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1.
Int J Oral Maxillofac Surg ; 31(3): 296-302, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12190137

ABSTRACT

Liquid nitrogen cryotherapy has been advocated as an adjunct in the enucleation and curettage of locally aggressive lesions of the jaws. Simultaneous autogenous bone grafting has also been advocated to accelerate bone formation and reduce morbidity. There is, however, relatively little scientific basis for either of these hypotheses. In this study, nine Yucatan minipigs had artificial defects created in the mandible, which were treated with liquid nitrogen spray. Half of the defects were grafted with autogenous bone from the chin and half were closed primarily. Two animals were sacrificed 3 days postoperatively to measure the width of necrosis and the rest were sacrificed at 3 months to assess healing and new bone formation. It was found that drilling the artificial defects alone caused bone necrosis for a mean depth of 0.09 mm. Liquid nitrogen cryospray caused a mean depth of bone necrosis of 0.82 mm (range 0.51-1.52 mm). The defects that were bone grafted healed well clinically. Defects not bone grafted showed a 50% rate of wound breakdown and sequestrum formation with delayed healing. Vital staining showed a non-significantly greater rate of bone formation in the grafted defects. Digitally superimposed radiography showed a non-significantly greater bone density in the non-grafted defects at 3 months postoperatively. It appears that liquid nitrogen cryospray does devitalize an area of bone around defects in the mandible. The width of necrosis is usually less than 1 mm and subsequent healing is enhanced by autogenous bone grafting. This has clinical implications.


Subject(s)
Bone Regeneration , Bone Transplantation , Cryosurgery/methods , Mandible/surgery , Oral Surgical Procedures/methods , Animals , Mandible/diagnostic imaging , Models, Animal , Nitrogen , Osteonecrosis , Radiography , Subtraction Technique , Swine , Swine, Miniature
3.
Article in English | MEDLINE | ID: mdl-11740483

ABSTRACT

The practice of pathology is currently undergoing significant change, in large part due to advances in the analysis of DNA, RNA, and proteins in tissues. These advances have permitted improved biologic insights into many developmental, inflammatory, metabolic, infectious, and neoplastic diseases. Moreover, molecular analysis has also led to improvements in accuracy of disease diagnosis and classification. It is likely that, in the future, these methods will increasingly enter into the day-to-day diagnosis and management of patients. The pathologist will continue to play a fundamental role in diagnosis and will likely be in a pivotal position to guide the implementation and interpretation of these tests as they move from the research laboratory into diagnostic pathology. The purpose of this 2-part series is to provide an overview of the principles and applications of current molecular biologic and immunologic tests. Part I will discuss the biologic fundamentals of DNA, RNA, and proteins and the methods that are currently available or likely to become available to the pathologist in the next several years for their isolation and analysis in tissue biopsies.


Subject(s)
Diagnosis, Oral/methods , Molecular Diagnostic Techniques , Pathology, Oral/methods , Flow Cytometry , Humans , Lasers , Nucleic Acid Hybridization , Polymerase Chain Reaction
4.
J Oral Maxillofac Surg ; 59(11): 1311-6; discussion 1316-8, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11688034

ABSTRACT

PURPOSE: This article presents a series of cystic ameloblastomas in which an unexpected capacity for bony destruction and recurrence was shown. Proliferation rates were evaluated to see if there is a correlation to the biologic behavior of these lesions. MATERIALS AND METHODS: Clinical and histologic material on 21 consecutive cystic ameloblastomas was retrieved and reviewed. Immunohistochemical analysis of proliferation-associated Ki-67 protein was carried out to determine mitotic indices for 10 cystic ameloblastomas, and these were compared to 10 solid ameloblastomas and 10. dentigerous cysts. RESULTS: Lesions from 10 males and 11 females (age range, 12 to 72 years; mean age, 35 years) were included. All lesions were in the mandible; 18 in posterior sites. Lesion size ranged from 2 to 8 cm in greatest dimension. Cortical perforation was evident in 7 lesions, and multilocularity (more often in older patients) was evident in 6 lesions. Recurrences were seen in 9 cases (43%), and the time between initial treatment and recurrence was as long as 10 years. The characteristic histopathologic feature was a thin, stratified squamous cystic lining with spongiosis and basal palisades. Ten cases also showed mural invasion, and 4 had plexiform luminal proliferation. The proliferation rate of the cystic ameloblastomas (represented as a percentage of cells in cell cycle) was 4.3%, compared with solid tumors at 2.8% and dentigerous cysts at 6.6%. CONCLUSIONS: Cystic ameloblastomas occur within a wide age range, but at slightly lower mean age than solid lesions. There is a very strong predilection for the mandible, and there appears to be no gender difference. Lesions frequently become large, destructive, and/or multilocular. There is a significant recurrence potential, and extended follow-up is advisable. The deceptively innocent histology of cystic ameloblastomas belies the biologic potential of these lesions. The mechanism(s) by which cystic ameloblastomas gain their destructive behavior seems less likely associated with acceleration of the cell cycle than with other factors. Simple enucleation or curettage of these lesions may be inappropriate treatment.


Subject(s)
Ameloblastoma/pathology , Mandibular Neoplasms/pathology , Adolescent , Adult , Aged , Ameloblastoma/surgery , Biomarkers, Tumor , Child , Female , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Male , Mandibular Neoplasms/surgery , Middle Aged , Mitotic Index , Neoplasm Invasiveness , Neoplasm Recurrence, Local
5.
J Calif Dent Assoc ; 29(8): 578-84, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11577668

ABSTRACT

Oral cancer represents an accumulation of defects in the genes that encode key proteins associated with growth and development. Dysregulation of these proteins is central to malignant conversion. This appears to involve three major changes in cell function: 1. altered cell growth, death and longevity; 2. unencumbered cell movement; and 3. development of a new blood supply (angiogenesis). Specific genes, such as p53, p27, p16, and cyclin D-1, are altered in oral cancer through mutation, amplification, or deactivation. These genes are also frequently altered in many other malignancies. In oral mucosa, etiologic agents--especially tobacco and alcohol, and possibly some viruses--are known to induce alterations in the genes and gene functions associated with cell cycle regulation, contributing to the development of squamous cell carcinoma and epithelial dysplasias. Identification of the specific genes/proteins and the sequence in which they appear in the transformation of a normal cell to a malignant cell is necessary for the formulation of new treatment strategies, the development of early detection methods, and the prediction of patient outcome.


Subject(s)
Mouth Neoplasms/genetics , Carcinoma, Squamous Cell/genetics , Cell Death/genetics , Cell Division/genetics , Cell Movement/genetics , Cell Transformation, Neoplastic/genetics , Cocarcinogenesis , Epithelial Cells/pathology , Gene Expression Regulation, Neoplastic/genetics , Humans , Mutation/genetics , Neovascularization, Pathologic/genetics
6.
Cancer Res ; 61(6): 2371-5, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11289098

ABSTRACT

The CDKN2A gene locus encodes two different proteins derived from alternative splicing. p16 (exons 1alpha, 2, and 3) acts as a G1 cell cycle regulator, and p14ARF (exons 1beta, 2, and 3) acts to modulate MDM2-mediated degradation of p53. Inactivation of p16 is a common finding in many cancers; however, there is little data on CDKN2A gene abnormalities in oral precancer. In this longitudinal study, we examined changes in the CDKN2A gene locus in sequential epithelial dysplasias and oral carcinomas from 11 patients. Genomic DNA was extracted from laser-microdissected lesional tissue, and exons 1alpha, 1beta, and 2 were analyzed by duplex PCR. Immunohistochemistry was done to identify p16 and p14ARF protein expression. Two adjacent polymorphic microsatellite markers were used for allelotyping. Homozygous deletion of exon 1alpha was identified in 2 of 17 (12%) precancerous lesions. Loss of either exon 1alpha, exon 2, or both was seen in seven of nine (78%) carcinomas. In five of these carcinomas, there was loss of only exon 1alpha. No case showed deletion of exon 1beta. In 5 of 11 patients, microsatellite markers showed differing patterns of allelic imbalance in the precancerous lesions and the subsequent carcinoma, suggesting a complex genetic pattern of progression from dysplasia to carcinoma. We conclude that during oral carcinogenesis homozygous deletion of exon 1alpha of the CDKN2A gene is common but that deletion of exon 2 and 1beta is less frequent. Moreover, our results suggest that the progression from oral precancer to cancer, in some cases, is more complex genetically than predicted by linear models of carcinogenesis.


Subject(s)
Carcinoma, Squamous Cell/genetics , Gene Deletion , Genes, p16/genetics , Mouth Mucosa/pathology , Mouth Neoplasms/genetics , Precancerous Conditions/genetics , Actins/genetics , Carcinoma in Situ/genetics , Carcinoma in Situ/metabolism , Carcinoma in Situ/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Disease Progression , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gene Amplification , Humans , Immunohistochemistry , Longitudinal Studies , Male , Microsatellite Repeats/genetics , Mouth Mucosa/metabolism , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Polymerase Chain Reaction , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Proteins/metabolism , Tumor Suppressor Protein p14ARF
7.
Article in English | MEDLINE | ID: mdl-11113818

ABSTRACT

OBJECTIVE: The purpose of this study was to describe the clinical-pathologic features of what appears to be a gingival form of proliferative verrucous leukoplakia. STUDY DESIGN: Ten adult patients with recurrent and histologically progressive gingival leukoplakias who were diagnosed and treated at the University of California, San Francisco between 1994 and 1999, comprised the subject group for this investigation. Clinical and microscopic features were reviewed. Proliferation indices and p53 expression were evaluated immunohistochemically, and the presence of human papillomavirus (HPV) DNA was determined by using polymerase chain reaction (PCR) amplification. RESULTS: Lesions presented as solitary or regional flat/papillary/verrucal leukoplakias of the free and attached gingiva (tooth-bearing areas only). With time, flat lesions developed a papillary or verruciform profile. Although lesions were recurrent, they were confined to the gingiva, and multiple lesions did not develop. Half the patients used tobacco, and HPV could not be detected by using PCR. Microscopically, 6 cases began as hyperkeratotic lesions, and 4 initially exhibited a psoriasiform pattern with a marked inflammatory component. With recurrences, the lesions became progressively atypical histologically. The proliferation indices for these lesions showed modest increases over normal epithelium, and positive p53 staining was evident in 4 of 10 cases, indicating a disruption of the keratinocyte cell cycle in these lesions. The mechanism associated with the positive p53 staining (protein binding to wild type p53 versus mutation of the p53 gene) was not determined. Lesions recurred after conservative scalpel or laser excision, and many developed into verrucous or squamous cell carcinoma. CONCLUSIONS: Proliferative verrucous leukoplakia of the gingiva (PVLG) appears to be a subset of oral proliferative verrucous leukoplakia. It can be characterized as a solitary, recurring, progressive white patch that develops a verruciform architecture and may not be associated with HPV. PVLG has an unpredictable course and is at risk for development into verrucous or squamous cell carcinoma. Currently, there is no way to determine or predict which gingival white lesions will follow the clinical course described for this group of patients with PVLG.


Subject(s)
Gingival Neoplasms/pathology , Leukoplakia, Oral/pathology , Aged , Aged, 80 and over , Cell Transformation, Neoplastic , DNA, Viral/analysis , Female , Gingival Neoplasms/chemistry , Gingival Neoplasms/virology , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Leukoplakia, Oral/chemistry , Leukoplakia, Oral/virology , Male , Middle Aged , Papillomaviridae/isolation & purification , Polymerase Chain Reaction , Tumor Suppressor Protein p53/analysis
8.
J Pathol ; 190(4): 417-22, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10699989

ABSTRACT

Previous studies of oral cancer have suggested that alterations of the p53 tumour suppressor gene occur early in the precancerous stage of development. However, these observations have been based on cross-sectional assessment of abnormal p53 protein staining by immunohistochemistry and may not necessarily reflect gene changes. The purpose of this longitudinal study was to examine the changes in the p53 gene in progressive, sequential epithelial dysplasias and carcinomas from the oral cavity. The study analysed 24 formalin-fixed, paraffin-embedded tissue biopsies from ten patients with two or more temporally distinct lesions from the same site in the oral cavity with the diagnosis of hyperkeratosis, epithelial dysplasia, carcinoma in situ or squamous cell carcinoma. Exons 5-8 of the p53 gene were amplified from genomic DNA using intronic primers and directly sequenced using fluorescent-labelled primers. Standard immunohistochemistry with the DO7 monoclonal antibody was used to detect mutant and wild-type p53 protein. Mutations of the p53 gene were identified in 9 of 24 samples. Eight were missense mutations and one occurred at a splice site. In six patients, mutations of the p53 gene occurred late after the transformation of epithelial dysplasia to carcinoma. In two patients with progressive dysplasia, but who had yet to develop invasive carcinoma, p53 missense mutations occurred at the carcinoma in situ stage in one case and in a moderate dysplasia in the other. There was an inconsistent relationship between gene mutations and the level of p53 protein staining by immunohistochemistry. It is concluded that during oral carcinogenesis, p53 gene mutations seem to occur relatively late and are associated with transformation to the invasive phenotype.


Subject(s)
Carcinoma in Situ/genetics , Carcinoma, Squamous Cell/genetics , Genes, p53/genetics , Mouth Neoplasms/genetics , Mutation/genetics , Precancerous Conditions/genetics , Biopsy , Carcinoma in Situ/pathology , Carcinoma, Squamous Cell/pathology , Disease Progression , Female , Gene Expression , Humans , Male , Middle Aged , Mouth Neoplasms/pathology , Polymerase Chain Reaction/methods , Precancerous Conditions/pathology , Sequence Analysis, DNA
9.
Arch Pathol Lab Med ; 124(3): 401-5, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10705394

ABSTRACT

OBJECTIVE: To evaluate cellular composition of salivary gland adenomas using 3 monoclonal antibodies that recognize a smooth muscle phenotype confirmed to be sensitive for myoepithelial differentiation. DESIGN: Immunohistochemical evaluation of 25 salivary gland basal cell and canalicular adenomas. SETTING: Archival pathology material from the files of Henry Ford Hospital, Detroit, Mich, and the University of California at San Francisco. RESULTS: All basal cell adenoma variants exhibit some degree of myoepithelial cell participation with periductal, epithelioid, and spindled (stromal-like) morphologic structures. Only the canalicular adenomas, even if mixed with trabecular and solid patterns, are devoid of staining with these 3 antibodies, suggesting an adenoma composed exclusively of ductal luminal cells. CONCLUSIONS: There is an overlapping histomorphologic and common cellular composition of the basal cell adenoma variants with other recognized adenomas, such as pleomorphic adenoma and myoepithelioma. Relative differentiation toward 3 cell phenotypes (ductal luminal, basal, and myoepithelial) and the character of extracellular matrix production in varying proportions by the neoplastic myoepithelial cells distinguishes the spectrum of salivary gland adenomas identified in current classification schemes.


Subject(s)
Adenoma/pathology , Epithelial Cells/pathology , Muscle, Smooth/pathology , Salivary Gland Neoplasms/pathology , Actins/immunology , Actins/metabolism , Adenoma/classification , Adenoma/metabolism , Adenoma, Pleomorphic/classification , Adenoma, Pleomorphic/pathology , Antibodies, Monoclonal/immunology , Calcium-Binding Proteins/immunology , Calcium-Binding Proteins/metabolism , Epithelial Cells/metabolism , Humans , Immunoenzyme Techniques , Microfilament Proteins , Muscle, Smooth/immunology , Muscle, Smooth/metabolism , Myoepithelioma/classification , Myoepithelioma/pathology , Myosin Heavy Chains/immunology , Myosin Heavy Chains/metabolism , Salivary Gland Neoplasms/classification , Salivary Gland Neoplasms/metabolism , Calponins
10.
J Calif Dent Assoc ; 27(4): 285-9, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10528561

ABSTRACT

There are a variety of lesions besides the typical granulomas and cysts that can appear at the apices of teeth. These other lesions must receive consideration in the diagnosis of periapical disease because of their potential impact on patient treatment and outcome. This paper will review the spectrum of diseases that may present in periapical tissues, the pathogenesis, of periapical inflammatory disease, and the signs and symptoms that separate periapical inflammatory disease from neoplastic disease.


Subject(s)
Periapical Diseases/pathology , Diagnosis, Differential , Humans , Inflammation , Periapical Diseases/diagnostic imaging , Radiography
12.
Laryngoscope ; 109(6): 949-53, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10369289

ABSTRACT

OBJECTIVES/HYPOTHESIS: To assess the efficacy of laser therapy for the management of premalignant oral lesions. STUDY DESIGN: The study group consisted of seventy consecutive laser-treated patients with oral leukoplakia. The microscopic diagnosis included idiopathic focal keratosis, dysplasias of all grades, and verrucous hyperplasia (proliferative verrucous leukoplakia). Thirty-nine patients had some degree of microscopic dysplasia and six demonstrated high-risk proliferative verrucous leukoplakia. The clinical appearances of the lesions were white (homogeneous leukoplakia) in 48, red and white (erythroleukoplakia) in 8, and verrucous in 14. There were 38 men and 32 women in this group. The average age was 63 years (range, 31-90 y). METHODS: Lasers employed were the CO2 and Nd:YAG lasers, and standard laser safety protocols were used. RESULTS: There was no postoperative infection, hemorrhage, or paresthesia Two patients developed pyogenic granulomas in their surgical sites. Fifty-five of 70 patients were followed for more than 6 months; follow-up averaged 32 months (range 6-178 mo). Twenty-nine patients had complete control of their lesions; 19 patients had small recurrences removed with subsequent laser surgeries, leading to control; 2 patients had complete recurrences; and 5 patients developed squamous cell carcinoma at the lesion site. Verrucous lesions had an especially high rate of recurrence (83%), with 9 of 12 ultimately controlled with subsequent surgeries. CONCLUSIONS: Laser surgery of oral leukoplakia is an effective tool in a complete management strategy that includes careful clinical follow-up, patient education to eliminate risk factors and report suspicious lesions, and biopsy of suspicious lesions when appropriate. However, recurrence and progression to cancer remain a risk.


Subject(s)
Laser Therapy , Leukoplakia, Oral/surgery , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/etiology , Cell Transformation, Neoplastic , Disease Progression , Female , Follow-Up Studies , Humans , Leukoplakia, Oral/complications , Leukoplakia, Oral/pathology , Male , Middle Aged , Mouth Neoplasms/etiology , Recurrence , Treatment Failure , Treatment Outcome
13.
Oral Oncol ; 35(1): 63-9, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10211312

ABSTRACT

The cyclin-dependent kinase inhibitor p21/waf1 is regulated by p53-dependent and p53-independent pathways. In addition, mdm2 is an oncogene which forms an auto-regulatory loop with the normal p53 protein and its role has been implicated in oncogenesis. To determine whether a correlation exists between the expression of these gene products, tumor differentiation, tumor staging and radiation therapy, we investigated the expression of p21, p53 and mdm2, and cellular proliferation by Ki-67 (MIB1) labeling index using immunohistochemistry in 88 human oral squamous cell carcinoma (SCC) samples from 56 patients. Tumor expression of all nuclear proteins was scored according to the percentage of positive cancer nuclei, both with the cancer tissue as a whole as well as in different epithelial compartments of differentiation. Positive p21, p53, mdm2 and MIB1 staining was present in 82.4, 67.8, 25.9 and 98.8% of the SCC samples. The staining in different epithelial compartments of differentiation varied: those of p21 and mdm2 present predominantly in suprabasal and upper regions of the tumors: those of p53 and MIB1 in basal and suprabasal regions. Higher levels of p21 expression were seen in actively proliferating tumors (P = 0.025). p21 expression positively correlated with mdm2 expression but not with p53 expression. Moreover, the level of p21 expression was higher in older patients (P = 0.024) and female patients (P = 0.008). There was no significant association among p53, mdm2 and MIB1. Expression of p53 was higher in tumors with poorer cellular differentiation and in younger patients (P = 0.038 and 0.028). There was no association between tumor stage by TNM classification and the expression of any of these gene products or proliferation index. Radiation therapy did not alter the expression of any of these. To conclude, p21 protein was overexpressed in oral SCCs, and this overexpression was related to cell proliferation index and mdm2 expression but independent of p53 protein alteration. Overexpression of p21 alone appeared to be insufficient to suppress tumor progression.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cyclins/metabolism , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Proto-Oncogene Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Adult , Age Factors , Aged , Aged, 80 and over , Antigens, Nuclear , Carcinoma, Squamous Cell/genetics , Cell Division , Cyclin-Dependent Kinase Inhibitor p21 , Female , Humans , Immunohistochemistry , Male , Middle Aged , Mouth Neoplasms/genetics , Nuclear Proteins/metabolism , Proto-Oncogene Proteins c-mdm2 , Sex Factors
14.
Oral Oncol ; 35(1): 77-85, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10211314

ABSTRACT

Expression of apoptosis-associated proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of apoptosis may be altered in the development of oral squamous cell carcinoma. Ninety archived paraffin-embedded specimens from 25 patients (two or more sequential biopsies each) and eight control specimens were evaluated in immunohistochemically stained sections for tumor suppressor protein p53, p53 binding protein mdm-2, and apoptosis regulatory proteins Bcl-2, Bcl-X, Bax, and Bak. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty of 90 specimens showed positive p53 expression, nine of which were dysplasias. In patients with one or more lesions displaying p53 expression, there was increased intensity of staining with disease progression. Bak was expressed in 57/90 specimens, including 27 dysplasias of various grades. There was also a significantly increased intensity of Bak staining with disease progression, which did not appear to be dependent upon p53 status. Bcl-X was expressed in 73/90 specimens, with staining displayed earlier in premalignant lesions than either p53 or Bak. Ten of 90 specimens were positive for Bcl-2 (all were dysplasias or carcinomas), and only 2/90 specimens were positive for Bax. Eleven of 90 specimens were positive for mdm-2; six of which were also positive for p53. These data show that apoptosis-associated proteins are altered in variable patterns in both premalignant and malignant oral epithelial lesions. p53 and especially Bak and Bcl-X are expressed early; Bax is largely absent; and Bcl-2 and mdm-2 show sporadic expression in the development of oral premalignant and malignant disease.


Subject(s)
Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/pathology , Neoplasm Proteins/metabolism , Nuclear Proteins , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Adult , Aged , Apoptosis/physiology , Biopsy , Carcinoma, Squamous Cell/etiology , Carcinoma, Squamous Cell/metabolism , Female , Humans , Immunohistochemistry , Male , Middle Aged , Mouth Neoplasms/etiology , Mouth Neoplasms/metabolism , Proto-Oncogene Proteins c-mdm2
15.
Oral Oncol ; 35(3): 333-42, 1999 May.
Article in English | MEDLINE | ID: mdl-10621856

ABSTRACT

Expression of cell cycle regulatory proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of the cell cycle may be altered in the development of oral squamous cell carcinoma. Archived paraffin-embedded specimens (n = 90) from 25 patients with recurrent or persistent lesions were evaluated in immunohistochemically stained sections for cell cycle regulatory proteins p53, Rb, Cyclin D1, p27, and p21. The cell cycle was also evaluated by expression of nuclear protein Ki 67. Sections were graded semiquantitatively using a 0-3 + scale to indicate the percentage of positively stained cells. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty-three of 90 specimens showed positive p53 expression, 11 of which were dysplasias. Eighty-nine of 90 specimens, from all stages of disease, showed positive Rb expression. Twenty-three of 90 specimens showed positive Cyclin D1 expression, typically in the later stages (carcinoma) of a patient's disease. Eighty-four of 90 specimens showed positive p21 expression; while 55 of 90 specimens were positive for p27. In control mucosa, p27 was highly expressed, while Rb and p21 proteins were expressed at relatively low levels; p53 and Cyclin D1 proteins were largely absent. Generally, staining of p53, Rb, p21, and Ki 67 increased with time in serial biopsies, while p27 showed decreased staining with disease progression. These data show that cell cycle regulatory proteins are altered in both premalignant and malignant disease, and that protein phenotypes are heterogeneous. P53 expression is seen early, and Cyclin D1 expression is seen late in the development of oral premalignant and malignant disease. Expression of p53, Rb, p21 and Ki67 increased, while p27 decreased, with disease progression.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Cell Cycle Proteins/metabolism , Mouth Neoplasms/metabolism , Adult , Aged , Female , Humans , Immunohistochemistry , Male , Middle Aged , Precancerous Conditions
16.
Oral Oncol ; 35(4): 379-83, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10645402

ABSTRACT

Relatively rare squamous cell carcinomas of the tongue in young patients may be associated with different etiologic factors and pathogenetic mechanisms than carcinomas from the same site in older patients. Alterations in cell cycle proteins likely contribute to the biologic behavior of these neoplasms. The purpose of this investigation was to evaluate cell cycle proteins (p53, p21, Rb, MDM2) in lateral tongue cancers from patients at the two ends of the age spectrum. All available archived lateral tongue carcinomas from patients < 35 years (n = 36, 23 males and 13 females) were sectioned, immunohistochemically stained, and evaluated. Protein expression was scored as percent positive nuclei. An equal number of sequentially accessioned lateral tongue specimens from patients > 75 years (23 males and 13 females) were stained and compared. Positive p53 staining was seen in 18/36 of the < 35-year group versus 24/36 of the > 75-year group (p = 0.149). Increased p21 staining (both percent of positive cells and intensity) was evident in 25/32 of the < 35-year group versus 24/32 of the > 75-year group (p = 1.0). Increased p21 expression was seen in both p53-positive and -negative cases in both age groups. Rb protein was increased in 16/29 of the < 35-year group versus 17/26 of the > 75-year group (p = 0.58). Fourteen cases (4/35 vs 10/36, p = 0.135) showed positive MDM2 staining; MDM2-positive cases were also p53 positive in 4/4 younger and 8/10 older patients. We conclude that p53, p21, Rb, and MDM2 are over-expressed in lateral tongue cancers, and that immunohistochemical profiles are heterogeneous. A p53-independent pathway of p21 induction is supported by the results; p53 suppression may be associated with MDM2 protein expression in a subset of cancers. Significant differences in the expression of p53, p21, Rb, and MDM2 proteins are not evident in lateral tongue carcinomas from patients < 35 years as compared to patients > 75 years.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Cyclins/metabolism , Neoplasm Proteins/metabolism , Nuclear Proteins , Proto-Oncogene Proteins/metabolism , Retinoblastoma Protein/metabolism , Tongue Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Cyclin-Dependent Kinase Inhibitor p21 , Female , Humans , Immunohistochemistry , Male , Proto-Oncogene Proteins c-mdm2
17.
Article in English | MEDLINE | ID: mdl-9720096

ABSTRACT

Extranodal oral lymphomas, seen with increasing frequency in HIV infection, may have dysfunctional apoptotic mechanisms that favor tumor progression. The purpose of this study was to evaluate extranodal lymphomas from HIV-positive patients for expression of apoptosis-associated proteins. Correlations were made with 10 histologically comparable extranodal lymphomas from HIV-negative patients and 6 hyperplastic lymph nodes from otherwise healthy young adults. Formalin-fixed tissue sections were immunohistochemically stained for apoptosis-associated proteins (Bcl-2, Bcl-x, Bax, Bak, p53, MDM2, BHRF). In situ hybridization was also done on deparaffinized sections for Epstein-Barr virus EBER mRNA. Eighteen consecutive oral lymphomas were studied in HIV/AIDS-positive patients. Four of 5 intermediate-grade lymphomas expressed Bcl-2 to a greater degree than did high-grade lymphomas (4 of 13). Most lymphomas were positive for Bcl-x and Bax, and few expressed Bak. The staining patterns for these proteins were similar to those seen in HIV-negative patients. Staining patterns were relatively consistent in the hyperplastic lymph nodes, whereas such patterns were irregular in lymphomas. Positive p53 staining was seen in 11 of 18 HIV-positive cases; 9 of these were also MDM2-positive. Double stains suggested that both p53 and MDM2 proteins were expressed in the same cells in these nine cases. Epstein-Barr virus-EBER mRNA was detected in 14 of 18 cases and in 3 of 10 cases from HIV-negative patients. BHRF staining was evident in only a few cells of three HIV-positive lymphomas. The irregular expression of Bcl-2, Bcl-x, Bax, and Bak in oral lymphomas indicates dysfunctional apoptotic mechanisms in these tumors. Bcl-2 staining differs with tumor grade. Positive staining for p53 and MDM2 proteins is a notable feature of lymphomas in HIV-positive patients and may relate to binding of MDM2 to wild-type p53. Epstein-Barr virus is more commonly associated with oral lymphomas in HIV-positive patients, although the Epstein-Barr virus-produced protein BHRF, which has Bcl-2-like activity, is minimally expressed.


Subject(s)
Apoptosis , HIV Seropositivity , Lymphoma, AIDS-Related/chemistry , Mouth Neoplasms/chemistry , Nuclear Proteins , Proteins/analysis , Adolescent , Adult , Aged , Apoptosis/genetics , Child , Disease Progression , Female , Gene Expression Regulation, Neoplastic , HIV Seronegativity , Humans , Hyperplasia , Lymph Nodes/chemistry , Lymph Nodes/pathology , Male , Membrane Proteins/analysis , Membrane Proteins/genetics , Middle Aged , Neoplasm Proteins/analysis , Neoplasm Proteins/genetics , Proteins/genetics , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/analysis , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-mdm2 , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/genetics , Viral Proteins/analysis , Viral Proteins/genetics , bcl-2 Homologous Antagonist-Killer Protein , bcl-2-Associated X Protein , bcl-X Protein
18.
Oral Dis ; 4(2): 95-9, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9680897

ABSTRACT

OBJECTIVE: It has been observed that the cytopathic changes in hairy leukoplakia (HL) correlate with ultrastructural evidence of intra-keratinocyte herpes-type viral particles. In situ hybridization is considered to be the definitive confirmation of Epstein-Barr virus (EBV)-induced HL. This study evaluated the consistency of histopathological findings, which many believe to be diagnostic, with in situ hybridization for EBV-DNA in 60 patients with lesions clinically suggestive of HL. MATERIALS AND METHODS: Hematoxylin and eosin (H&E)-stained sections were reviewed independently by three oral pathologists who did not know the hybridization results. The presence in keratinocytes of nuclear inclusions and/or homogenization, believed to be specific for EBV in these lesions, was used as an indicator for infection. Cytoplasmic changes were evaluated separately. RESULTS: With in situ hybridization, 48 cases were positive and 12 were negative. When the two methods were compared, pathologist concurrence ranged from 83% to 92%. False negatives ranged from 6% to 19%, and false positives ranged from 8% to 25%. Cytoplasmic ballooning, homogenization, and perinuclear clearing were evident in all cases of hybridization-confirmed HL; however, these changes were also noted in 75% (9/12) of the cases with negative hybridization results. Most confirmed HL cases exhibited both nuclear homogenization and inclusions, although the former was more consistently seen. CONCLUSION: Cytoplasmic changes did not agree well with EBV-DNA hybridization results, whereas nuclear changes demonstrated good, but not complete, agreement. In appropriate clinical settings, the finding of nuclear inclusions and/or homogenization may be of diagnostic value. However, because the potential for false positives and negatives is high, H&E cytopathology should not be used as a substitute for in situ hybridization in the definitive diagnosis of oral hairy leukoplakia.


Subject(s)
Herpesvirus 4, Human/isolation & purification , Leukoplakia, Hairy/pathology , Leukoplakia, Hairy/virology , Cytopathogenic Effect, Viral , DNA, Viral/analysis , False Negative Reactions , False Positive Reactions , Herpesvirus 4, Human/genetics , Humans , In Situ Hybridization , Keratinocytes/pathology , Keratinocytes/virology , Leukoplakia, Hairy/diagnosis , Observer Variation , Predictive Value of Tests , Reproducibility of Results
19.
Oral Dis ; 4(4): 241-7, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10200702

ABSTRACT

OBJECTIVES: Hyaluronan (HA) and CD44 are most likely associated with tumor invasion and metastasis. Malignancies with different degrees of aggressiveness may express different levels and patterns of HA and CD44. The aim of this project was to examine the distribution of HA and CD44 in minor salivary gland tumors to determine if staining could be correlated with biologic behavior or tumor type. MATERIALS AND METHODS: Biotinylated hyaluronan binding protein as a probe for HA and monoclonal antibodies specific for CD44 were used to stain classic examples of the five most commonly encountered minor salivary gland tumors: monomorphic adenomas, pleomorphic adenomas, polymorphous low grade adenocarcinomas, mucoepidermoid carcinomas, and adenoid cystic carcinomas. RESULTS: Tumor cells of monomorphic adenomas were negative for both HA and CD44, and tumor capsules were intensely HA-positive. Pleomorphic adenomas exhibited HA and CD44 positivity in both mesenchymal and epithelial components, and HA in capsular tissues. All malignant salivary gland tumors expressed similar intense HA in tumor stroma. HA staining was more intense in stroma than in parenchymal cells. Tumor cells of most adenoid cystic carcinomas were HA-positive, while most polymorphous low grade adenocarcinomas were HA-negative. HA was uniformly distributed throughout supporting stroma of high and low grade malignancies, except for two polymorphous low grade adenocarcinomas (PLGAs) in which HA was more intense at the invading edge of the tumors. CD44 expression was seen only in tumor cells (not stroma) of malignancies, and was of similar intensity in both low and high grade tumors. CONCLUSIONS: Differences in the expression of HA and CD44 among different types of salivary gland tumors were noted. These findings, however, could not be correlated with known biologic behaviors of the tumor groups studied. Immunohistochemical staining of salivary gland tumors for HA and CD44 may be useful in separating monomorphic adenoma, polymorphous low grade adenocarcinoma and adenoid cystic carcinoma, lesions that may be difficult to distinguish with routine light microscopy.


Subject(s)
Adjuvants, Immunologic/analysis , Hyaluronan Receptors/analysis , Hyaluronic Acid/analysis , Salivary Gland Neoplasms/chemistry , Salivary Glands, Minor/chemistry , Adenocarcinoma/chemistry , Adenocarcinoma/diagnosis , Adenoma/chemistry , Adenoma/diagnosis , Biomarkers, Tumor , Carcinoma, Adenoid Cystic/chemistry , Carcinoma, Adenoid Cystic/diagnosis , Carcinoma, Mucoepidermoid/chemistry , Carcinoma, Mucoepidermoid/diagnosis , Diagnosis, Differential , Humans , Immunohistochemistry , Neoplasm Invasiveness , Salivary Gland Neoplasms/diagnosis
20.
Article in English | MEDLINE | ID: mdl-9347502

ABSTRACT

To determine if immunohistochemistry can be used as adjunct to the diagnosis and classification of oral benign neural tumors, we stained 77 neurally differentiated tumors with a panel of neural-associated antibodies (S-100 protein, CD57, epithelial membrane antigen, factor XIIIa, CD34, CD68, collagen IV). Using standard histologic criteria, we identified 13 schwannomas, 16 neurofibromas, 23 traumatic neuromas, 16 palisaded and encapsulated neuromas, and 9 granular cell tumors from archived oral pathology specimens. Silver stains showed that neurofibromas, traumatic neuromas, and palisaded and encapsulated neuromas consistently contained axon filaments. Although all neural tumors contained S-100-positive cells, schwannomas and palisaded and encapsulated neuromas contained the most. All tumors expressed CD57; traumatic neuromas were stained intensely and the others stained weakly. The consistent epithelial membrane antigen capsular staining of schwannomas and the absence of factor XIIIa-positive dendritic/spindle cells helped distinguish these tumors from others. Many CD34-positive cells were found in schwannomas, and few were found in palisaded and encapsulated neuromas. Variable numbers CD68-positive cells were seen in all neural tumor types; some of these cells appeared to be macrophages and mast cells, but many were thought to be Schwann cells expressing this antigen. Collagen IV staining, apparently representing basement membrane, was generally a feature of all benign neural tumors. The immunophenotype of the granular cells of the GCTs was S-100+, CD57+, and collagen IV+ supporting the putative neural origin of these tumors. We conclude that neural origin/differentiation of a connective tissue tumor can be confirmed with stains for S-100 protein, epithelial membrane antigen, CD57, and collagen IV. Staining patterns and intensities associated with the panel of antibodies tested can be useful in tumor classification.


Subject(s)
Mouth Neoplasms/pathology , Nerve Sheath Neoplasms/pathology , Antigens, CD/analysis , Antigens, CD34/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Axons/ultrastructure , Basement Membrane/pathology , CD57 Antigens/analysis , Cell Differentiation , Collagen/analysis , Coloring Agents , Dendrites/ultrastructure , Granular Cell Tumor/etiology , Granular Cell Tumor/pathology , Humans , Immunohistochemistry , Immunophenotyping , Intermediate Filaments/ultrastructure , Keratinocytes/pathology , Macrophages/pathology , Mast Cells/pathology , Mouth Neoplasms/classification , Mouth Neoplasms/diagnosis , Mucin-1/analysis , Nerve Sheath Neoplasms/classification , Nerve Sheath Neoplasms/diagnosis , Neurilemmoma/pathology , Neurofibroma/pathology , Neuroma/etiology , Neuroma/pathology , S100 Proteins/analysis , Schwann Cells/pathology , Silver , Transglutaminases/analysis
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