Mutation of a type II keratin gene (K6a) in pachyonychia congenita.

Pachyonychia congenita (PC) is a rare autosomal dominant condition characterized by multiple ectodermal abnormalities. Patients with Jadassohn-Lewandowsky Syndrome (MIM #167200; PC-1) have nail defects (onchyogryposis), palmoplantar hyperkeratosis, follicular hyperkeratosis and oral leukokeratosis. Those with the rarer Jackson-Lawler Syndrome (MIM #167210; PC-2) lack oral involvement but have natal teeth and cutaneous cysts. Ultra-structural studies have identified abnormal keratin tonofilaments and linkage to the keratin gene cluster on chromosome 17 has been found in PC families. Keratins are the major structural proteins of the epidermis and associated appendages and the nail, hair follicle, palm, sole and tongue are the main sites of constitutive K6, K16 and K17 expression. Furthermore, mutations in K16 and K17 have recently been identified in some PC patients. Although we did not detect K16 or K17 mutations in PC families from Slovenia, we have found a heterozygous deletion in a K6 isoform (K6a) in the affected members of one family. This 3 bp deletion (AAC) in exon 1 of K6a removes a highly conserved asparagine residue (delta N170) from position 8 of the 1A helical domain (delta N8). This is the first K6a mutation to be described and this heterozygous K6a deletion is sufficient to explain the pathology observed in this PC-1 family.

Photodynamic treatment of oral lesions.

Photodynamic treatment (PDT) was first started in the oral cavity in the mid 1980s. Hematoporphyrins were rapidly replaced by Photofrin and meta-tetrahydroxyphenylchlorin (mTHPC) as photosensitisers of choice, and over the years these two have been approved by several health authorities for PDT. 5-aminolevulinic acid (ALA) and some dyes (e.g., toluidine and methyene blue) have also been tested. Several different nonthermal lasers have been used and lately light-emitting diodes (LEDs) have been tried. Most of the clinical treatments have been carried out on oral squamous cell carcinoma (OSSC), either primary or metastatic lesions, with good results. The treatment leaves little scarring and can be used before, in conjunction with, and adjunctive to other treatment modalities. The greatest disadvantage is that the patients are photosensitive for several weeks following systemic administration of the photosensitiser. PDT is now an accepted palliative treatment. Systemic administration of ALA has been more successful than local application in the treatment of precancerous lesions such as oral leukoplakia. PDT following topical application of photosensitiser (metylene blue and methyl-ALA) has shown improvement in cutaneous diseases of the oral mucous membrane such as oral lichen planus. The bactericidal effect of PDT has also been tested on oral plaque, but little clinical work has been performed so far. Instead of mechanical cleaning or antibiotic therapy, PDT may also play a role in dental diseases.

Pathology of malignant and premalignant oral epithelial lesions.

Oral mucous membranes and the surrounding structures are largely composed of stratified squamous epithelium that is supported by a fibrous connective tissue lamina propria and a submucosa of fibroadipose tissue. Minor salivary glands, nerves, and capillaries course abundantly throughout the supporting collagen and fibro-fatty submucosa. Premalignant and malignant lesions arise most frequently from epithelium, and these epithelial lesions ultimately account for 95% of all cancers of the oral cavity. Malignant neoplasia of bone, cartilage, salivary glands, and connective tissue and those of lymphoproliferative derivatives are far less common occurrences in the oral cavity. Malignant neoplasms can and do arise from the tooth germ apparatus, but neoplasms of odontogenic elements are rare and are not included in this discussion.

Acquired dyskeratotic leukoplakia.

A 36-year-old woman developed progressive dyskeratotic leukoplakia of the palate, lips, attached gingiva, and labial surfaces of the genitalia. On microscopic examination, clusters of dyskeratotic cells were found throughout the epithelium, except in the basal cell layer. The clinical and histologic differential diagnosis included candidiasis, oral hairy leukoplakia, lichen planus, condyloma acuminatum, Darier's disease, hereditary benign intraepithelial dyskeratosis, and white sponge nevus. Her clinical and histologic findings do not permit classification into any of these well-recognized entities.

Oral epithelial dysplasia: clinical characteristics of western European residents.

To detail the clinical presentation of oral epithelial dysplasia in a large cohort of residents in western Europe. Descriptive statistical analysis of the data were calculated using chi-square and Fisher's exact tests. Oral epithelial dysplasia manifested typically as a white or mixed red and white lesion on the tongue, buccal mucosa or floor of mouth. The peak age of presentation of oral epithelial dysplasia was the 6th decade. Most clinically detected lesions had only mild oral epithelial dysplasia. Although uncommon, lesions with severe dysplasia were most likely to arise on the floor of mouth or lateral border of tongue. Oral epithelial dysplasia is likely to manifest as a solitary white patch, but it is not possible to accurately predict the likely degree of dysplasia from the clinical features of such lesions.

Diseases of the oral mucosa.

The dermatologist is often called upon to evaluate diseases of the oral mucosa. He should be prepared to give expert advice based on sound knowledge of oral diseases. This may be aided by biopsy study if the principles and pitfalls of obtaining and interpreting a biopsy specimen are followed. These are discussed and examples are given to illustrate some of the more common and important problems that may be encountered.

Case study: pachyonychia congenita: a mixed type II-type IV presentation.

A 52-year-old woman in good health with a family history negative for dermatologic diseases presented to our department with thickening and dystrophy of all her fingernails and toenails that started when she was born. She also had hyperkeratosis on the palms of her hands and soles of her feet that was confined to sites of pressure and recurrent plantar blisters that began appearing at puberty. The patient reported marked pain while walking from such plantar involvement. Her medical history revealed a persistent hoarseness; palmoplantar hyperhidrosis; and the appearance of numerous cysts on her back, neck, and scalp since she was 20 years old. These latter lesions had been diagnosed as multiple steatocystoma on the basis of the histologic features. Upon examination, all of her fingernails and toenails appeared shortened, thickened,and dystrophic (Figures 1-3). In addition, they presented subungual keratosis and a yellowish-gray color. Hyperkeratosis and small ulcerations were present on the perionychium. Palmoplantar keratoderma was evident, especially on the soles,in association with superficial erosions (Figure 4). Keratosis pilaris was evident on the extensor surfaces of the forearms as well as on the anterior surfaces of the legs. Multiple nodules were detected on the patient's neck, trunk, and axillary regions(Figure 5). They consisted of multiplex steatocystoma and were characterized by a hemispheric shape, a normal-appearing skin color, and by an elastic consistency on palpation. Oral and dental changes were not detected, although hair anomalies were evident. Laboratory parameters disclosed eosinophilia and increased total IgE levels. The results of serum protein electrophoresis was normal, as were those concerning hepatic and renal functions. The ophthalmology examination showed neither corneal dyskeratosis nor cataracts. The neurologic-psychiatric visit revealed slight mental retardation.

[Lesions of the mouth mucosa. An anamnestic and clinical study of 100 consecutive patients with mucosal lesions]. / Veränderungen der Mundschleimhaut. Eine anamnestische und klinische Untersuchung von 100 konsekutiv zugeviesenen Patienten mit Mukosaläsionen.

The present study evaluates and analyzes anamnestic and clinical findings of 100 consecutively referred patients with oral mucosal lesions. The mean age of the cohort was 50.5 years (range 8-91 years) with a female rate of 60 percent. A total of 9 malignant neoplasia were found among the 100 mucosal lesions, including 7 squamous cell carcinomas and 2 mucoepidermoid carcinomas. In addition, 11 cases presented with leukoplakia and 4 cases with lichen planus, both recognized as possible precancerous conditions. These figures support the essential role of the dentist with respect to initial diagnosis and prevention of oral cancer. In addition, stomatologic follow-up examinations are recommended to be performed by each and every general practitioner. In the near future, the dentist will assess oral mucosal lesions more frequently due to the increasing number of elderly patients and to the fact that elderly people present with more lesions compared to younger patients. consistent to literature data, patients with leukoplasia and squamous cell carcinoma had the highest rates of tobacco and alcohol consumption. Therefore, the dentist may also become active in giving preventive information to the patient. the results of the present study showed, that--by employing a standardized examination--a correct clinical diagnosis was identical to the final diagnosis established by laboratory techniques.

Anatomic site based ploidy analysis of oral premalignant lesions.

The location of oral leukoplakia correlates strongly with the probability of finding dysplastic or malignant alterations at biopsy. It is well established that early detection can dramatically improve the 5-year survival rates for oral squamous cell carcinomas. Since aneuploidy is predictive of future conversion to malignancy, we hypothesized that dysplastic lesions from high-risk sites (floor of mouth, tongue and lips) would exhibit greater aneuploidy than low-risk sites (palate, gingiva and buccal mucosa). Epithelial sections from 60 archival samples diagnosed as mild dysplasia (36 females, 20 males) from various high/low risk locations were stained with Blue Feulgen Stain for DNA Ploidy Analysis (Clarient, Aliso Viejo, CA) and ploidy was analyzed using a ChromaVision ACIS II (Clarient, ALiso Viejo, CA) Image cytometry system. A DNA histogram was generated using an image analyzing software that evaluated the amount of Feulgen stain which is proportional to the amount of nuclear DNA. An ANOVA analysis followed by the Student's't' test revealed significant differences between means (P

Exposure to alcohol or tobacco affects the pattern of maturation in oral mucosal cells: a cytohistological study.

OBJECTIVE: To assess the maturation pattern of oral mucosal cells of patients exposed to tobacco and alcohol. METHODS: (i) Group without lesions. Smears obtained from the lower lip, border of the tongue and floor of the mouth of 31 control individuals (group I), 49 tobacco users (group II) and 27 tobacco/alcohol users (group III) were stained using the Papanicolaou method. The first 100 cells counted on each smear determined the maturation pattern and the keratinization index (KI). Analysis of variance (ANOVA) and the Tukey multiple comparison test were used for statistical analysis, at a 5% significance level. (ii) Group with lesions. Cytopathological and histopathological studies were conducted for 15 patients: eight with leucoplakia without epithelial dysplasia, two with epithelial dysplasia and five with squamous cell carcinoma. RESULTS: (i) Group without lesions. Statistical analysis revealed a smaller number of superficial cells with nuclei in all sites of the group of tobacco/alcohol users (group III) when compared to the control group (group I), and this difference was statistically significant (P<0.005). (ii) Group with lesions. The severity of histopathological findings increased with the increase in the number of cells of the deeper epithelial layers, with a statistically significant difference in the number of intermediate (P=0.013) and parabasal cells (P=0.049), which increased with the severity of the epithelial maturation disorder: leucoplakias with dysplasia had a greater number of intermediate and parabasal cells than leucoplakias without dysplasia; and the number in squamous cell carcinomas was greater than in leucoplakias with dysplasia. CONCLUSION: The maturation pattern of cells in the three anatomic sites showed changes that may be associated with the synergistic effect of tobacco and alcohol. Also, the severity of histopathological findings was associated with the increase in the number of cells in the deeper epithelial layers.

[Differential diagnosis of lichen ruber planus of the mouth mucosa and leukoplakia]. / Differentialdiagnose des Lichen ruber planus der Mundschleimhaut und der Leukoplakie

Lichen ruber planus of the oral mucosa is shown in a few examples. Differential diagnosis to leucoplakia can usually be obtained clinically and is confirmed histologically. Treatment consists of the elimination of irritation factors, polyvitamin preparations and local application of beta methason.

[Leukoplakia simplex or metaplastic keratosis of the mouth mucosa?]. / Leukoplakia simplex, oder metaplastische Keratose der Mundschleimhaut?

Leukoplakia simplex lesions affecting the oral mucous membrane of cheeks and the floor of the mouth were characterized from the clinical, histological, electron-microscopical and stereological point of view. An integration of the various observations suggested that a combination of atrophic and metaplastic processes give rise to this type of leukoplakia-lesion which imitates epidermal structures and, therefore, could be defined as a metaplastic keratosis. Possible pathogenetic mechanisms are formulated which might be responsible for and cause this type of oral mucous membrane lesion.

Thermally induced 'nicotine' stomatitis. A case report.

A palatal lesion resembling "nicotine" stomatitis was found in a woman who did not smoke. However, the patient frequently drank extremely hot beverages. After she was instructed to reduce the temperature of the beverages, the lesion almost completely resolved. This suggests that heat was the primary cause of this lesion and also implicates heat as the major cause of nicotine stomatitis.

[Effect of taixian tablet on hamster buccal pouch carcinogenesis].

Eighty syrian hamsters were divided into 4 equal groups. The right buccal pouches of hamsters in group I and group II were painted three times weekly with 0.5% DMBA dissolved in acetone, but the hamsters in group I received 0.45 g Taixian tablet daily by mouth. The animals in group III only received 0.45 g Taixian tablet daily and group IV was control group. After 9, 12 weeks, animals were killed with their pouches excised, and tumors were counted and measured. The results showed; 1. Comparing with group II, the malignant rate of group I was lower after 9 weeks and the tumor volume was smaller after 12 weeks (P < 0.01); 2. It was found histologically many inflammatory cells locating in the epithelial layer and lamina propria of group I after 9 weeks, while only a few inflammatory cells in group II. The high differentiated squamous cell carcinoma could be seen in group I and group II after 12 weeks, but no abnormal changes in cervical lymphnodes and organs (lung, liver, spleen, et al) of all animals in 4 groups. It suggests that Taixian tablet can restrain the development of oral carcinogenesis.

Leukoplakia revisited. A clinicopathologic study 3256 oral leukoplakias.

During a 13-year period, 3256 specimens clinically diagnosed as leukoplakia (('keratosis," "white patch") were submitted to the oral pathology laboratories of Indiana University School of Dentistry and Emory University School of Dentistry. These comprised 6.2% of the tissue specimens processed by these laboratories. The cases were analyzed as to age of occurrence, site of involvement, and pathologic findings. It was found that: leukoplakia occurs chiefly in the 5th, 6th, and 7th decades; about half of the lesions involved the mandibular mucosa, mandibular sulcus, and buccal mucosa; leukoplakia was slightly more common in men (54.2%). Microscopic study showed that 80.1% of the leukoplakias were varying combinations of hyperorthokeratosis, hyperparakeratosis, and acanthosis without evidence of epithelial dysplasia. Mild to moderate epithelial dysplasia was noted in 12.2% of specimens, and severe epithelial dysplasia or carcinoma in situ was found in 4.5%. Infiltrating squamous cell carcinoma was diagnosed in 3.1% of specimens submitted with a clinical diagnosis of leukoplakia. The risk of epithelial dysplasia, carcinoma in situ, or carcinoma varied between the anatomical locations of leukoplakia. The incidence of epithelial alteration, ranging from dysplasia to carcinoma, was 42.9% for lesions of the floor of the mouth, 24.2% for tongue lesions, and 24.0% for lip leukoplakias. The incidence of similar epithelial alterations in other sites varied from 18.8% for palatal lesions to 11.7% for leukoplakias of the retromolar area. The data suggest that there are regional differences in the incidence and character of leukoplakia in the United States. The Emory material, obtained almost exclusively from patients residing in the Southeastern United States, showed a proportionately higher total incidence, a lower male/female ratio, and a greater frequency of epithelial dysplasia, particularly in females, than the Indiana material, which came almost entirely from residents in the Northcentral United States.

Evidence for polymorphism of Merkel cells in the adult human oral mucosa.

We recently reported that Merkel cells in the normal palatine mucosa of adult rodents are highly polymorphic. In order to ascertain whether or not this polymorphism is also evident in the human oral mucosa, palatine mucosae from cadavers without oral diseases and perilesional palatine mucosae of patients with pleomorphic adenoma were examined by immunohistochemistry using an antibody against cytokeratin 20. Findings showed that Merkel cells in the human normal palatine mucosa were polymorphic, and a number of irregular-shaped Merkel cells (dendritic Merkel cells) with apparent cytoplasmic projections were present among typical oval to round Merkel cells. The mucosa usually contained a small number of oval to round Merkel cells residing in ectopic places such as prickle and granular cell layers. On the other hand, the slightly inflamed perilesional palatine mucosa contained an increased incidence of dendritic Merkel cells. Ectopic Merkel cells were rare in the perilesional palatine mucosa. Characteristics of dendritic Merkel cells were examined using specimens from perilesional palatine mucosae by means of immunohistochemistry and electron microscopy. It was shown that every dendritic Merkel cell and most roundish Merkel cells in the perilesional mucosa lacked innervation. Electron microscopy suggested that dendritic Merkel cells release secretory granules from the tip of the cytoplasmic process and the basal cytoplasm towards the lamina propria mucosae, in a manner resembling the case of similar cells in rodents.

Acitretin and treatment of the oral leucoplakias. A model to have an active molecules release.

AIMS: The aim of this study was to investigate the effectiveness of acitretin in a new topical formulation (mucoadhesive two-layer tablets) for the treatment of oral leucoplakias. METHODS: Twenty-one volunteers, 16 men, five women, with oral leucoplakia (histologically diagnosed), were included in this double-blind placebo-controlled study. Patients were randomized in three groups (A, B, C) of seven patients each. Groups A and B received tablets with different in vitro release profiles, and group C subjects (controls) received tablets without acitretin. The acitretin dose was 20 mg/day (two 10 mg tablets daily). Serum aspartate aminotransferase, alanine aminotransferase, cholesterol and triglycerides were evaluated before and after treatment. At the end of therapy the concentrations of acitretin in plasma, saliva and tissue were measured by high-performance liquid chromatography. RESULTS: At the end of the study 71% (groups A and B) of patients showed clinical remission or marked improvement. No improvement was noted in the control subjects (group C). These results were further confirmed by histological findings. There were no significant changes in laboratory values in the three groups. The acitretin concentration in plasma and tissue ranged from 0 to 50 mg with no difference between groups A and B, and it was very high in saliva (ranging from 4.9 to 43 mg) with higher concentrations in group A than in group B (due to a longer adhesion time in group A). Patients' compliance was excellent. The results show that mucoadhesive tablets of topical acitretin are efficacious in the treatment of oral leucoplakia without systemic side-effects.