Severe periodontitis in a 5-year-old girl with hyperimmunoglobulin E syndrome.

The hyperimmunoglobulin E syndrome (HIES) is a multisystem disorder that affects the: (1) dentition; (2) skeleton; (3) connective tissues; and (4) immune system. Little is known about periodontal manifestations of the syndrome. The purpose of this report was to describe a 5-year-old girl with suspected autosomal-recessive HIES syndrome who revealed profusely bleeding and painful gingiva and generalized aggressive periodontitis. A polymerase chain reaction (PCR)-based microbiological examination detected Porphyromonas gingivalis, Tannerella forsythia, Prevotella nigrescens, Treponema denticola, Eikenella corrodens, and Campylobacter rectus in the deep periodontitis lesions. The extraction of all deciduous teeth due to a poor prognosis and risk of systemic infection led to resolution of the oral inflammation. Long-term follow-up is required to determine the periodontal prognosis of the erupting permanent teeth.

Impact of localized treatment in reducing risk of progression of low-grade oral dysplasia: molecular evidence of incomplete resection.

Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This is mainly due to the difficulty in predicting outcome for this heterogeneous group of lesions. In this study, we constructed a detailed clinical history of 66 mild and moderate dysplasias in order to determine how treatment affected outcome, and to evaluate the effect of treatment on lesions with different genetic profiles, which are defined by patterns of loss of heterozygosity (LOH) associated with low, intermediate and high risk of progression [Clin. Cancer Res., 6, 357-62, 2000]. The results showed that although treatment guided by clinical removal of leukoplakia reduced cancer progression risk in all three risk groups, the amount of reduction in our study group did not reach statistical significance. To assess whether completeness of lesion removal was a major factor in recurrence, repeat biopsies at the primary sites were analyzed for persistent LOH status on chromosomes 3p, 4q, 8p, 9p, 11q, 13q and 17p. Strikingly, eight of 17 cases judged clinically removed contained the same molecular clones in the initial and subsequent biopsies, suggesting incomplete removal. When molecular information was included in the assessment of lesion removal, treatment significantly reduced the risk of progression for cases with intermediate (P=0.043) and high risk (P=0.001) genetic profiles, but not cases with low-risk profiles. A 9.1-fold decrease in progression risk was observed for those with high-risk profile. Altogether, these data suggest the use of molecular profiles to guide the treatment of low-grade dysplasia. Our data also suggest that currently an inadequate margin may in part be responsible for the high rate of recurrence, especially in high-risk lesions.

Increased genetic damage in oral leukoplakia from high risk sites: potential impact on staging and clinical management.

BACKGROUND: Two staging systems for oral leukoplakias have been proposed to better predict prognosis. Although one system includes site as an independent determinant, its use is controversial. METHODS: Recent studies have shown that loss of heterozygosity (LOH) in oral premalignancies is associated with risk of progression. The authors analyzed 127 oral dysplasias for LOH on 3 chromosome arms (3p, 9p, and 17p). The lesions included 71 from the floor of mouth, ventrolateral tongue, and soft palate complex (designated high risk [HR] sites) and 56 from the rest of the oral cavity (low risk [LR] sites). RESULTS: Dysplasias from HR sites contained significantly higher LOH frequencies than LR sites (percentage with any loss, P = 0.0004; percentage with multiple losses, P = 0.0001; percentage loss on each of the arms, P < 0.05). Loss on 3p and/or 9p, a pattern associated with a 24-fold increased risk of progression (Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357-62) was more frequent among HR lesions (P = 0.0005). Loss of heterozygosity frequencies were elevated at HR sites among both genders and among smokers and nonsmokers. For different histologic groups, LOH frequencies were elevated for HR sites in mild dysplasias (P < 0.05) and moderate dysplasias (marginal significance, P = 0.06), but not in severe dysplasias/carcinoma in situ. CONCLUSIONS: Anatomic location of mild and moderate oral dysplasias in Western populations may be an important diagnostic indicator because lesions at HR sites have a greater tendency to include genetic alterations associated with elevated risk of progression.

A high frequency of allelic loss in oral verrucous lesions may explain malignant risk.

Verrucous carcinoma (VC), a variant of squamous cell carcinoma (SCC), is distinct from SCC in morphology and behavior. The underlying genetic changes involved in the development of VC and its precursor verrucous hyperplasia (VH) are unknown. This study determined whether chromosomal regions frequently lost during the development of SCC are also lost in the VH/VC variant. Twenty-five VH and 17 VC were analyzed for loss of heterozygosity (LOH) at 19 loci on 7 chromosome arms using microsatellite analysis. These data were compared with those from 47 reactive hyperplasias, 92 dysplasias (54 low- and 38 high-grade), and 41 SCCS: The results showed that VC/VH shared many of the losses present in dysplasia/SCC but differed in two aspects. First, VC/VH showed early acquisition of loss, compared with a gradual accumulation of losses from dysplasias to SCC. The LOH pattern of VH was similar to that of high-grade dysplasia and sharply different from reactive hyperplasia. The loss in VH often involved multiple arms (in 60% of VH vs 0% of reactive lesions). Only a marginal elevation of loss was observed at 9p (p = 0.06) and 4q (p = 0.05) from VH to VC because of the high degree of loss already present in VH. Second, a strikingly lower frequency of loss at 17p was noted in VH/VC compared with dysplasia/SCC and may indicate human papillomavirus (HPV) involvement. The finding of high-risk LOH profiles in VH may partly account for the high-progression risk seen for VH and also has potentially important clinical implications. The difficult pathological diagnosis of VH/VC from reactive hyperplasia frequently requires repeated biopsies and results in delay in diagnosis and significantly increased mortality/morbidity. Microsatellite analysis might facilitate this differential diagnosis.

High frequency of allelic loss in dysplastic lichenoid lesions.

Oral lichen planus (OLP) is a common mucosal condition that is considered premalignant by some, whereas others argue that only lichenoid lesions with epithelial dysplasia are at risk of progressing into oral carcinoma. A recent study from this laboratory used microsatellite analysis to evaluate OLP for loss of heterozygosity (LOH) at loci on three chromosomal arms (3p, 9p, and 17p) (Am J Path 1997;Vol151:Page323-Page327). Loss on these arms is a common event in oral epithelial dysplasia and has been associated with risk of progression of oral leukoplakia to cancer. The data showed that, although dysplastic epithelium demonstrated a high frequency of LOH (40% for mild dysplasia), a significantly lower frequency of LOH was noted in OLP (6%), which is even lower than that in hyperplasia (14%). Such results do not support OLP as a lesion at risk for malignant transformation. As a second step of the research, we determined LOH frequencies in 61 dysplastic lichenoid lesions (mild 35; moderate 19; severe 7) using the same microsatellite markers and compared these results with data obtained from the first study and from 13 normal mucosal specimens. Dysplastic lichenoid lesions showed a high frequency of loss (54% for lichenoid lesions with mild dysplasia), but values did not differ significantly from those observed in dysplasia of similar degree without lichenoid appearance. None of the normal mucosa demonstrated LOH. Epithelial dysplasia is a sign of malignant risk, independent of lichenoid changes. Such results suggest that pathologists should search for dysplasia carefully in lesions that otherwise qualify as OLP and that caution should be used when discounting dysplasia as being merely a reactive condition in lichenoid lesions.

Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia.

One of the best approaches to identifying genetic changes critical to oral cancer progression is to compare progressing and nonprogressing oral premalignant lesions. However, such samples are rare, and they require long-term follow-up. The current study used the large archive network and clinical database in British Columbia to study loss of heterozygosity (LOH) in cases of early oral premalignancies, comparing those with a history of progression to carcinoma in situ or invasive cancer and those without a history of progression (referred to as nonprogressing cases). Each of 116 cases was analyzed for LOH at 19 microsatellite loci on seven chromosome arms (3p, 4q, 8p, 9p, 11q, 13q, and 17p). The progressing and nonprogressing cases showed dramatically different LOH patterns of multiple allelic losses. An essential step for progression seems to involve LOH at 3p and/or 9p because virtually all progressing cases showed such loss. However, LOH at 3p and/or 9p also occurred in nonprogressing cases. Individuals with LOH at 3p and/or 9p but at no other arms exhibit only a slight increase of 3.8-fold in relative risk for developing cancer. In contrast, individuals with additional losses (on 4q, 8p, 11q, or 17p), which appeared uncommon in nonprogressing cases, showed 33-fold increases in relative cancer risk. In conclusion, analysis of LOH at 3p and 9p could serve as an initial screening for cancer risk of early premalignancies. Follow-up investigation for additional losses would be essential for predicting cancer progression.

Molecular analysis of oral lichen planus. A premalignant lesion?

Oral lichen planus (OLP) is a common mucosal condition that is considered premalignant by some, although others argue that only lichenoid lesions with dysplasia are precancerous. To address the question of whether OLP without dysplasia is premalignant, we used microsatellite analysis to examine 33 cases of OLP for allelic loss at nine loci located on chromosomes 3p, 9p, and 17p. Loss of heterozygosity (LOH) on these three arms occurs frequently in oral tumors, and the presence of these alterations in premalignant lesions suggests that they may play an important role in tumor progression. Results were compared with those observed in oral dysplasias (10 mild, 11 moderate, 16 severe/carcinoma in situ), 22 oral squamous cell carcinomas, and 29 reactive lesions. LOH was present in 6% of OLP, 14% of reactive lesions, 40% of mild dysplasia, 46% of moderate dysplasia, 81% of severe dysplasia/carcinoma in situ, and 91% of squamous cell carcinomas. LOH was detected on only a single arm in OLP and reactive lesions but occurred on more than one chromosome in dysplasia and cancer, and the frequency of this multiple loss correlated significantly with increasing degrees of dysplasia and progression into squamous cell carcinoma (P = 0.0028). Although these findings do not support OLP as a lesion at risk for malignant transformation, such results need to be confirmed by use of other genetic markers as OLP may undergo malignant transformation through genetic pathways different from those of oral dysplasia.

p53 overexpression in oral lichen planus.

Oral lichen planus (OLP) is considered as a premalignant lesion, but some argue that only lichenoid lesions with dysplasia is precancerous. To address the question whether OLP without dysplasia is premalignant, we investigated the immunohistochemical expression of p53 in OLPs without dysplasia. Half of the OLPs showed p53 positive cells in the basal epithelium. SSCP-PCR analysis of 4 p53 positive OLPs failed to demonstrate mutations. What is the significance of p53 expression in these OLPs? The confinement of p53 positive cells to the basal cells seems to be against false positivity. Since the pathogenesis of OLPs involves cell-mediated cytotoxicity (CMC) which causes marked apoptosis, it is possible that the p53 expression represents wild-type p53 that may be regulating the apoptosis. Alternatively p53 protein may be stabilized by some mechanisms other than gene mutation as a result of cellular insults from CMC.

High prevalence of expression of p53 oncoprotein in oral carcinomas from India associated with betel and tobacco chewing.

A recent study reported a low prevalence of p53 expression (11%) in oral squamous cell carcinomas (SCCs) from South Asia, in contrast to a high prevalence (averaging 52%) in other studies. It was proposed that the different aetiologies for oral SCCs in the South Asia population, i.e. betel and tobacco chewing in combination with smoking and alcohol consumption as compared to smoking and alcohol consumption alone in other populations, may account for the low prevalence of p53 expression. To confirm this hypothesis, we examined p53 expression immunohistochemically in 23 cases of oral SCC from patients in Southern India. Thirteen of the 23 SCCs (56.5%) demonstrated nuclear p53 staining. The expression of p53 was strongly correlated with the number of tobacco-containing quids chewed per day (r = 0.8). These data support the hypothesis that carcinogens derived from tobacco and betel chewing may induce p53 mutations, which in turn are involved in the development of oral cancer.

Increase in placental glutathione S-transferase in human oral epithelial dysplastic lesions and squamous cell carcinomas.

This study investigated the immunohistochemical expression of human placental glutathione S-transferase (GST-pi) in the epithelium of oral premalignant and malignant lesions. Epithelial lining of normal oral mucosa, hyperplastic lesions and oral epithelium exhibiting mild dysplasia showed weak to moderate GST-pi staining. Moderate epithelial dysplasia revealed an increased antibody content while severe dysplasia, carcinoma-in-situ (CIS) and squamous cell carcinoma (SCC) demonstrated markedly increased antibody binding. The GST-pi staining was evident mainly in the cytoplasm. Severe dysplasia, CIS and SCC were also characterized by areas of cells with intensive nuclear GST-pi staining. These findings support the hypothesis that GST-pi plays a role in human oral carcinogenesis and may be used as a tumor marker for human oral premalignant and malignant lesions.

The value of epidermal growth-factor receptor (egfr) as a tumor-marker for human oral premalignant and malignant lesions.

A previous study demonstrated increased epidermal growth factor receptor (EGFR) in oral dysplasia while another showed decreased EGFR in oral dysplasia. The present study examined immunohistochemical expression of EGFR in 33 dysplastic oral lesions as well as in 9 normal oral mucosa specimens, 12 hyperplastic oral lesions and 10 oral squamous cell carcinomas (SCCs). There were no significant differences in EGFR staining either in intensity or in the epithelial layers stained among the normal oral epithelium, hyperplastic and dysplastic lesions. In addition, no significant difference was noted between keratinized and non-keratinized specimens and among lesions from different sites. Oral SCCs demonstrated significantly stronger staining than the normal oral mucosa, hyperplastic and dysplastic lesions (p=0.0011). At this time, the conflicting data on the EGFR expression in oral dysplastic lesions indicate that this receptor is not a good marker for oral dysplasia. Because most of the available data (including our results) show that the majority of oral SCC overexpress EGFR, this receptor may be useful in the diagnosis and treatment of some oral cancers.

The expression of placental glutathione-s-transferase (gst-pi) in human normal salivary-glands and tumors.

Immunohistochemical localization of placental glutathione S-transferase (GST-pi) in normal and inflammatory salivary glands (74 cases) and tumors (71 cases) was studied. In the normal and inflamed salivary glands of all locations (including major and minor salivary glands), the ductal epithelial cells showed moderate to strong GST-pi staining, myoepithelial cells showed weak staining and the acinar cells were negative. The staining pattern of the tumor cells was similar to that of their normal counterparts. The tumor cells were generally positive with GST-pi staining except those tumor cells demonstrating acini differentiation (serous cells in acinic cell carcinoma, mucous cells in mucinous cystadenoma and mucoepidermoid carcinomas). Most of the salivary gland tumors, benign or malignant, showed a weak GST-pi staining. Only mucoepidermoid carcinomas demonstrated significantly increased GST-pi reactivity compared to other tumors (p<0.0001), which may be a reflection of both malignancy and squamous differentiation of the tumor. The marked increase in GST-pi activity in mucoepidermoid carcinomas may be useful in serological screening of recurrent and metastatic mucoepidermoid carcinomas.

P53 expression during multistage human oral carcinogenesis.

This study examined the immunohistochemical expression of p53 in human oral premalignancies and squamous cell carcinomas (SCC), and analyzed the relationship between the expression of p53 and the degree of dysplasia. p53 staining was observed in 15 of the 27 oral premalignant lesions (56%), including mild dysplasia, and 7 of the 10 oral SCC (70%), but in none of the 10 hyperplastic oral lesions. With increasing degrees of dysplasia and the appearance of SCC, not only was there an increase in the percentage of cases demonstrating p53 staining, but also an increase in the staining intensity of the positive cells and expansion of these positive cells. The results suggest that mutation of p53 is an early event during oral cancer development and p53 protein may be used as an early adjunct marker for identification of those premalignant lesions with higher malignant potential.

Inflammatory hyperplasias of the oral mucosa.

Reactive inflammatory hyperplastic lesions of the oral mucous membranes comprise one of the most common pathological conditions seen in the oral cavity. Over the years, these "lumps and bumps" have been given a wide variety of names and have engendered a spectrum of theories regarding pathogenesis. This article presents a brief overview of these conditions from the perspective of those lesions that are "common" and those that are "not so common." Clinical examples are featured and, while their pathogenesis receives some comment, no attempt has been made to present either an in-depth discussion or a detailed histomorphological description of the various entities. The accompanying bibliography provides sufficient reference material for those wishing more detail regarding reactive hyperplasias of the oral mucosa.

The influence of cryogenic brain injury on the pharmacodynamics of pentobarbital. Evidence for a serotonergic mechanism.

To study of the influence of brain injury on the pharmacodynamics of pentobarbital, the authors examined the effect of a focal cortical freezing lesion in rats on the brain concentration of pentobarbital associated with lack of response to tail clamp. The freezing lesion was made with a probe (-50 degrees C) applied through a craniotomy to the intact dura over the left parietal cortex. Three days after injury the rats were anesthetized with a continuous intravenous infusion of pentobarbital until they first did not respond to tail clamp stimulation. The brains were then removed for determination of pentobarbital by high-performance liquid chromatography. The brain pentobarbital concentration required to prevent response to tail clamp (EC50) was reduced from 209 +/- 39 nmol/g (mean +/- standard deviation) in rats without brain injury to 149 +/- 28 nmol/g in the injured animals (P = 0.005). The cortical serotonin (5-HT) concentration was increased from 1904 +/- 358 pmol/g in uninjured rats to 2513 +/- 598 pmol/g (P less than 0.01) in injured animals ipsilateral to the lesion. Pretreatment of the rats with p-chlorophenylalanine (PCPA, 200 mg/kg by intraperitoneal injection) to inhibit 5-HT synthesis abolished both the increase in 5-HT concentration associated with the injury (left cortex, 708 +/- 389 pmol/g; right cortex, 911 +/- 979 pmol/g) and the effect of the lesion on EC50 (uninjured, EC50 = 186 +/- 24 nmol/g; injured, EC50 = 179 +/- 47 nmol/g). Prevention of the decrease in EC50 by inhibition of 5-HT synthesis provides support for a functional role for 5-HT in the influence of cold injury on the pharmacodynamics of pentobarbital.

Cerebral perfusion and metabolism during profound hypothermia in children. A study of middle cerebral artery ultrasonic variables and cerebral extraction of oxygen.

Flow velocity of the right middle cerebral artery was studied in eight children during cardiac operations performed with profound hypothermia. Cerebral oxygen consumption was estimated by relating the difference in oxygen content between arterial and venous blood (jugular bulb) to flow velocity. In another six children, also during profound hypothermic procedures, the diameter of the middle cerebral artery was studied with an electronic echo-tracking instrument connected to a real-time ultrasound scanner. Flow velocity and estimated oxygen consumption decreased during cooling in proportion to the temperature decrease (r = 0.67, p less than 0.001, and r = 0.86, p less than 0.001, respectively), whereas the diameter was unaffected by temperature. At a nasopharyngeal temperature of 16.9 degrees +/- 1.9 degrees C flow velocity was reduced to 33.1% +/- 7.0% of the value obtained at 35 degrees C after induction of anesthesia. Correspondingly, the oxygen consumption decreased to 20.1% +/- 6.4%. The increase in oxygen consumption per 10 degrees C change in temperature was 3.6 (2.0 to 3.9) during surface cooling, 2.6 (1.9 to 2.7) during cardiopulmonary bypass cooling, and 2.7 (1.5 to 4.6) during rewarming. Flow velocity was not influenced by perfusion pressure during profound hypothermia within the range of 20 to 42 mm Hg (r = 0.14, p = 0.52) but was related to pump flow (r = 0.73, p less than 0.001). A pump flow down to 0.5 L/min/m2 was found to be adequate during stable profound hypothermia, as judged from the maintained high jugular bulb venous oxygen saturation (70% to 80%). It is concluded that flow velocity is reduced at hypothermia in proportion to the reduced metabolic rate, although modified by other factors that influence cerebral blood flow.