involucrin and Uterine-Cervical-Neoplasms

The objective was to discover whether the oxygen-regulated protein, metallothionein, is expressed in the hypoxic cells of squamous cell carcinomas. Twenty patients with squamous cell carcinoma of the uterine cervix or head and neck were infused with a solution of the hypoxia marker, pimonidazole hydrochloride, at a dose of 0.5 g/m2. The following day, biopsies were collected, formalin fixed, paraffin embedded, and sectioned at 4 microm. Sections from each biopsy were immunostained for pimonidazole binding, metallothioneins I and II, involucrin, and proliferating cell nuclear antigen. A total of 84 biopsies were analyzed. Sixty-four of 84 biopsy sections contained hypoxia. Of the hypoxia-containing sections, 43 of 64 or 67% showed no microregional overlap between hypoxia and metallothionein; 7 of 64 showed overlap; and 14 of 64 showed a combination of overlap and no overlap. On a tumor-by-tumor basis, 5 of 7 head and neck and 7 of 13 cervix tumors showed no overlap between metallothionein and hypoxia at the microregional level. Ranges for the percentage of the area of hypoxia in head and neck (<0.9 to 17%) and cervix (<0.1 to 14%) tumors were similar. In the hypoxia-containing sections, immunostaining for involucrin, a molecular marker for differentiation, overlapped with that for hypoxia in 82% of the cases. The majority of hypoxic cells in squamous cell carcinomas do not express metallothionein protein, although metallothionein is induced by hypoxia in human tumor cells in vitro. Hypoxic cells in human tumors tend to be in regions immunostaining for involucrin, and it seems possible that differentiation of hypoxic cells in squamous cell carcinomas might affect metallothionein I and II expression.

Topics: Biomarkers; Carcinoma, Squamous Cell; Cell Hypoxia; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Metallothionein; Neoplasm Staging; Nitroimidazoles; Proliferating Cell Nuclear Antigen; Protein Precursors; Uterine Cervical Neoplasms

The majority of hypoxic cells in squamous cell carcinomas of the head and neck and cervix express involucrin, a molecular marker for differentiation. This raises the question of whether involucrin is an oxygen-regulated protein and, if so, whether it could serve as an endogenous marker for tumour hypoxia. Consistent with oxygen regulation, involucrin protein was found to increase with increasing hypoxia in confluent cultures of moderately differentiated human SCC9 cells. Cells harvested at the point of confluence and exposed to graded concentrations of oxygen revealed a K(m) of approximately 15 mmHg for involucrin induction. This is similar to K(m)s for HIF-1alpha, CAIX and VEGF. Involucrin induction showed a steep dependence on pO(2) with a transition from minimum to maximum expression occurring over less than an order of magnitude change in pO(2). In contrast to SCC9 cells, involucrin was not induced by hypoxia in poorly differentiated SCC4 cells. It is concluded that involucrin is an oxygen-regulated protein, but that differentiation modulates its transcription status with respect to hypoxia induction.

Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Cell Hypoxia; Female; Head and Neck Neoplasms; Humans; Oxygen; Protein Precursors; Transcription, Genetic; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Pimonidazole binding (hypoxia) and involucrin expression (differentiation) overlap extensively in squamous cell carcinomas. This study asks whether involucrin might serve as an endogenous marker for tumor hypoxia. A second question is whether differentiation affects hypoxia-inducible metallothionein (MT) expression in normal human epithelia and squamous cell carcinomas as it does in rodent epithelia.. Thirty-four patients with squamous cell carcinoma of the uterine cervix were infused with pimonidazole hydrochloride solution. The next day, multiple biopsies were formalin-fixed, paraffin-embedded and sectioned at 4 micro m. Qualitative and quantitative analyses for involucrin expression, pimonidazole binding, and human MT-IIa mRNA expression were performed.. No overall correlation between the extent of involucrin expression and pimonidazole binding was observed. The lack of correlation was because of heterogeneous patterns of immunostaining for involucrin generally related to tumor grade. Colocalized immunostaining for involucrin and pimonidazole binding was observed in intermediate grade tumors but not in well-differentiated or poorly differentiated tumors. Human MT-IIa mRNA and MT protein were expressed in basal lamina of normal human epithelia and in the proliferative rims of tumor nests.. Colocalization of immunostaining for involucrin and pimonidazole binding is consistent with oxygen regulation, but the lack of involucrin expression in hypoxic regions of poorly differentiated tumors indicates that its transcriptional status with respect to hypoxia induction is altered by cell differentiation. The localization of MT message and protein in the outer rims of most tumor nests indicates that the transcriptional status of metallothionein is also altered by differentiation.

Topics: Biopsy; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line, Tumor; Female; Humans; Hypoxia; Immunohistochemistry; In Situ Hybridization; Metallothionein; Nitroimidazoles; Oxygen; Prognosis; Protein Precursors; Radiation-Sensitizing Agents; RNA, Messenger; Transcription, Genetic; Uterine Cervical Neoplasms

In a recent study of low-grade cervical squamous intraepithelial lesions (SILs), we reported that infection with both low- and high-risk human papillomaviruses (HPVs) upregulated cyclin A, B, E, and Ki67 expression in basal and suprabasal cells. In view of the intricate link between cell cycle exit, proliferation, and differentiation, we examined the morphologic distribution of cytokeratins 13 and 14 and involucrin expression in 49 low-grade SILs infected with HPV types 6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 56, 58, and 66; 2 lesions contained both low- and high-risk HPVs. The findings were compared with 30 high-grade SILs infected with HPV types 16, 31, 33, 51, 58, 66, and 67; 3 of these were infected with 2 different HPVs. In low-grade lesions, the differentiation markers were expressed normally, showing that differentiation proceeds despite upregulation of cell cycle--associated proteins. Loss of involucrin (3 of 33) and cytokeratin 13 (8 of 33) expression occurred only in the high-grade lesions and was therefore related to lesion grade. Loss of cytokeratin 14 expression was also significantly more frequent in high-grade than in low-grade lesions (19 of 33 v 12 of 51; P < .01). In addition, cytokeratin 14 expression was significantly less frequent in the intermediate and superficial layers of low-grade SILs infected with high-risk HPVs than in those infected with low-risk HPVs (3 of 27 v 14 of 24; P < .001). These findings are consistent with in vitro data and suggest that abnormalities of both cell cycle control and squamous differentiation are important in HPV-associated neoplastic transformation.

Topics: DNA, Viral; Female; Humans; Immunoenzyme Techniques; In Situ Hybridization; Keratin-14; Keratins; Papillomaviridae; Papillomavirus Infections; Polymerase Chain Reaction; Protein Precursors; Transcription Factor AP-1; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Cervical intraepithelial neoplasia (CIN) I, II, and III represent a spectrum of premalignant epithelial changes and are ideal targets for application of chemoprevention strategies. Intermediate end point biomarkers are increasingly being used as surrogate end points to monitor clinical chemoprevention trials. To identify potential biomarkers in cervical epithelium, we analyzed the expression of nuclear retinoic acid receptor (RAR) mRNA by in situ hybridization, involucrin, cornifin, and transforming growth factors (TGFs) beta1 and beta2 by immunohistochemistry in cervical specimens, which contained adjacent normal epithelium and CIN lesions from 52 patients. These biomarkers were expressed in all adjacent normal cervical epithelia, whereas all CIN lesions including CIN I, CIN II, and CIN III exhibited decreased expression of RAR-alpha by 55.8%, RAR-beta by 64.7%, RAR-gamma by 54.9%, involucrin by 80.8%, cornifin by 88.5%, TGF-beta1 by 89.7%, and TGF-beta2 by 85.7%. Viewed as a whole, these biomarkers were down-regulated in 100% of the CIN lesions. Because all of these biomarkers can be modulated in vitro by retinoids, they may serve as intermediate biomarkers for retinoid chemoprevention trials in the patients with CIN lesions.

Topics: Biomarkers, Tumor; Cornified Envelope Proline-Rich Proteins; Down-Regulation; Female; Humans; Immunohistochemistry; In Situ Hybridization; Membrane Proteins; Protein Precursors; Receptors, Retinoic Acid; RNA, Messenger; Transforming Growth Factor beta; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The expression of involucrin, a cytoplasmic protein synthesized during squamous maturation, was assessed by immunocytochemistry in different grades of cervical lesions. In normal/benign cervical epithelium and low-grade squamous intraepithelial lesions [SILS or cervical intraepithelial neoplasia (CIN)-1] involucrin showed intense and homogenous cytoplasmic expression in the spinal layers of 75 and 57% of samples, respectively. The basal cell layers showed no expression of involucrin. In high-grade SILs (CIN-2/3) 40% of the samples showed diffuse and focal cytoplasmic expression of involucrin in the differentiated basaloid cells. In the squamous cell carcinomas (SCCs) analyzed, well-differentiated tumors showed intense focal expression in 61% of the cases, moderately differentiated SCCs showed intense expression in 33% of the cases, while poorly differentiated SCCs (PDSCC) showed only a mild focal expression in 7% of cases. With increasing severity of the lesions, patchy expression of involucrin with a mixture of reactive and nonreactive cells predominated. Patterns of immunocytochemical staining for involucrin in cervical lesions of different grades, from low-grade to high-grade SILs, and invasive carcinoma may be of critical importance, if loss of involucrin expression is used as a criterion for neoplastic transformation in cervical epithelium. Our findings suggest that involucrin may be a sensitive marker in identifying the differentiation status of the lesion while the absence of involucrin in PDSCC may be helpful in differential diagnosis.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Female; Humans; Immunohistochemistry; Middle Aged; Protein Precursors; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Researchers have previously demonstrated that organotypic cultures of cervical tumor cell lines exhibit morphological characteristics similar to the in vivo biopsies from which they were derived (Rader et al., 1990). Both the in vivo biopsy and organotypic culture appeared undifferentiated. We have extended these studies with immunohistochemical analysis using the proliferation and differentiation markers, proliferating cell nuclear antigen (PCNA) and involucrin, respectively, to evaluate in more detail the ability of cervical tumor cell lines to differentiate in organotypic culture. An HPV-immortalized keratinocyte cell line, PE-4, expressed PCNA in the lower half and involucrin in the upper half of the organotypic culture which is consistent with the characteristics of a preneoplastic lesion in vivo. The CC-1 cell line, derived from an invasive squamous cell carcinoma, appeared undifferentiated, but expressed involucrin in the upper half of the organotypic culture. This is the first observation of expression of a differentiation marker in an organotypic culture of a cervical tumor cell line. The other cervical tumor cell lines, SiHa and HeLa, derived from a squamous cell carcinoma, and an adenocarcinoma of the cervix, respectively, did not express detectable levels of involucrin or mucin. All three cervical tumor cell lines, CC-1, SiHa and HeLa, expressed PCNA throughout their entire thickness. The majority of nuclei in SiHa and HeLa cultures were PCNA-positive, while the CC-1 cell line exhibited a lower growth fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biomarkers, Tumor; Cell Differentiation; Cell Division; Female; HeLa Cells; Humans; Mucins; Organ Culture Techniques; Proliferating Cell Nuclear Antigen; Protein Precursors; Tumor Cells, Cultured; Uterine Cervical Neoplasms

The purpose of the present study was to establish culture conditions for human uterine cervical epithelial cells on permeable support and to determine how it affects cervical cell differentiation. Human ectocervical epithelial cells (hECE), HPV-16 immortalized hECE cells (ECE16-1) and Caski cells were grown on collagen-coated filters. Culture conditions, density of cells in culture and expression of epithelial and cervical-cell phenotypic markers were determined and compared in cells grown on filter and on solid support. Compared with the latter, cultures on filter had a higher cell density, hECE cells stratified to 5-12 cell layers compared to 1-3 on solid support, and cells of all three types expressed intercellular tight junctions. The cytokeratin profiles revealed differences between the three cell types as well as differences within the same cell species when grown on filter, compared to solid support. Of particular importance was the finding of a higher expression of K-13 in hECE grown on filter compared to solid support; K-13 is a marker of ectocervical cell differentiation. The cytokeratin profiles of the cultured hECE, ECE16-1 and Caski cells resembled those of ectocervical, squamous metaplastic and endocervical epithelia, respectively. hECE and ECE16-1 expressed involucrin protein, the level of which in both was higher in cells grown on filter compared to solid support. Polarization of the cultures was determined by morphology (stratification of hECE cells, expression of pseudomicrovilli in the apical cell membrane), selective apical vs. basolateral secretion of [35S]methionine- and [35S]cysteine-, [3H]fucose- and [14C]glucosamine-labeled molecules, and positive short-circuit current (Isc) under voltage-clamp conditions. Confluency of the cultures was determined by measuring transepithelial unidirectional fluxes of inert molecules with different molecular weights (MWs) through the paracellular pathway, and by measuring transepithelial conductance. The results indicated transepithelial permeability of 7-22.10(-6) cm.sec-1, which was 5-100 fold smaller compared to blank inserts, with a cut-off MW of 40-70 kDa for hECE and Caski cells. Transepithelial conductance ranged 18.5 to 51.5 mS.cm-2, indicating a leaky but confluent epithelia. Collectively the results indicate the epithelial nature of the cells and their improved differentiation when grown on filter support; hECE is a model for ectocervical epithelium while ECE16-1 and Caski express phenoty

Topics: Carcinoma, Squamous Cell; Cell Differentiation; Cell Line, Transformed; Cell Polarity; Cells, Cultured; Ceramics; Cervix Uteri; Collagen; Culture Techniques; Epithelial Cells; Epithelium; Female; Humans; Hydrocortisone; Keratins; Permeability; Polytetrafluoroethylene; Protein Precursors; Tretinoin; Tumor Cells, Cultured; Uterine Cervical Neoplasms; Vimentin

The identification of pretreatment markers with predictive significance for the presence of lymph node metastases and treatment outcome in low stage cancer of the uterine cervix is clinically important. Because the presence of differentiation-related markers varies in this type of cancer, the authors investigated whether loss of these markers is related to a poor clinical course.. An indirect immunoperoxidase technique was applied to formalin fixed, paraffin embedded tissue sections of 80 patients with International Federation of Gynecology and Obstetrics Stage IB and IIA primary squamous cell cervical carcinomas for detection of expression of cytokeratin 10 and 13, and involucrin. Comparisons were made of the expression of each of these markers among 40 patients with regional node metastases and 40 age-matched patients with no lymph node metastases. Differences in the frequency of expression of these markers also were analyzed in relation to histopathologic characteristics, recurrence, and survival.. Expression of cytokeratin 10, 13, and involucrin was found in 24, 64, and 53%, respectively, of all patients studied. The authors found no differences between patients with positive regional lymph nodes and those with negative lymph nodes. Expression of cytokeratin 13 and involucrin was associated with tumor grade (P = 0.01). No relationship was found between expression of the markers used and recurrence or survival in the entire group. Within the lymph node-positive group, however, the survival rate of patients with tumors with cytokeratin 13 expression was significantly higher than that of patients with tumors lacking cytokeratin 13 expression (P = 0.02).. Expression of cytokeratin 10, 13, or involucrin in the primary tumor is of no predictive value with respect to the presence of regional lymph node metastases in low stage squamous cell cervical cancer. However, cytokeratin 13 expression appears to be of prognostic significance in patients with positive regional lymph nodes.

Topics: Adult; Aged; Antibodies, Monoclonal; Biomarkers; Carcinoma, Squamous Cell; Female; Humans; Immunoenzyme Techniques; Keratins; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Prognosis; Protein Precursors; Retrospective Studies; Uterine Cervical Neoplasms

A study was undertaken to determine the potential value of involucrin immunostaining, a protein synthesized by mature squamous epithelial cells, in distinguishing benign from neoplastic lesions in cervical pathology. A total of 146 cervical biopsies were analyzed using an indirect immunoperoxidase method and polyclonal antibody. A suprabasal homogeneous cytoplasmic staining pattern was consistently observed in normal squamous cervical epithelium. In contrast, 43.7% of cervical condylomas showed involucrin at all levels of the epithelium including the basal layer. Variable patterns were seen in cervical intraepithelial neoplasia (CIN), with 46% of full-thickness stainings, although no significant difference was obtained among the different grades of CIN lesions. Distribution of involucrin was correlated (P less than 0.05) with the degree of tumor differentiation in squamous cell carcinomas, being absent in 71.4% of poorly differentiated carcinomas and focally present in 75% of well-differentiated carcinoma. Lesions of endocervical origin, either benign or malignant, were entirely negative for involucrin. It is concluded that involucrin seems unable to establish a reliable differential diagnosis between benign and neoplastic conditions in cervical pathology, and should therefore be considered only a specific marker of squamous differentiation in both normal and pathological human uterine cervix.

Topics: Adult; Aged; Cervix Uteri; Diagnosis, Differential; Epithelium; Female; Humans; Middle Aged; Precancerous Conditions; Protein Precursors; Uterine Cervical Diseases; Uterine Cervical Neoplasms

Undifferentiated cervical carcinomas vary considerably in their intercellular organization and patterns of invasion. In spite of its clinical significance, the basis for such variation is poorly understood. We investigated the cellular properties that may be responsible for this diversity, using as a model two human cervical carcinoma cell lines that were derived from the same tumor specimen and the same clone. It was shown previously that, in spite of their common origin, each line forms a histologically distinct type of undifferentiated carcinoma when heterotransplanted in vivo: cells of line C-4I grow as compact expanding masses with central necrosis, while tumors of line C-4II infiltrate host tissues as small, well-vascularized, dispersed cell groups. The characteristic behavior of each line was retained in culture, where C-4I cells formed highly multilayered cohesive colonies, while C-4II cells formed diffuse, monolayered colonies and shed into the culture medium. These observations as well as ultrastructural data suggested that each line may be arrested at a different stage of stratified squamous differentiation. In the present study, this hypothesis was tested by examining specific differentiation markers. An analysis of the cultures by immunofluorescence microscopy and immunoblotting revealed that keratin was more abundant in the compact C-4I line than in the dispersed C-4II line. C-4I cells expressed keratins 5, 6, 8, 16, 18, and 19, while C-4II expressed only keratins 8, 16, 18, and 19. In the multilayered C-4I colonies, involucrin-positive cells occurred in the apical cell layers only. In C-4II, involucrin-positive cells occurred in monolayers and domes, and they were most consistently located apically in crowded cultures. Laminin was secreted by both lines, but only C-4II cells deposited a fibronectin matrix. The results suggest that C-4I cells resemble normal cervical cells at the spinous stage of stratified squamous differentiation, while C-4II cells resemble basal/suprabasal cells. The different growth patterns of the tumors, formed by the lines in vivo, therefore likely reflect functional and behavioral differences that normally exist between spinous and basal cervical epithelial cells. The results suggest that differentiation-related functional properties may lead to histological diversity among cervical carcinomas that are categorized as undifferentiated by histopathological criteria.

Topics: Carcinoma; Cell Differentiation; Female; Fibronectins; Humans; Keratins; Laminin; Neoplasm Proteins; Protein Precursors; Tumor Cells, Cultured; Uterine Cervical Neoplasms

We used immunoperoxidase methods employing antibodies against involucrin and filaggrin, both markers of squamous terminal differentiation, to study squamous metaplastic transformation in the human endocervix. Expression of involucrin and filaggrin was restricted to squamous metaplastic cells whereas columnar epithelial cells were constantly negative. Immature squamous metaplastic epithelium also showed a positive immunostaining. In mature squamous metaplasia a suprabasal homogeneous staining pattern similar to that found in the exocervical epithelium was detected, although with full-thickness filaggrin immunoreactivity in 45% of cases (P less than 0.05). These results support the hypothesis of an epithelial origin of reserve subcolumnar cells, and suggest that precocious squamous differentiation seems to take place in metaplastic cells of the human endocervix.

Topics: Adult; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cervix Uteri; Epithelium; Female; Filaggrin Proteins; Humans; Intermediate Filament Proteins; Protein Precursors; Uterine Cervical Neoplasms

Involucrin is a keratinocyte envelope protein precursor which is synthesized at an early stage of differentiation in normal squamous epithelium. Recent studies suggest that this protein may be a marker for neoplastic epithelium. To address this issue, we analyzed involucrin expression in 105 biopsies containing 119 areas of normal, condylomatous, and neoplastic epithelium. Overall, 88, 75, and 55% of condylomata, well-differentiated CIN, and poorly differentiated CIN (carcinoma in situ) contained positive staining for involucrin. Excluding lesions with severe inflammation, 100, 88, and 55% of these lesions, respectively, were positive. Staining patterns in neoplastic lesions differed from those in the normal epithelium and condylomata; the staining in CIN tended to be focal, and intensity of staining varied widely from cell to cell in all layers of the epithelium. In high grade CIN, staining correlated with increases in cell size and cytoplasmic differentiation. These studies suggest that involucrin will not differentiate between lesions of low versus high risk for progressing to invasive carcinoma. However, the patterns of involucrin expression confirm the marked differences in patterns of cellular differentiation between classical condylomata and CIN.

Topics: Condylomata Acuminata; Epithelium; Female; Histocytochemistry; Humans; Protein Precursors; Uterine Cervical Neoplasms

Ninety-three cervical conization specimens with condyloma or intraepithelial neoplasia were stained by the peroxidase-antiperoxidase technique for involucrin. Diffuse, homogeneous suprabasal staining was observed in the ectocervical squamous mucosa and mature squamous metaplasia. In immature squamous metaplasia, staining was limited to cells with apparent squamous differentiation. Although diffusely reactive in the upper layers of condyloma and cervical intraepithelial neoplasia (CIN) grade I, the stain was uneven in the former and lacking in the parabasal layers of the latter. The staining intensity, distribution, and pattern were more variable in CIN grade II and grade III. With increasing severity, a patchy pattern with a mixture of reactive and nonreactive cells predominated. Although immunoreactivity with involucrin could not distinguish immature squamous metaplasia from neoplasia, the staining patterns in CIN correlated with extent of disease, degree of squamous differentiation, and cellular disorganization.

Topics: Carcinoma in Situ; Carcinoma, Squamous Cell; Condylomata Acuminata; Female; Humans; Immunoenzyme Techniques; Protein Precursors; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Immunohistochemical staining for involucrin, a cytoplasmic protein synthesized during squamous maturation, was assessed in histologic sections from hysterectomy and cone biopsy specimens from patients with cervical neoplasia. In normal and condylomatous squamous epithelium, diffuse cytoplasmic staining was seen in the suprabasal layers, with no staining of the basal cells. Staining was absent in two cases of cervical intraepithelial neoplasia (CIN), grade III, in which the lesions were composed entirely of undifferentiated cells and markedly decreased in cases involving large numbers of basal cells. In 19 of 23 cases (83 per cent) of CIN, however, focal staining for involucrin was seen in large differentiated cells in the more superficial layers, and in two cases of keratinized CIN diffuse suprabasal staining was observed. Similarly, strong staining for involucrin was present in differentiated areas in one case of microinvasive squamous cell carcinoma and in 93 per cent of cases of infiltrating squamous cell carcinoma. These findings suggest that involucrin is a marker for maturation in cervical squamous epithelial neoplasms. Patterns of immunohistochemical staining for involucrin in keratinized dysplasia and differentiated squamous carcinomas should be taken into consideration if loss of involucrin staining is used as a criterion for neoplastic transformation of cervical epithelium, as has been proposed.

Topics: Carcinoma, Squamous Cell; Cervix Uteri; Female; Histocytochemistry; Humans; Immunoenzyme Techniques; Neoplasm Invasiveness; Protein Precursors; Uterine Cervical Neoplasms

Forty-two cervical biopsies with cervical intraepithelial neoplasia were compared with respect to the expression of human papillomavirus (HPV) structural proteins and the expression of the cellular structural protein involucrin, a marker of suprabasal squamous differentiation. HPV structural protein and involucrin expression displayed an inverse correlation with the severity of dysplasia. Both of these proteins were detected in 11 of 28 cases (39%) of mild and moderate dysplasia, but in only two of 14 (14%) cases of severe dysplasia. This difference was statistically significant (p less than 0.001). The presence of HPV was also associated with expression of involucrin in the full thickness of the epithelium, including the basal layer, and an altered staining pattern in the more superficial cells, particularly the koilocytotic cells. These findings support the hypothesis that squamous differentiation is required for the expression of viral structural proteins and that HPV infection begins in the basal epithelium. The study also demonstrates the utility of involucrin staining in differentiating virus-induced cytologic atypia from true neoplasia.

Topics: Adult; Animals; Carcinoma in Situ; Cell Differentiation; Female; Humans; Papillomaviridae; Protein Precursors; Tumor Virus Infections; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Viral Proteins; Viral Structural Proteins