Mucin carbohydrate antigens (T, Tn, and sialyl-Tn) in human ovarian carcinomas: relationship with histopathology and prognosis

Altered glycosylation of mucins leading to the expression of T, Tn, and sialyl-Tn antigens has been shown in ovarian carcinoma, but its relationship with prognosis is still unclear. We investigated immunohistochemically the expression of these antigens in 38 (17 serous and 21 mucinous) ovarian carcinomas to assess their potential prognostic value as compared with stage of disease, histopathology of tumors, and survival time of patients. Eight benign ovarian tumors (four serous and four mucinous), and four normal ovarian tissues also were studied. Of the 38 carcinomas, 25 (66%) expressed T, 27 (71%) expressed Tn, and 33 (87%) expressed sialyl-Tn antigens. Most cases (83%) expressed two or all of the three types of antigens simultaneously. Normal ovarian epithelia showed no staining for these antigens, and benign ovarian tumors were either negative or occasionally expressed weak staining in less than 25% of epithelial cell areas. Statistical analyses showed strong associations between Tn and sialyl-Tn antigen expressions and disease stage as well as histological grade. In 19 ovarian carcinoma patients with available survival data, the overall survival times of patients with high Tn or sialyl-Tn antigen expression were significantly worse than those of the patients with negative and low expression (P < .05 and P < .01). In multivariate stepwise regression analysis, disease stage (P = .000) and Tn antigen expression (P = .02) were found to be significant independent parameters associated with the overall survival time. These findings suggest that, with exception of T antigen expression, the expression of Tn and sialyl-Tn antigens in ovarian carcinomas may provide additional prognostic information on patient outcome.     

Glycopathological study of eyelid tumors and pseudotumors

The expression of MUC1, Tn (GalNAc alpha 1-O-Ser/Thr) and sialosyl Tn (STn) (NeuAc alpha 2,6 GalNAc alpha 1-O-Ser/Thr) antigens, which are useful markers for the prognosis of cancer in other organs, was examined immunohistochemically in a series of 45 eyelid tumors and 5 pseudotumors: basal cell carcinoma, 18; squamous cell carcinoma, 11; sebaceous gland carcinoma, 6; seborrheic keratosis, 4; papilloma, 3; verruca vulgaris, 2; nevus, 1; and granuloma, 5. The MUC1 antigen was identified in all squamous cell and sebaceous gland carcinomas, but not in basal cell carcinoma or the benign tumors. The Tn antigen was expressed in all the sebaceous gland, half of the squamous cell, and only rarely in the basal cell carcinomas. The STn antigen was expressed in all seborrheic keratosis and in the majority of squamous cell carcinomas, but only rarely in sebaceous gland and basal cell carcinomas. Eyelid tumors are frequently associated with apomucin and mucin-carbohydrate antigens: the MUC1 glycoprotein appears to be related to the malignant potential of eyelid tumors, and may be a useful marker for the differential diagnosis of invasive tumors, including sebaceous gland and squamous cell carcinomas.     

The action of chlorpromazine on the electrodermal response in the cat

Fourty one vulvectomy operation specimens and seventeen biopsies from the vulva were examined. They represented either dysplasias, carcinomata in situ or invasive squamous cell carcinoma. Slightly more than a third of the cases showed early stromal invasion as well in dysplasias and carcinomata in situ as in the margins of the invasive carcinomas. On the other hand the early stromal invasion of the vulva doesn't show that striking alterations as does that of the cervix uteri.     

DNA ploidy, P53 expression, and cellular proliferation in normal epithelium and squamous dysplasia of non-cancerous and cancerous human oesophagi

Ki67 expression, S-phase fraction, p53 immunoreactivity and DNA content were examined in morphologically normal mucosa and squamous dysplasia of both cancerous and non-cancerous human oesophagi in order to understand possible early events in the development of esophageal squamous cell carcinoma. 103 different foci from cancerous esophagi including 17 non-pathological epithelium, 10 mild, 17 moderate and 15 severe dysplasia, 14 intraepithelial carcinomas and 30 invasive squamous cell carcinomas were examined. Also studied were 57 biopsy specimens from cancer-free individuals, including 12 normal epithelia, 15 oesophagitis, and 16 mild, 11 moderate and 3 severe dysplasia. Areas of squamous dysplasia from both cancer-free and cancerous oesophagi were morphologically indistinguishable and both demonstrated increased cellular proliferation compared to normal or non-pathological epithelia. However, squamous dysplasia in cancerous oesophagi demonstrated significantly larger ki67 labelling indices and smaller S-phase fractions than dysplasia in cancer-free patients. Squamous dysplasia in cancerous and non-cancerous oesophagi demonstrated an non-diploid DNA histogram in 67.9% and 43.3% respectively. However, dysplasia from cancer-free individuals demonstrated a non-diploid pattern with one or more peaks (Type I non-diploid histogram) and that from oesophageal cancer patients predominantly exhibited non-diploid histograms without any distinctive peaks (Type II non-diploid histogram). Significant differences in the frequency of p53 positive foci were observed between dysplasia of cancer-free (23.3%) and cancerous (56.8%) oesophagi. IN cancerous oesophagi, dysplasia associated with Type II non-diploid histograms had a significantly larger number of p53-positive foci than those with diploid histograms or Type I non-diploid histograms. These results indicated that the biological features of squamous dysplasia were different between cancerous and non-cancerous human oesophagi despite indistinguishable morphological features. In addition, the combination of p53 immuno-histochemistry and DNA ploidy analysis may contribute to identify possible high-risk squamous dysplasia of the oesophagus.     

Blood group antigens in differentiated thyroid neoplasms

Alteration of cell-surface blood group antigens during malignant transformation is a well-known phenomenon that has not yet been sufficiently investigated in thyroid gland neoplasms. We evaluated 50 normal thyroid glands and 141 differentiated thyroid neoplasms (29 follicular adenomas, 30 follicular carcinomas, 56 papillary carcinomas, and 26 medullary carcinomas) both by the immunoperoxidase technique, using monoclonal antibodies against blood group antigens (A, B, H, Le(a), Le(b), Le(x), and Le(y)) and precursor substances (T, Tn, and sTn), and by affinity to the lectin from Arachis hypogea, to determine the usefulness of these antigens as tumor markers and prognostic factors. Neoplastic tissues showed immunostaining with concordant and nonconcordant expression of ABH antigens. There were statistically significant differences between normal and neoplastic tissues but not among the different neoplasms. Statistically significant differences in Lewis antigen expression were noted between normal and neoplastic tissues and between benign and malignant tumors. Tn and sTn antigen expression showed statistically significant differences between normal and neoplastic tissues. In conclusion, blood group antigens are tumor markers that are expressed more frequently in malignant than in benign neoplasms. The presence of metastases was correlated with enhanced peanut lectin receptors and a loss of A or B antigens.     

Expression of the adherens junction protein vinculin in human basal and squamous cell tumors: relationship to invasiveness and metastatic potential

The acquisition of an invasive or metastatic phenotype in malignant neoplasms is often correlated with reduced cellular adhesiveness. We investigated the expression of the adhesion-associated cytoplasmic protein, vinculin, in normal and neoplastic human squamous epithelia, as well as in metastases of squamous cell carcinomas, and correlated the results with invasiveness and metastatic potential. Tissue samples from various tumors were examined, including basal cell carcinomas (BCC), keratoacanthomas, and squamous cell carcinomas (SCC). In addition, lymph node metastases from nine of the SCC were tested in this study. Our results indicate that most BCC, keratoacanthomas, and in situ SCC display strong positive staining for vinculin. The level of immunolabeling for vinculin and its pattern of distribution in the low malignant, nonmetastasizing lesions was similar to those observed in normal squamous epithelia. In contrast, in SCC, which are invasive and possess metastatic potential, as well as in their metastases, vinculin labeling was negative or poor, irrespective of their degree of differentiation. In conclusion, poor vinculin labeling in tumors of squamous epithelial origin examined here appears to be related to the metastatic potential of the tumor. Vinculin immunostaining of primary tumors originating in stratified squamous epithelia may thus be of value in helping to determine the metastatic potential of these neoplasms.     

Evaluation of a new rapid detection system for mycobacteria using an oxygen sensitive fluorescent sensor

Gallbladder carcinoma is one of the most frequent neoplasms diagnosed in Chile. Although the premalignant lesions have been extensively studied and are well characterized, there is only limited information about the genetic abnormalities that might be important in the pathogenesis of gallbladder carcinoma or that might have prognostic implications. The present study evaluates the immunohistochemical expression of p53 protein in premalignant lesions and invasive carcinoma of the gallbladder, and correlates the p53 expression with histological type, grade of differentiation, and level of invasion of the tumor. The authors studied the immunohistochemical p53 protein overexpression in 52 gallbladder carcinomas, 47 carcinomas in situ (CISs), 34 dysplasias, and 10 specimens with chronic cholecystitis containing normal and metaplastic epithelium. A semiquantitative scoring system was used to assess the p53 reactivity. p53 overexpression was found in 34 of 52 (65.4%) carcinomas, 21 of 47 (44.7%) CISs, and 11 of 34 (32.4%) dysplasias. There were no significant differences in p53 expression in premalignant lesions associated with invasive carcinoma and those that were not. Normal and metaplastic epithelium did not overexpress p53 protein. In adenocarcinomas, no correlation was found between p53 protein overexpression and histological subtype, grade of differentiation, or level of invasion. The high incidence of p53 overexpression in gallbladder carcinoma and its presence in dysplasia, even in specimens without invasive carcinomas, suggests that this abnormality is an important and early event in the pathogenesis of the tumor. The progressively increasing incidence of p53 overexpression observed from premalignant lesions to invasive tumor provides additional support to the view that this is the usual route for the development of infiltrating gallbladder carcinoma.     

Expression of p21WAF1 predicts outcome of esophageal cancer patients treated by surgery alone or by combined therapy modalities

The p21WAF1 protein is an important regulator of the cell cycle. Its expression and prognostic significance were investigated immunohistochemically in samples of normal esophageal squamous epithelium (n = 10), severe squamous cell dysplasia (n = 20), carcinoma in situ (n = 14), permanent esophageal squamous cell carcinoma cell lines (n = 3), and invasive squamous cell carcinomas treated either by potentially curative resection (n = 172) or by combined modality therapy (radiochemotherapy +/- surgery; n = 38). Whereas p21WAF1 expression in the normal epithelium was restricted to a few cells adjacent to the basal cell layer, p21WAF1 overexpression was frequently found in preneoplasias and invasive carcinomas. Expression of p21WAF1 in invasive carcinomas was not correlated with tumor differentiation, pT category, or pN category. Among carcinomas treated by potential curative resection, univariate (P = 0.0025) and multivariate (P = 0.0081) survival analysis showed significant correlation of strong p21WAF1 expression (> or =50% p21WAF1-positive tumor cells) with poor overall survival. Univariate survival analysis (P = 0.0006) revealed the same prognostic influence in the group of patients treated by combined modality therapy. We conclude that overexpression of p21WAF1 protein is a frequent event in preneoplasias and neoplasias of the esophagus. Immunohistochemical examination of p21WAF1 expression may provide important prognostic information for decision-making in the treatment of patients with esophageal cancer.     

Multiple early gastric stump carcinomas after gastrectomy for peptic ulcer

The remnant stomach after partial gastrectomy is considered to have a predilection for the development of primary gastric carcinoma. However, early gastric stump carcinomas are uncommon because the diagnosis of gastric stump carcinoma is more difficult than that of carcinoma in the intact stomach. Triple early gastric stump carcinomas, as in the present case, are exceedingly rare and may provide some clues for further investigation of carcinogenesis in the gastric stump. We studied about the histological appearance, genetic alterations (P-53 gene, c-erbB-2 gene and K-ras gene), and expression of tumor-associated antigens (carcinoembryonic antigen, carbohydrate antigen 19-9, and sialyl-Tn) in this rare case. The three carcinomas differed from each other histologically. With respect to genetic alterations, c-erbB-2 was amplified in one lesion, but no mutations of K-ras and P-53 gene were detected. The three carcinomas also differed from each other on the expression of tumor-associated antigens. In noncancerous mucosal epithelium at the anastomosis showing hyperplasia and cystic formation of glandular epithelial cells, no genetic alterations were detected, but sialyl-Tn and carbohydrate antigen 19-9 were expressed. These results suggest that there may be different processes of carcinogenesis of the three carcinomas even though they occurred under identical environmental conditions to those that have increased cancer risk.     

Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy

Aberrant glycosylation is a hallmark of cancer cells. The blood group precursors T (Thomsen-Friedenreich) and Tn epitopes are shielded in healthy and benign-diseased tissues but uncovered in approx. 90% of carcinomas. T and Tn glycoproteins are specific, autoimmunogenic pancarcinoma antigens. These antigens may also be found in neoplastic blood cells (and on LTV-II infected T lymphocytes). Fundamental chemical and physical aspects of these glycoproteins of primary carcinomas are discussed first. Tn and T epitopes are cell and tissue adhesion molecules, essential in invasion by and metastasis of carcinoma which includes adherent and proliferative phases. These properties are then delineated next, followed by consideration of pathophysiological and clinical aspects of these antigens. Immunohistochemical studies of the extent of Tn antigen expression in primary breast carcinoma demonstrate it highly significant correlation with clinicopathological tumor stages, and hence its value as a reliable prognosticator. On the other hand, there is no significant, prognostically useful association between T antigen expression and clinical disease course. Everyone has "preexisting" anticarcinoma anti-Tn and anti-T antibodies, induced predominantly by the intestinal flora, while cellular immune responses to T and Tn epitopes are evoked only by carcinomas and some lymphomas. Carcinoma dedifferentiation leading to predominance of Tn over T epitopes is described, as is the role of Tn and T epitopes in very early, including preclinical, carcinoma detection. The highest sensitivities in carcinoma detection are for preclinical and the earliest clinical stages. Obviously, preclinical carcinoma detection is of practical importance. T/anti-T tests detected preclinical carcinoma in 77% of 48 patients long (mean 6 years) before their biopsy/X-ray results became positive. There were no false predictions of carcinoma in 38 control persons with benign diseases (observation average 4.8 years). These findings open a novel window for both curative approaches and pathophysiological studies. The autoimmunogenicity of carcinoma T/Tn antigen led us more than two decades ago to begin intradermal vaccination of patients with advanced breast carcinoma of stages IV-IIb, predominately after modified radical mastectomy and sometimes lumpectomy plus axillary dissection always followed by adjuvant radio/chemotherapy. The vaccine consists of human group O red blood cell membrane derived, HLA-free T/Tn antigen containing as adjuvant Ca3(PO4)2 plus a trace of phosphoglycolipid A hyperantigen, i.e., S typhi vaccine (USP), which itself has T and Tn specificities. Our efforts have now for up to 20 years remained successful in a large majority of the 32 patients. All 32 patients survived at least 5 years; 10-year survival was statistically highly significantly improved (5-year survival: P < 1 x 10(-7); 10-year survival: P < 1 x 10(-5)) compared to statistics of the United States National Cancer Institute. Because these vaccinations are successful, their extension to large populations with major types of carcinomas should be considered, and even immunological carcinoma prevention may be contemplated.     

The multicentric occurrence of squamous epithelial dysplasia and squamous cell carcinoma in the esophagus

BACKGROUND: The biologic significance of esophageal dysplasia has not yet been completely elucidated, especially regarding the process of multiple occurrences of squamous cell carcinoma. METHODS: The multiplicity of dysplasia in 73 patients with solitary carcinoma of the esophagus (Group I) and 21 with multiple carcinomas (Group II) was compared in surgically resected specimens. RESULTS: Thirty-nine second carcinomas were identified in 13 patients of Group II, and all were superficial. The incidences of five or more isolated dysplasias in cases without continuity to a carcinomatous lesion, was 6.8% and 66.7% in Groups I and II, respectively (P < 0.01). In a case with three or more carcinomas, the incidence increased to 84.6%. The coexistence of all grades of isolated dysplasias was observed in 10 patients (47.6%) in Group II but in only 6 patients (8.2%) in Group I (P < 0.01). CONCLUSIONS: These findings suggest that various degrees of evolving biologically related lesions, such as dysplasia and carcinoma, can occur multicentrically in the same esophagus.     

Nutrition-related research at USDA''s Eastern Regional Research Center

Forty thousand consecutive cytologic smears and subsequent diagnostic procedures resulted in the diagnosis of 41 carcinomas in situ, 35 microinvasive and invasive carcinomas, and 24 severe dysplasias for a yield of significant neoplasia of one lesion per 400 Papanicolaou smears. Twenty-five of the carcinomas in situ and microinvasive and invasive carcinomas were diagnosed in patients with atypical smears indicating that all patients with persistent atypical smears require evaluation by tissue examination. Seventy-eight percent of the 119 patients subjected to conization either had carcinoma in situ, microinvasive and invasive carcinoma, or significant cervical dysplasia. Post-operative complications following conization were negligible. In addition there were no postconization deleterious effects on three concurrent and nine subsequent pregnancies. A history of gonorrhea places a patient at a higher risk of developing cervical carcinoma. Annual performance of cytologic smear evaluation is indicated in all sexually active women and in all virginal women over 20 years of age.     

Rectal epithelial proliferation in persons with or without a history of adenoma and its association with diet and lifestyle habits

BACKGROUND: The authors investigated telomerase enzyme activity and expression of its RNA component (hTR) during the multistage pathogenesis of cervical carcinomas, and correlated activation with histopathologic findings and human papillomavirus (HPV) infection. METHODS: The authors analyzed 180 cervical specimens for enzyme activity, and analyzed hTR expression in an additional 55 samples from archival carcinoma cases. Polymerase chain reaction-based assays were used to determine telomerase enzyme activity and HPV infection, whereas a radioactive in situ assay was used for hTR expression. RESULTS: Telomerase enzyme activity was present in some samples of histologically normal epithelium (18 of 138; 13%) and low grade squamous intraepithelial lesions (LSIL) (7 of 21; 33%), and in most high grade squamous intraepithelial lesions (HSIL) (13 of 21; 62%). The relative levels of telomerase activity were low in all preinvasive specimens except for three samples of HSIL with high activity. Although 21% of the brush samples had evidence of HPV infection, there was no obvious correlation between telomerase activity and HPV status. hTR expression was low in normal squamous/glandular epithelium and LSIL lesions, in which it was limited to the basal cells. In squamous and glandular in situ and invasive carcinomas, increased and dysregulated hTR expression was observed, although heterogeneity was noted. Intense focal up-regulation of hTR expression occurred in a subset of in situ lesions. CONCLUSIONS: Increased frequency and dysregulation of telomerase activation is correlated with increasing severity of histopathologic changes, but not with HPV infection. Whether dysregulated activity is a prognostic marker for development of invasive carcinoma remains to be determined.     

Factors regulating SCC antigen expression in squamous cell carcinoma of the uterine cervix

Expression of squamous cell carcinoma (SCC) antigen emerged concurrently with squamous formation of the uterine cervix and increased during the neoplastic transformation of the cervical squamous epithelium. SCC antigen expression differed considerably among the histomorphologic cell types of cervical carcinoma. Large cell nonkeratinizing carcinoma contained high levels of the antigen. In contrast, no appreciable expression of SCC antigen was observed in small cell nonkeratinizing carcinoma. The pattern of SCC antigen expression closely coincided with EGF receptor (EGF-R) expression in cervical squamous neoplasia. This suggests that the expression of SCC and EGF-R in cervical carcinoma is related to the differentiation or dedifferentiation processes of the tumor cells. SCC production by CaSki cervical epidermoid carcinoma cells was stimulated by EGF. It seems likely that an autocrine system, in which EGF serves as the signal, may exist in cervical squamous carcinoma. 17beta-estradiol and L-triiodothyronine were found to upregulate EGF-R expression, proliferative potential and SCC production in the CaSki cervical carcinoma cells.     

Jack fruit lectin-specific glycoconjugate expression during the progression of cervical intraepithelial neoplasia: a study on exfoliated cells

The expression of glycoconjugates specific to Jack fruit lectin (JFL) was studied in the exfoliated squamous cells of different grades of intraepithelial and invasive neoplasia of the uterine cervix. It was observed that while normal cells showed almost negative binding, the lectin binding percentage of squamous cells significantly increased with increasing atypia of the epithelium. Correlation analysis between different groups revealed that mild lectin binding in cells had a negative correlation and intense binding had a positive correlation with various stages of tumor progression. These results indicate that the number of cells with aberrant expression of glycoconjugates increases as neoplastic transformation advances. The percentage of labeled and unlabeled cells also shows a continuous transition from low to severe grades of cervical intraepithelial neoplasia and invasive carcinomas. The present study therefore shows that JFL may be used as a probe for further elaboration of detection and grading of precancerous and cancerous lesions of the uterine cervix.     

Results in irradiation of the in situ carcinomas of the vocal cords

From 1952 through 1973, 79 patients with the diagnosis of in situ carcinoma and seven with the diagnosis of leukoplakia and/or atypical hyperplasia were treated with irradiation. The staging system was the same as for the invasive squamous carcinomas. The irradiation techniques were also identical to those used for invasive squamous cell carcinomas. The failure rate for the T1 lesions was 11% and 26% for the T2 lesions--in the same range as the failure rates observed for the invasive squamous carcinomas. Only two of the 12 failures were on the initially involved cord. These two facts suggest that most of the failures were not recurrences but were new disease developing on the dysplastic epithelium. There was a delay in the appearance of failure for the in situ carcinomas as compared with that for the invasive squamous cell carcinomas of the supraglottic larynx. Seventy-six percent of the patients have a normal voice.     

Clonal analysis of urothelial carcinomas in C3H/HeN<-->BALB/c chimeric mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine

The histological background for multifocal and metachronous development of urothelial carcinomas remains equivocal, although accumulated genetic evidence suggests monoclonal origin of multiple urothelial carcinomas. Clonal development of various preneoplastic and neoplastic urothelial lesions of C3H<-->BALB/c chimeric mice induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was immunohistochemically investigated using a C3H strain-specific antibody. All tumor masses induced in the mice treated with 0.05% BBN for 20 weeks were composed of neoplastic cells of a single parental type, which is indicative of monoclonal lesions. Three of 10 animals harbored two or more separate carcinomas of different clonal type, which is indicative of multicentric development applicable in this model. Using DNAs derived from urothelial carcinomas and tumor-adjacent urothelium of chimeric mice, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing were performed for p53 gene exons 5-7. p53 mutations were identified in four of 11 (36%) dysplasias and non-invasive carcinomas (carcinoma in situ and pTa tumor) and 13 of 22 (59%) invasive carcinomas. Only in a single case were identical p53 mutations found in separate urinary bladder carcinomas. In contrast to the random distribution of urothelial proliferating units in chimeric mice without chemical supplement, invasive carcinomas in BBN-treated mice were accompanied by widely-distributed preneoplastic and neoplastic lesions of the same clonality, which occasionally had frequent foci of microinvasion. This is indicative of lateral clonal expansion of the clones, which precedes the bulk of invasive carcinomas. Thus, two aspects of 'field change' of the urothelium became evident in this model: either independent transformation events or lateral clonal expansion might, respectively, result in multicentric and monoclonal carcinoma development in the urinary tract.     

Limitations of imaging choroidal tumors in vivo by optical coherence tomography

AIM: To study the immunohistochemical expression of the Thomsen-Friedenreich antigen (T) and its precursor, Tn, in the skin in various cancers. METHODS: T and Tn antigens were studied with monoclonal antibodies in 91 primary premalignant and malignant lesions, 13 cases of Paget's disease, and 26 carcinomas metastatic to the skin. The material had been collected over a 10 year period, formalin fixed, and paraffin embedded. Diagnoses had been made after examination of standard histological sections, supplemented when needed by appropriate immunohistochemical staining. RESULTS: 21% and 29% of the primary cutaneous premalignant and malignant epithelial tumours expressed the Tn and T antigens, respectively. By contrast, 81% of metastatic carcinomas to the skin were Tn positive, while only 23% of them expressed the T antigen. All cases of Paget's disease were Tn positive but only 15% of them expressed the T antigen. The 21 nonepithelial tumours (including melanomas) were as a rule unreactive. CONCLUSIONS: The accumulation of the precursor (Tn) antigen in tumours metastasising to the skin highlights the incomplete glycosylation of carbohydrate antigens occurring in these tumours. The predominant Tn versus T antigen expression appears to be a useful immunohistochemical feature which may aid in the differentiation of primary cutaneous carcinomas from metastatic tumours.     

Immunohistochemical study on the expression of carbohydrate antigens in normal squamous epithelia and squamous cell carcinomas of the uterine cervix

The expression of 4 kinds of carbohydrate antigens, CA50, CA19-9, sialyl SSEA-1, and DU-PAN-2 was studied immunohistochemically in 15 normal cervical squamous epithelia and 49 cervical carcinomas. (1) In normal epithelia, CA50 and CA19-9 were expressed in all cell layers and all cell layers except for the basal layer, respectively, and a gradual decrease in the intensity of staining was observed in the upper layer. Sialyl SSEA-1 was expressed only in the superficial layer, but DU-PAN-2 was not found in any normal epithelia. (2) In cervical carcinomas, CA50, CA19-9, sialyl SSEA-1 and DU-PAN-2 were observed in 51.0%, 49.0%, 55.1% and 26.7%, respectively. (3) The number of Ki67 positive cells tended to be lower in the area with sialyl SSEA-1 immunostaining. (4) In the cases in which sialyl SSEA-1 positive cells were distributed diffusely in cancer nests, the incidence of lymph node metastasis was significantly higher. These result suggest that the expression of CA50, CA19-9 and sialyl SSEA-1 is related to the differentiation of normal squamous epithelial cells, and sialyl SSEA-1 may be related to cell differentiation also in cervical carcinomas, and the features of its expression may be useful in predicting the biologic properties of cervical carcinomas.     

Reduced levels of the cell-cycle inhibitor p27Kip1 in epithelial dysplasia and carcinoma of the oral cavity

Recent studies have shown that the cyclin-dependent kinase (cdk) inhibitors play important roles in cell cycle progression in normal cells. Alterations in the cdk inhibitors also appear to be important in cancer development in a number of human tumors. p27Kip1 is a member of the CIP/KIP family of cdk inhibitors that negatively regulates cyclin-cdk complexes. Reduced levels of p27Kip1 protein have been identified in a number of human cancers, and in some cases reduced p27Kip1 is associated with an increase in proliferative fraction. In the present study, we examined p27Kip1 protein by immunohistochemistry in 10 normal and 36 dysplastic epithelia and in 8 squamous cell carcinomas from one anatomical site within the oral cavity, the floor of the mouth. Proliferative activity was assessed in serial sections by determining the expression of the cell cycle proteins Ki-67 and cyclin A. p27kip1 protein was significantly reduced in oral dysplasias and carcinomas compared with that in normal epithelial controls. In addition, there was a significant reduction in p27Kip1 protein between low- and high-grade dysplasias, suggesting that changes in p27Kip1 expression may be an early event in oral carcinogenesis. There was increasing expression of Ki-67 and cyclin A proteins with increasingly severe grades of dysplasia compared with normal controls. Although there was a strong correlation between Ki-67 and cyclin A scores (r2= 0.61) for all categories of disease, there was a weak negative correlation between Ki-67 and p27Kip1 levels (r2 = 0.29) and between cyclin A and p27Kip1 levels (r2 = 0.25). In conclusion, this study has found that a reduction in the proportion of cells expressing p27Kip1 protein is frequently associated with oral dysplasia and carcinoma from the floor of the mouth. Furthermore, reductions in p27Kip1 levels are associated with increased cell proliferation, although other changes likely contribute to altered cell kinetics during carcinogenesis at this site.