperplasia (74.1%) and erythematous candidiasis (15.5%).[8] However, a study from Spain reported only 1 case of hairy leukoplakia in 500 renal transplant recipients studied.[9]

Mortality/Morbidity
In patients with HIV, the median CD4 count when oral hairy leukoplakia is first detected is 468/µL. If these patients do not have AIDS-defining disease at the time oral hairy leukoplakia is diagnosed, the probability of developing AIDS if not receiving highly active antiretroviral therapy (HAART) is 48% by 16 months and 83% at 31 months. In addition, studies have shown that patients with AIDS with oral hairy leukoplakia have a shorter lifespan than those that do not present this lesion. Furthermore, if these patients are concomitantly co-infected with hepatitis B virus, the risk of early progression to AIDS increases 4-fold.

Race
No racial predilection has been established for oral hairy leukoplakia.

Sex
Oral hairy leukoplakia is most commonly observed in homosexual men who are HIV positive, especially in those who smoke.

Age
No age predilection has been established for oral hairy leukoplakia

 As a benign lesion with low morbidity, oral hairy leukoplakia (OHL) does not require specific treatment in every case. Indications for treatment include symptoms attributable to the lesion, or a patient’s desire to eliminate the lesion for cosmetic reasons. The variable natural history of the lesion and its tendency toward spontaneous resolution should be considered in any management decision. Several treatment options are available.

Systemic antiviral therapy usually achieves resolution of the lesion within 1-2 weeks of therapy.[12] Oral therapy with acyclovir requires high doses (800 mg 5 times per day) to achieve therapeutic levels.[13] Valacyclovir (1000 mg 3 times a day) and famciclovir (500 mg 3 times a day) are newer antiviral drugs with higher oral bioavailability than acyclovir and can be dosed less often. Antiviral drugs inhibit productive EBV replication but do not eliminate the latent state of infection. Hairy leukoplakia often recurs several weeks after the cessation of antiviral therapy.
Topical therapy with podophyllin resin 25% solution usually achieves resolution after 1-2 treatment applications. The treatments may temporarily cause local pain, discomfort, and alteration of taste. Podophyllin has cellular cytotoxic effects, but the mechanism of action in resolving hairy leukoplakia is not known. Again, hairy leukoplakia often recurs several weeks after successful podophyllin therapy.[14]
Topical therapy with retinoic acid (tretinoin) has been reported to resolve hairy leukoplakia. Retinoic acids are known to inhibit EBV replication in vitro and induce epithelial cell differentiation. As with the antiviral agents and podophyllin, hairy leukoplakia often recurs several weeks after successful retinoic acid therapy.
Ablative therapy can also be considered for small hairy leukoplakia lesions. Cryotherapy has been reported as successful but is not widely used.[15]
Institution of HAART, considered to be the standard care in the United States, is useful in eliminating the lesions of oral hairy leukoplakia.

Superinfection with Candida can be addressed with medical therapyhe goals of pharmacotherapy are to reduce morbidity and prevent complicationsThe complication associated with oral hairy leukoplakia (OHL) is an occasional candidal superinfection, which often results in an uncomfortable glossopyrosis (burning tongue).
Altered taste sensation is a rare complication.
The presence of oral lesions has a significant impact on health-related quality of life, because oral health is associated with physical and mental health.

        

[drmithila]

Unilateral or bilateral nonpainful white lesions can be seen on the margins, dorsal or ventral surfaces of the tongue, or on buccal mucosa. The lesions may vary in appearance from smooth, flat, small lesions to irregular "hairy" or "feathery" lesions with prominent folds or projections.

Lesions may be either continuous or discontinuous along both tongue borders, and they are often not bilaterally symmetric. Lesions are adherent, and only the most superficial layers can be removed by scraping. There is no associated erythema or edema of the surrounding tissue. Hairy leukoplakia may also involve dorsal and ventral tongue surfaces, the buccal mucosa, or the gingiva. On the ventral tongue, buccal mucosa, or gingiva, the lesion may be flat and smooth, lacking the characteristic "hairy" appearance.

Causes
Oral hairy leukoplakia has been associated with HIV infection and/or immunosuppression.[10] The risk of developing oral hairy leukoplakia doubles with each 300-unit decrease in CD4 count. A high viral load was strongly associated to the oral lesions occurrence independently of CD4+ cell count.[4] More recently, it has been described in patients with other forms of severe immunodeficiency including those associated with chemotherapy, organ transplant, and leukemia. Rarely, it may occur in patients who are immunocompetent.

Oral hairy leukoplakia also has been described in association with Behçet syndrome and ulcerative colitis.

Smoking more than a pack of cigarettes a day is positively correlated with the development of oral hairy leukoplakia in HIV positive men.

No increase in oral hairy leukoplakia was observed when controlled for number of oral sex partners.

 

        

[Drsumitra]

An interesting read on a connection between periodontitis and leukoplakia
Author: Donna Domino
Periodontitis increases the risk of developing oral leukoplakia and mucosal lesions that are predisposed to become oral cancer, according to a study in Oral Oncology (September 2012, Vol. 48:9, pp. 859-863).
The findings provide clues into the complex relationship between systemic and local disease, noted the study authors from the University of Greifswald in Germany.
The development of oral cancer proceeds through discrete molecular changes that are acquired from loss of genomic integrity after continued exposure to environmental risk factors. It is preceded in the majority of cases by clinically evident, potentially malignant oral disorders, the most common of which is leukoplakia, the researchers noted.
Leukoplakia is an asymptomatic lesion in the oral mucosa. Oral cancer — especially oral squamous cell carcinoma — often develops out of these lesions, they added. Studies have shown that as many as 18% of oral premalignant lesions will develop into oral cancer. In addition, periodontal sites are often involved in proliferative types of leukoplakia.
The oral cancer rate attributed to leukoplakia is between six and 29 per 100,000, according to the authors. Smoking and drinking alcohol are the main risk factors for this disease, but acute infections in the oral cavity may contribute to the risk.
Inflammatory markers
The study evaluated 4,310 German residents ages 20 to79 from 1997 to 2001. After five years, 3,300 participants were available for follow-up.
The periodontal assessment included probing depth, clinical attachment loss, plaque, bleeding on probing, and the number of teeth. Among the study population, 123 (2.9%) of the participants had oral leukoplakia, compared with 246 people in the control group who did not have oral lesions.
Patients with oral leukoplakia showed significantly higher measures of periodontal parameters, especially bleeding on probing and gingival attachment loss, the study found. Despite a high variance, the leukoplakia group also exhibited a higher incidence of tooth loss, and there were more diabetics than in the control group (22% versus 13%).
Gingivitis (as characterized by bleeding on probing) is associated with the occurrence of leukoplakia in a dose-dependent manner, the researchers found.
“From the results it may be concluded that there is a continuously increasing risk of leukoplakia with increasing severity of periodontitis or gingivitis,” they wrote. “Increased concentrations of inflammatory markers suggest that tissues irritated by defense processes such as periodontitis are vulnerable to premalignant transformations.”
These study findings echo a 2011 study by researchers in India that showed elevated levels of salivary interleukin-6 — which was used as a marker of malignant progression — among patients with leukoplakia and periodontitis (Clinical Oral Investigations, October 2011, Vol. 15:5, pp. 705-714). Excluding people with periodontitis, the researchers found the leukoplakia cases still had elevated levels of systemic markers of inflammation. Good oral hygiene (brushing at least twice a day) was associated with decreased risk.
One limitation of the German study was that the oral lesions were not biopsied, the researchers noted.
“Our findings give new hints into the complex interrelationship between systemic and local diseases,” they concluded. “Periodontal inflammation may be considered an additional risk acting synergistically with smoking and/or metabolic factors.”

 

        

[drmithila]

HIV could be reduced to a “minor chronic infection” akin to herpes, scientists developing a new vaccine have claimed.

Spanish researchers found that 22 out of 24 healthy people developed an immune response to HIV after being given the MVA-B vaccine.

Prof Mariano Esteban of the National Biotech Centre in Madrid, said of the vaccination: “It is like showing it a picture of the HIV so that it is able to recognise it if it sees it again in the future.”

The injection contains four HIV genes which stimulate T and B lymphocytes – types of white blood cells.

Prof Esteban said: “Our body is full of lymphocytes, each of them programmed to fight against a different pathogen. Training is needed when it involves a pathogen, like the HIV one, which cannot be naturally defeated.” B cells produce antibodies which attack viruses before they infect cells, while T cells detect and destroy infected cells.

The study showed that almost three-quarters of participants had developed HIV-specific antibodies 11 months after vaccination. More than a third developed a type of T cell that fights HIV, called CD4+, while more than two thirds developed another, called CD8+.

Overall, 92 per cent developed some sort of immune response. Prof Esteban acknowledged the vaccine was at an early stage, describing it as promising. But if it passed clinical trials and made it into production in the future HIV could be compared to herpes virus nowadays, a minor chronic infection that only resulted in disease when the immune system was otherwise compromised.

        

[drmithila]

When OSCC is detected in its early stages, the prognosis is better and the cost of care is lower, according to the study authors. However, some two-thirds of OSCCs are diagnosed at stage III or IV, indicating a need for improved detection and diagnostic methods.

A clinical oral exam — which involves a head and neck examination, visual inspection of the oral mucosa under incandescent overhead or halogen illumination, and palpation — is currently the most common technique used by dental practitioners to detect abnormal oral mucosal changes.

“Relying on a COE to detect oral dysplasia and OSCC, however, may be inadequate, as suggested by the finding that more than 30% of patients with OSCC and oropharyngeal cancer had undergone oral cancer screening during the three years before receiving a diagnosis of OSCC,” the study authors wrote.

Comprehensive lit review

To evaluate the effectiveness of the clinical oral exam in predicting oral dysplasia or oral cancer, the researchers conducted a literature search on PubMed, Web of Knowledge, and the Cochrane Library of articles published from January 1966 through January 2010.

Using the search terms “oral mucosal lesion screening” and “oral lesions,” they found 1,252 articles that met their criteria, but after excluding duplicates, case reports, expert opinions, animal studies, non-English studies, and articles that included data regarding only the detection of a particular lesion or did not include histologic diagnosis of oral mucosal lesions, they ended up with 24 observational studies that included 7,079 patients and 1,956 biopsies. These studies “reported histologic confirmation of clinically detected lesions identified by means of visual examination as subsets of data in studies assessing the COE and the use of adjunctive techniques,” the researchers noted.

Because the 24 studies classified the patient’s degrees of dysplasia in different ways, the study authors subgrouped the data into five categories:

All types of dysplasia were considered as test-positive for potentially malignant epithelial lesions or OSCC.
Mild dysplasia was considered as test-negative, and moderate and severe dysplasia as test-positive.
Mild and moderate dysplasia were considered test-negative, but severe dysplasia as test-positive.
All dysplasia was considered test-negative.
Only a dichotomous evaluation (benign or malignant) was conducted.
The researchers then conducted a meta-analysis of the studies that considered all dysplasia as test-positive. They determined the quality (sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic odds ratio [DOR]) of the studies using the Quality Assessment of Diagnostic Accuracy Studies tool.

Poor specificity

While the researchers found the sensitivity of the clinical oral exam to be good, it was not 100% because patients who had oral mucosal dysplasia or OSCC that had not been biopsied ultimately underwent histologic examination at some point. The researchers considered the lesions that were not biopsied initially but were found to have dysplasia or OSCC histologically to be false-negative, which lowered the sensitivity.

However, they found the specificity of the COE to be relatively poor, as were the positive and negative likelihood ratios (PLR and NLR). Given that the diagnostic odds ratio is PLR divided by NLR, the overall DOR was 6.1 (95% confidence interval), “which indicates the ineffectiveness of the COE to predict oral dysplasia or OSCC,” the study authors wrote.

A COE alone may not detect the nature of an oral mucosal lesion accurately, “thus creating the potential for missed clinical lesions, which can affect the true outcomes of care,” they added.

As a result, practitioners need to be vigilant when conducting head and neck and oral and oropharyngeal examinations, as well as during lymph node palpation, the researchers emphasized. “Considering that the dental office is the most common site for detecting oral cancer, proper education and training of dental professionals may assist in improving the sensitivity, specificity, and accuracy of oral cancer screening,” they wrote.

Adjuncts continue to be sought to improve the findings and accuracy of the clinical oral exam, the researchers added.

“The fact that OSCCs often are diagnosed at an advanced stage emphasizes the need for improving the COE and the need to develop adjuncts to assist in oral mucosal lesion detection and diagnosis,” they concluded.

        

[drsushant]

The International Agency for Research on Cancer, part of the World Health Organization (WHO), predicts that more than 790,000 people worldwide will be diagnosed with oral cancer by 2030, an increase of more than 63% compared with 2008.

Mortality rates for mouth cancer are predicted to be even higher with more than 460,000 deaths forecast by 2030, more than 67% higher than 2008 rates, according to the International Dental Health Foundation (IDHF).

The WHO believes modifying and avoiding risk factors could result in up to 30% of cancers being avoided, noted Nigel Carter, BDS, chief executive of the IDHF.

“Although cancer is not wholly preventable, mouth cancer is very closely related to lifestyle choices. Making more people aware of the risks and symptoms for mouth cancer will undoubtedly save lives,” Dr. Carter stated in a press release. “Forecasts for the incidence and mortality of mouth cancer are very grim. We hope more countries will develop their own oral cancer action campaigns to raise awareness.”

November is Mouth Cancer Action Month, sponsored annually by the IDHF.

        

[Drsumitra]

Researchers at the Stanford University School of Medicine have found a novel way to engineer key cells of the immune system so they remain resistant to infection with HIV, the virus that causes AIDS.

A new study describes the use of a kind of molecular scissors to cut and paste a series of HIV-resistant genes into T cells, specialized immune cells targeted by the AIDS virus. The genome editing was made in a gene that the virus uses to gain entry into the cell. By inactivating a receptor gene and inserting additional anti-HIV genes, the virus was blocked from entering the cells, thus preventing it from destroying the immune system, said Matthew Porteus, MD, an associate professor of pediatrics at Stanford and a pediatric hematologist/oncologist at Lucile Packard Children’s Hospital.
"We inactivated one of the receptors that HIV uses to gain entry and added new genes to protect against HIV, so we have multiple layers of protection — what we call stacking," said Porteus, the study’s principal investigator. "We can use this strategy to make cells that are resistant to both major types of HIV."
He said the new approach, a form of tailored gene therapy, could ultimately replace drug treatment, in which patients have to take multiple medications daily to keep the virus in check and prevent the potentially fatal infections wrought by AIDS. The work was done in the laboratory, and clinical trials would still be needed to determine whether the approach would work as a therapy.
"Providing an infected person with resistant T cells would not cure their viral infection," said Sara Sawyer, PhD, assistant professor of molecular genetics and microbiology at the University of Texas-Austin and a co-author of the study. "However, it would provide them with a protected set of T cells that would ward off the immune collapse that typically gives rise to AIDS."
The study was published in the Jan. 22 issue of Molecular Therapy.
One of the big challenges in treating AIDS is that the virus is notorious for mutating, so patients must be treated with a cocktail of drugs — known as highly active antiretroviral therapy or HAART — which hit it at various stages of the replication process. The researchers were able to get around that problem with a new, multi-pronged genetic attack that blocks HIV on several fronts. Essentially, they hope to mimic HAART through genetic manipulation.
The technique hinges on the fact that the virus typically enters T cells by latching onto one of two surface proteins known as CCR5 and CXCR4. Some of the latest drugs now used in treatment work by interfering with these receptors’ activity. A small number of people carry a mutation in CCR5 that makes them naturally resistant to HIV. One AIDS patient with leukemia, now famously known as the Berlin patient, was cured of HIV when he received a bone marrow transplant from a donor who had the resistant CCR5 gene.
Scientists at Sangamo BioSciences in Richmond, Calif., have developed a technique using a protein that recognizes and binds to the CCR5 receptor gene, genetically modifying it to mimic the naturally resistant version. The technique uses a zinc finger nuclease, a protein that can break up pieces of DNA, to effectively inactivate the receptor gene. The company is now testing its CCR5-resistant genes in phase-1 and -2 trials with AIDS patients at the University of Pennsylvania.
The Stanford scientists used a similar approach but with an added twist. They used the same nuclease to zero in on an undamaged section of the CCR5 receptor’s DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said. This technique of placing several useful genes at a particular site is known as "stacking."
Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.
Blocking HIV infection through both the CCR5 and CXCR4 receptors is important, Porteus said, as it hasn’t been achieved before by genome editing. To test the T cells’ protective abilities, the scientists created versions in which they inserted one, two and all three of the genes and then exposed the T cells to HIV.
Though the T cells with the single- and double-gene modifications were somewhat protected against an onslaught of HIV, the triplets were by far the most resistant to infection. These triplet cells had more than 1,200-fold protection against HIV carrying the CCR5 receptor and more than 1,700-fold protection against those with the CXCR4 receptor, the researchers reported. The T cells that hadn’t been altered succumbed to infection with 25 days.
Porteus said he views the work as an important step forward in developing a gene therapy for HIV.
"I’m very excited about what’s happened already," he said. "This is a significant improvement in that first-generation application."
He said a potential drawback of the strategy is that while the nuclease is designed to create a break in one spot, it could possibly cause a break elsewhere, leading to cancer or other cell aberration. He said it’s also possible the cells may not tolerate the genetic change.
"It’s possible the cells won’t like the proteins they’re asked to express, so they won’t grow," he said.
But he said he believes both problems are technically surmountable. He said the researchers’ next step is to test the strategy in T cells taken from AIDS patients, and then move on to animal testing. He said he hopes to begin clinical trials within three to five years.
Though the method is labor-intensive, requiring a tailored approach for each patient, it would save patients from a lifelong dependence on antiretroviral drugs, which have adverse side effects, Porteus noted.
He said he also hopes to adapt these techniques for use against other diseases, such as sickle cell anemia, one of his areas of interest. Porteus works with patients in the Pediatric Bone Marrow Transplant service at Packard Children’s.
In addition to Sawyer, he collaborated with Richard Voit, a former Stanford graduate student who is now an MD/PhD candidate at the University of Texas Southwestern Medical Center, and Moira McMahon, PhD, a former postdoctoral scholar at Stanford who is now at the University of California-San Diego.
The study was supported by a grant from the American Foundation for AIDS Research and by a Laurie Krauss Lacob Faculty Scholar Award from the Lucile Packard Foundation for Children’s Health.

 

        

[Author]

Posts