Dysplastic Squamous Epithelium Research Articles

Oral Squamous Cell Carcinoma with an unusual clinical manifestation: a case report

IntroductionSquamous cell carcinoma is the most common malignant tumor of the oral cavity and one of the 10th most common causes of death. It arises from dysplastic oral squamous epithelium. By considering the pathogenesis of squamous cell carcinoma, the smooth and intact surface for this lesion is not usual.Case presentationA painful nodular lesion with smooth surface on the left buccal mucosa of a 75-year-old female patient was observed. She noticed it 2 weeks ago. Histopathological examination revealed oral squamous cell carcinoma.ConclusionIn this paper, we report an unusual clinical presentation of oral squamous cell carcinoma in buccal mucosa which is very rare.

Oral Squamous Cell Car-cinoma with an Unusual Clinical Manifestation: A Case Report.

Squamous cell carcinoma (SCC) is the most com-mon malignant tumor of the oral cavity and one of the ten most common causes of death. It arises from dysplastic oral squamous epithelium. Considering the pathogenesis of SCC, a smooth and intact surface in this lesion is not a usual finding. In this paper, we report an extremely rare case of oral SCC in buccal mucosa presenting as an exo-phytic lesion with smooth and intact surface, very unusual for oral SCC.

Variations of mitotic index in normal and dysplastic squamous epithelium of the uterine cervix as a function of endometrial maturation

Cervical intraepithelial neoplasia is a premalignant (dysplastic) lesion that is characterized by abnormal cellular proliferation, maturation and nuclear atypia. The intraepithelial distribution, density, and nature (typical or atypical) of mitotic figures are routinely utilized diagnostic criteria to grade dysplasia and to distinguish high-grade dysplasia from potential histologic mimics such as transitional metaplasia, atrophy or immature squamous metaplasia. In this study, we evaluated the total mitotic indices of the cervical epithelia in hysterectomy specimens from patients with and without dysplastic lesions and investigated a possible relationship between mitotic index and hormonal status, using the endometrial maturation phase as a surrogate indicator of the latter. Two hundred seventy-four cervices from hysterectomy specimens (135 cases without dysplasia, 33, 35 and 71 cases with grades 1, 2 and 3 cervical intraepithelial neoplasia, respectively) were analyzed. A cervical mitotic index (total mitotic figures/10 high-power fields in the most proliferative area) was determined for each case. The endometrium in each case was classified into atrophic, early proliferative, late proliferative and secretory. For all three dysplasia grades, cases in the proliferative endometrium group always had a higher average mitotic index than those in the secretory and atrophic endometrium groups; this observation also held true for the benign cases. Furthermore, in all three dysplasia grades, the average mitotic index was always lowest in the atrophic endometrium group. Although the mitotic index showed expected patterns of increases with increasing dysplasia grades for most of the endometrial phases, this was not a universal finding. Notably, the average mitotic index for our cervical intraepithelial neoplasia 1 cases with late proliferative endometrium was higher than our cervical intraepithelial neoplasia 2 cases with secretory and atrophic endometrium. It is concluded that hormonal status, as reflected in endometrial maturation, can significantly affect the mitotic index of dysplastic squamous epithelium of the uterine cervix. Our findings confirm that the pathologic grading of dysplasia, especially in equivocal cases such as in metaplastic squamous epithelium, should not be solely dependent on the finding mitoses in the cervical squamous epithelium. The full composite of histopathologic features should form the basis for this determination.

Expression of Glucose Transporter Protein-1 (Glut-1) in Ocular Surface Squamous Neoplasia

To examine the expression of glucose transporter protein-1 (GLUT-1) in ocular surface squamous neoplasia and to study its relationship with degree of neoplasia and cell proliferation index (Ki-67 labeling index). Twelve cases diagnosed as ocular surface squamous neoplasia (4 invasive and 8 intraepithelial tumors) at Inonu University Faculty of Medicine, Department of Pathology, were included in this study. There were 3 squamous cell carcinomas, 1 basosquamous cell carcinoma, and 8 conjunctival intraepithelial neoplasms. Immunohistochemically, GLUT-1 and Ki-67 antibody staining were performed. GLUT-1 membranous immunoreactivity was seen in all tumors except in 1 case. GLUT-1 immunostaining was observed in all layers of the neoplastic epithelium of squamous cell carcinoma. Intense staining for GLUT-1 was determined in the upper two thirds of the severe dysplastic squamous epithelium. Although immunoreactivity for Ki-67 nuclear antigen was present throughout the epithelium, it was higher in the lower two thirds. Ki-67 labeling index ranged between 6% and 80%, and the mean value was 35% for invasive tumors and 20% for intraepithelial tumors. Marked GLUT-1 and Ki-67 immunoreactive cells throughout the neoplastic epithelium of ocular surface squamous neoplasia were observed. In most cases, it was observed that GLUT-1 expression was severe in cases having >10% Ki-67 labeling index. These findings indicate that glucose uptake was increased in dysplastic cells, especially by GLUT-1. To our knowledge, this is the first study on the subject in the literature, and further studies with more cases are needed with GLUT-1 and other GLUT members.

Multifocal Squamous Cell Carcinoma of the Conjunctiva With Intraocular Penetration in a Patient With AIDS

To describe the clinical findings and to study the histopathology of conjunctival masses in a patient with HIV infection. A case report. The histopathology from a 38-year-old Thai female patient who presented with visual loss on the left eye was studied. She had been diagnosed with AIDS 3 years before and was treated with highly active antiretroviral therapy and anti-tuberculous drugs for 1 year. The left eye was blind and showed 2 separate whitish masses on the bulbar conjunctiva in adjacent to the inferomedial limbus. Multiple nodules under the conjunctiva were seen inferiorly. Computerized tomography of the orbit revealed slight thickening of the left lower eyelid but could not show any globe involvement. The patient underwent orbital exenteration. Gross pathology showed multiple areas of the tumor. Histopathology revealed dysplastic squamous epithelium invading into the substantia propria of the conjunctiva with intraocular penetration. The anterior surface of the iris was filled with tumor cells containing keratin pearls. Squamous cell carcinoma can be multifocal and aggressive in HIV-infected patients. Rapid progression to intraocular penetration can be observed.

Expression of p53 protein in oesophageal carcinoma: clinicopathological correlation and prognostic significance.

Correlation of p53 expression with 5-year survival and histopathological parameters was examined immunohistochemically in two groups of 30 patients with oesophageal carcinoma (5-year survivors versus non-survivors). Tumour type, sex, operative procedure and age were matched. Some 64 per cent of squamous carcinomas and 79 per cent of adenocarcinomas were p53 positive. Normal squamous, normal glandular and metaplastic glandular epithelia were negative. Dysplastic squamous and glandular epithelium adjacent to tumours was positive when the tumour was positive and negative when it was not. Univariate analysis showed that nodal status (P = 0.001), and grade and depth of invasion (both P = 0.01) correlated with outcome. Correlation of tumour grade with outcome, when the most poorly differentiated area is used, is a novel finding for oesophageal carcinoma. The p53 status was not significantly associated with survival or any of these parameters.

Correlation of expression of nuclear proteins pKi67 and p63 with lectin histochemical features in head and neck squamous cell cancer

This study represents a combined lectin and immuno-histochemical analysis of normal, dysplastic and malignant squamous epithelia of the upper aerodigestive tract with emphasis on the relation between lectin reactivity and the cells' proliferative/anti-apoptotic potential. Staining by double-labeling to detect pKi67, DeltaNp63alpha, alpha2,3/6-linked sialic acid (NeuNAc) and galectin-3-reactive epitopes was performed on specimens of 8 normal cases, 27 primary tumours and 15 regional lymph node metastases. Normal epithelia expressed alpha2,6-linked NeuNAc in the basal layer, while alpha2,3-linked NeuNAc was observed in suprabasal layers. In normal epithelium pKi67 and DeltaNp63alpha positivity was seen in the basal layer and galectin-3-reactive sites in suprabasal layers. The studied squamous cell carcinomas and their metastases showed a tendency for stratification but with markedly altered architecture. The expression of the studied markers was heterogeneous between the different cancer cases but comparable between the corresponding primary and secondary lesions. Glycophenotypic properties were correlated with the level of differentiation. Tumour cell populations were characterized by occurrence of the p63+/pKi67+ alpha2,3-NeuNAc+ alpha2,6-NeuNAc+ phenotype. Analysis of the expression patterns of pKi67, p63 and galectin-3-reactive epitopes (Gal-3-RE) delineated statistically significant interrelationships (Gal-3-RE vs. p63: r = -0.709; Gal-3-RE vs. pKi67: r = -0.623; pKi67 vs. p63: r = 0.895). Of the studied markers only Gal-3-RE expression was correlated to the differentiation-dependent grading (G1 vs. G2: p = 0.007, G2 vs. G3: p = 0.006, G1 vs. G3: p = 0.002). DeltaNp63alpha expression was statistically different only between G1 and G3 (p = 0.03). No statistically significant differences were detected between the primary tumours and the corresponding regional lymph node metastases. Based on the concept of the sugar code further analysis of cell characteristics such as proliferation together with lectin histochemical features, especially using tissue lectins as probes, is thus warranted.

Narrow Band Imaging: A New Diagnostic Approach to Visualize Angiogenesis in Superficial Neoplasia

Although numerous gastrointestinal endoscopes pass through the oropharynx and the hypopharynx, it is extremely difficult to detect an early cancer in these sites during routine endoscopic examination. Most patients with cancer in these sites are usually diagnosed in advanced stages. If effective screening methods can detect an earlier stage, such as carcinoma in situ, it would obviously be of great benefit. Narrow band imaging is an innovative optical technology that can clearly visualize the microvascular structure of the organ surface. Herein, we demonstrate that narrow band imaging combined with magnifying endoscopy can identify a carcinoma in situ in oropharyngeal and hypopharyngeal mucosal lesions. Scattered irregular foci of microvascular proliferation projecting to the dysplastic squamous epithelium are the typical features. These results indicate that an approach to visualize angiogenesis or morphologic changes of microvessels in the superficial neoplasm can be a new diagnostic method not only for the head and neck region but also for other sites in the gastrointestinal tract.

Angiogenesis Inhibition by Vascular Endothelial Growth Factor Receptor-2 Blockade Reduces Stromal Matrix Metalloproteinase Expression, Normalizes Stromal Tissue, and Reverts Epithelial Tumor Phenotype in Surface Heterotransplants

Inhibition of vascular endothelial growth factor (VEGF) signaling, a key regulator of tumor angiogenesis, through blockade of VEGF receptor (VEGFR)-2 by the monoclonal antibody DC101 inhibits angiogenesis, tumor growth, and invasion. In a surface xenotransplant assay on nude mice using a high-grade malignant squamous cell carcinoma cell line (A-5RT3), we show that DC101 causes vessel regression and normalization as well as stromal maturation resulting in a reversion to a noninvasive tumor phenotype. Vessel regression is followed by down-regulation of expression of both VEGFR-2 and VEGFR-1 on endothelial cells and increased association of alpha-smooth muscle actin-positive cells with small vessels indicating their normalization, which was further supported by a regular ultrastructure. The phenotypic regression of an invasive carcinoma to a well-demarcated dysplastic squamous epithelium is accentuated by the establishment of a clearly structured epithelial basement membrane and the accumulation of collagen bundles in the stabilized connective tissue. This normalization of the tumor-stroma border coincided with down-regulated expression of the stromal matrix metalloproteinases 9 and 13, which supposedly resulted in attenuated turnover of extracellular matrix components permitting their structural organization. Thus, in this mouse model of a human squamous cell carcinoma cell line, blockade of VEGF signaling resulted in the reversion of the epithelial tumor phenotype through stromal normalization, further substantiating the crucial role of stromal microenvironment in regulating the tumor phenotype.

Fourier transform infrared (FTIR) spectral mapping of the cervical transformation zone, and dysplastic squamous epithelium

Objective. This paper is aimed at establishing infrared spectral patterns for the different tissue types found in, and for different stages of disease of squamous cervical epithelium. Methods for the unsupervised distinction of these tissue types are discussed. Methods. Fourier transform infrared (FTIR) maps of the squamous and glandular cervical epithelium, and of the cervical transformation zone, were obtained and analyzed by multivariate unsupervised hierarchical cluster methods. The resulting clusters are correlated to the corresponding stained histopathological features in the tissue sections. Results. Multivariate statistical analysis of FTIR spectra collected for tissue sections permit an unsupervised method of distinguishing tissue types, and of differentiating between normal and diseased tissue. By analyzing different spectral windows and comparing the results with histology, we found the amide I and II region (1740–1470 cm −1) to be very important in correlating anatomical and histopathological features in tissue to spectral clusters. Since an unsupervised, rather than a diagnostic, algorithm was used in these efforts, no statistical analysis of false-positive/false-negative results is reported at this time. Conclusions. The combination of FTIR micro-spectroscopy and multivariate spectral processing provides important insights into the fundamental spectral signatures of individual cells and consequently shows potential as a diagnostic tool for cervical cancer.

Hypoxia-Inducible Erythropoietin Signaling in Squamous Dysplasia and Squamous Cell Carcinoma of the Uterine Cervix and Its Potential Role in Cervical Carcinogenesis and Tumor Progression

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barrett's mucosa.

Minichromosome maintenance (Mcm) proteins are essential for eukaryotic DNA replication, and their expression implies potential for cell proliferation. Expression is dysregulated in dysplastic states but data for oesophageal squamous mucosa and Barrett's mucosa have not been published. To test the hypothesis that Mcm proteins are downregulated together with the proliferation marker Ki-67 in differentiating epithelial compartments of non-dysplastic squamous and Barrett's epithelium, and that this process does not occur in dysplastic mucosae. METHODS AND CASES: Forty five patients with Barrett's oesophagus included 20 with glandular dysplasia (10 low grade, eight high grade, two both, and four with invasive adenocarcinoma). Twenty five other patients included 12 with oesophageal squamous dysplasia (three low grade, six high grade, three both, and four with invasive squamous carcinoma). Formalin fixed paraffin embedded tissue sections from biopsy series and resections were immunostained using antibodies to Mcm2, Mcm5, and Ki-67. Percentage of nuclei positive for Mcm2, Mcm5, and Ki-67 was estimated and scored from 0 to 6 as: 0, none +; 1, <10%+; 2, 10-30%+; 3, 30-70%+; 4, 70-90%+; 5, >90%+; 6, all+. Four separate epithelial strata were scored: in squamous epithelium the basal layer and thirds to the surface, in Barrett's mucosa the luminal surface, upper and lower crypt, and deep glands. In non-dysplastic squamous epithelium and Barrett's mucosa, high level expression of Mcm2, Mcm5, and Ki-67 proteins was largely confined to the proliferative compartments and downregulated in differentiated compartments. Expression persisted up to the mucosal surface in dysplastic squamous epithelium and Barrett's mucosa. Persistent expression of Mcm2, Mcm5, and Ki-67 proteins in luminal compartments of dysplastic oesophageal squamous epithelium and dysplastic Barrett's mucosa may be diagnostic markers and imply disruption of cell cycle control and differentiation in these dysplastic epithelia.

Ber‐EP4 immunoreactivity depends on the germ layer origin and maturity of the squamous epithelium

To map the expression of Ber-EP4 in well-differentiated squamous epithelia, metaplastic squamous epithelia and dysplastic squamous epithelia of different origins. Squamous epithelium of different origin was stained using a standard immunohistochemistry method applied to paraffin sections. We found that normal squamous epithelium of the oral cavity, oesophagus, uterine cervix, vagina, anal canal, and branchial cysts are Ber-Ep4-negative, as are the mature squamous metaplasia of bronchial mucosa, urinary bladder mucosa and uterine cervical mucosa. In contrast, immature squamous metaplasia of bronchial mucosa, or uterine cervical mucosa, and squamous dysplasia of oral mucosa of endodermal origin, or uterine cervical mucosa in most cases expressed Ber-EP4. Squamous epithelia of ectodermal origin never express Ber-EP4, whether normal, hyperplastic, dysplastic or neoplastic. In contrast, squamous epithelium of endodermal origin sometimes contains the target glycoproteins of Ber-EP4 when immature, metaplastic, dysplastic or neoplastic. The results indicate that the differences in expression of Ber-EP4 in squamous epithelium depend primarily on germ layer origin, and on the maturity of the epithelium.

Assessment of cervical dysplasia with DNA image cytometry

Dysplastic epithelia represent potentially precancerous conditions in which the risk of progression to cancer is unknown in the individual case. The positive predictive value of mild and moderate dysplasias of the uterine cervix is only about 13%. Using DNA image cytometry on restained, conventional Papsmears the cytometric equivalent of chromosomal aneuploidy can be detected as marker for neoplastic transformation of cells. The identification of DNA aneuploidy in dysplastic squamous epithelia can increase the predictive value for malignant transformation to over 90%. DNA aneuploidy qualifies squamous intraepithelial lesions as high grade (H-SIL) which have to be treated whereas lack of DNA aneuploidy characterizes low grade squamous intraepithelial lesions (L-SIL) which have only to be controlled. The methodology is meanwhile internationally standardized concerning performance and diagnostic interpretation.

MN antigen expression in normal, preneoplastic, and neoplastic esophagus: A clinicopathological study of a new cancer-associated biomarker

Recently, a novel tumor-associated protein, termed MN, has been described in carcinomas of the uterine cervix, where its expression has been shown to be associated with malignant transformation. Because malignant transformation in the esophagus develops through a dysplasia-carcinoma sequence similar to that which occurs in the cervix, this study was performed to evaluate MN expression in normal, preneoplastic, and neoplastic tissues of the esophagus. Esophageal tumor resection specimens from 27 patients (12 squamous cell carcinomas, one multifocal squamous dysplasia, 10 Barrett's-associated adenocarcinomas, two Barrett's esophagus with dysplasia, two adenosquamous carcinomas) were immunohistochemically stained with a monoclonal antibody (clone M75) directed against the MN antigen. The localization of MN antigen, as well as the proportion of positively stained cells, were determined in sections of normal, dysplastic, and carcinomatous tissues. The staining characteristics were correlated with the pathological features of the tumors. Weak intracellular MN expression was detected only in the basal cells of normal squamous epithelium. However, inflamed and reactive squamous epithelium showed increased staining in the basal layer and in the overlying mature squamous cells. MN expression was significantly increased in dysplastic squamous epithelium ( P < .001). All esophageal squamous cell carcinomas (100%) stained positively for MN antigen, where the pattern of staining was predominantly membranous. However, the degree of MN staining did not correlate with any of the pathological features of the tumors. In Barrett's epithelium, MN stained positively in all types of metaplastic cells and showed no difference in dysplastic epithelium. In contrast to squamous cell carcinomas, only 80% of esophageal adenocarcinomas were positive for MN, but the degree of MN expression was inversely correlated with histological tumor differentiation ( P < .015). The results of this study suggest that (1) the tumor-associated MN antigen may play a role in proliferation and regeneration in esophageal squamous epithelium, and (2) loss of MN expression may be related to cancer progression in Barrett's-associated adenocarcinomas.

Expression of mucin antigens and Lewis X-related antigens in carcinomas and dysplasia of the pharynx and larynx.

Recent studies have identified that mucin antigens and Lewis X (Lex)-related antigens behave like oncodevelopmental tumor-associated antigens in several human adenocarcinomas. However, the expression of these antigens in pharyngeal and laryngeal squamous cell carcinomas (SCC) and in the precursor lesion is not fully elucidated yet. In the present study, the expression of mucin core protein antigens associated with the MUC1 gene product (DF3 antigen, mammary-type apomucin) and the MUC2 gene product (intestinal-MRP antigen, intestinal-type apomucin) mucin carbohydrate antigens that are associated with the earliest steps in mucin glycosylation (Tn, sialyl-Tn and T), and Lex-related antigens (Lex, Ley and sialyl Lex-i) in biopsy or resected specimens from 26 normal squamous epithelia (NSE), 49 dysplastic squamous epithelia (DSE) and 51 SCC were examined. The DF3 antigen was not expressed in NSE (0%), whereas it was expressed in 20 DSE (41%) and in 31 SCC (61%). The intestinal-MRP antigen showed no expression in NSE, DSE or SCC. The Tn antigen showed no expression in NSE, but showed low expression rates in DSE (14%) and in SCC (16%). The sialyl-Tn and T antigens were expressed in NSE, as well as in DSE and SCC. The T antigen expression increased with progression from NSE to DSE to SCC, while the sialyl-Tn antigen did not show such a tendency. Any of the three Lex-related antigens showed no characteristic expression in DSE and SCC. In the eight antigens examined, only DF3 antigen was an effective marker for DSE and SCC in the pharyngeal and laryngeal region. Cytoplasmic expression of DF3 and sialyl-Tn antigens were more frequently seen in SCC than in DSE, and might be useful to differentiate SCC from DSE.

EXPRESSION OF CD44 SPLICE VARIANTS IN SQUAMOUS EPITHELIA AND SQUAMOUS CELL CARCINOMAS OF THE HEAD AND NECK

Splice variants of the adhesion molecule CD44 have been described as essential for the lymphatic spread of rat tumour cells and are claimed to be involved in the metastatic spread of several human tumours. Immunohistochemistry has been used to analyse the expression pattern of CD44 standard (CD44s) and variant (CD44v) isoforms in normal and dysplastic squamous epithelia, as well as in primary and metastatic squamous cell carcinomas (SCCs), which spread predominantly by way of the lymphatic system. Frozen sections of squamous epithelia and of squamous cell carcinomas were stained with a panel of monoclonal antibodies recognizing epitopes of CD44s as well as of the variant exons v5, v6, v7, v7-v8, and v10. The stratum basale and stratum suprabasale of squamous epithelia stained with all antibodies; the stratum spinosum stained with anti-CD44v5, anti-CD44v6, anti-CD44v7-8 and anti-CD44v10; the lower layers of the stratum corneum stained with anti-CD44v5. This expression profile was seen in epithelia of the lip, the tongue, the gingiva, the hard palate, the floor of the mouth, the buccal mucosa, and the pharynx. The same pattern of expression was also noted in dysplastic epithelia, but expression of the variant exons v7, v8, and v10 was significantly downregulated in primary squamous cell carcinomas and was not detected at all in the majority of metastasis-derived specimens. Expression of CD44v5 and CD44v6, on the other hand, was mainly unaltered. Thus, epithelial cell layers representing different stages of differentiation express distinct sets of CD44 variant isoforms, where especially exons v8-v10 might be required for the maintenance of the structural integrity of squamous epithelium. Downregulation of these exons on tumour cells could indicate that they are irrelevant for tumour progression or may even hamper infiltration of surrounding tissue or of lymphatics.

The p53 status of cultured human premalignant oral keratinocytes

Around 60% of oral squamous cell carcinomas (SCCs) have been shown to harbour p53 mutations, and other studies have demonstrated mutant p53 genes in normal and dysplastic squamous epithelium adjacent to these SCCs. In line with these earlier studies we show here that DOK, a keratinocyte cell line derived from a dysplasia, displays elevated levels of p53 protein and harbours a 12 bp in-frame deletion of the p53 gene spanning codons 188-191. In contrast, the coding region of the p53 gene was normal in a series of six benign recurrent laryngeal papillomas and a series of four premalignant oral erythroplakia biopsies and their cell cultures. All but one of these lesions were free of malignancy at the time of biopsy, in contrast to the premalignant lesions studied by previous investigators, but keratinocytes cultured from these lesions all displayed a partially transformed phenotype that was less pronounced than that of DOK. Since three out of four of the erythroplakia patients developed SCC within 1 year of biopsy, these lesions were by definition premalignant. The availability of strains of partially transformed keratinocytes from premalignant erythroplakias which possess normal p53 genes should enable us to test the role of mutant p53 in the progression of erythroplakia to SCC. The premalignant tissues and cultures were also tested for the presence of human papillomavirus (HPV), which is known to inactivate p53 function in some cases. Only the benign papillomas were shown to contain high levels of either HPV 6 or HPV 11 E6 DNA, but not both, and none of the samples contained detectable levels of HPV 16, HPV 18 or HPV 33 E6 DNA or L1 DNA of several other HPV types. There was therefore no evidence to suggest that p53 was being inactivated by a highly oncogenic HPV in these samples.

Integrin expression in squamous neoplasia of the cervix.

Epithelial cell-basement membrane interactions are important in maintaining tissue architecture and function, and the anatomical and functional relationships between epithelial cells and their basement membranes are clearly altered in malignancy. These interactions are thought to be largely mediated by the integrins, a family of heterodimeric transmembrane glycoproteins, each consisting of an alpha and a beta chain. Epithelial integrins mainly belong to the beta 1 (VLA) subfamily, which forms receptors for matrix macromolecules such as fibronectin, laminin, and collagen. There is evidence that integrin expression changes in some epithelial malignancies, possibly in relation to invasive potential. Integrin expression in cervical neoplasia was studied by immunohistochemical examination of prospectively collected colposcopic biopsies. Well-characterized monoclonal antibodies against beta 1-4, alpha 1-6, and alpha V integrins were used to examine normal, koilocytic, and dysplastic cervical squamous epithelium, and invasive squamous carcinoma. beta 1, beta 4, alpha 2, alpha 3, alpha 6, and alpha V were expressed by the basal layer of normal cervical squamous epithelium and by dysplastic cells in CIN (cervical intraepithelial neoplasia) 1 and 2, with none being lost and no new chains acquired. In CIN3, these integrins were either expressed throughout the ectocervical epithelium or restricted to the basal layer. In the latter cases, integrin expression was retained to a greater degree by dysplastic squamous epithelium within endocervical glands. These patterns could not be correlated with age or smear history in the cases examined. Patterns of integrin expression in neoplastic cervical epithelium therefore differ from those of normal cervical epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma In Situ of the Uterine Cervix

The clinicopathological features of nine patients with adenocarcinoma in situ (AIS) of the uterine cervix, one of them with microinvasion, were studied. In situ hybridization (ISH) with biotinylated probes to human papillomavirus (HPV) types 6/11, 16/18, and 31/35/51 was performed in eight tumors. The presence of HPV types 16 and 18 was also investigated by the polymerase chain reaction (PCR) in seven. Four tumors were of the endocervical type, two were endometrioid, and three were mixed (endocervical-intestinal). Coexisting cervical intraepithelial squamous neoplasia (CIN) was found in eight tumors. Only one of the eight tumors studied by ISH was positive for HPV 16/18 in the dysplastic squamous epithelium, but none of them showed positivity in the adenocarcinomatous areas. In contrast, four of seven AIS studied by PCR were positive: three for HPV 16 and one (the microinvasive adenocarcinoma) for HPV 18. The results confirm the frequent association of AIS with CIN and HPV.