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PubMed2005

Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib.

BACKGROUND & AIMS: Esophageal squamous cell carcinoma remains a leading cause of cancer death worldwide. Squamous dysplasia, the accepted histological precursor for esophageal squamous cell carcinoma, represents a potentially modifiable intermediate end point for chemoprevention trials in high-risk populations. METHODS: We conducted a randomized, controlled trial of selenomethionine 200 microg daily and/or celecoxib 200 mg twice daily (2 x 2 factorial design) among residents of Linxian, People's Republic of China. Subjects had histologically confirmed mild or moderate esophageal squamous dysplasia at baseline. Esophagogastroduodenoscopy was performed before and after a 10-month intervention. Per-subject change (regression, stable, or progression) in the worst dysplasia grade was defined as the primary end point. Results were compared by agent group (selenomethionine vs placebo; celecoxib vs placebo). RESULTS: Two hundred sixty-seven subjects fulfilled all eligibility criteria, and 238 (89%) completed the trial. Overall, selenomethionine resulted in a trend toward increased dysplasia regression (43% vs 32%) and decreased dysplasia progression (14% vs 19%) compared with no selenomethionine (P = .08). In unplanned stratified analyses, selenomethionine favorably affected a change in dysplasia grade among 115 subjects with mild esophageal squamous dysplasia at baseline (P = .02), but not among 123 subjects with moderate esophageal squamous dysplasia at baseline (P = 1.00). Celecoxib status did not influence changes in dysplasia grade overall (P = .78) or by baseline histology subgroup. CONCLUSIONS: After a 10-month intervention, neither selenomethionine nor celecoxib inhibited esophageal squamous carcinogenesis for all high-risk subjects. However, among subjects with mild esophageal squamous dysplasia at baseline, selenomethionine did have a protective effect. Although it is based on unplanned stratified analyses, this finding is the first report of a possible beneficial effect for any candidate esophageal squamous cell carcinoma chemopreventive agent in a randomized controlled trial.

Adult↗

PubMed2004

Aberrant methylation of the FHIT gene in chronic smokers with early stage squamous cell carcinoma of the lung.

Fragile histidine triad (FHIT) gene plays an important role in the pathogenesis of lung cancer. However, the clinicopathological significance of CpG island hypermethylation of FHIT gene in non-small cell lung cancer (NSCLC) remains to be elucidated. We studied FHIT methylation in 254 NSCLCs in order to further understand the clinicopathological and prognostic significance of FHIT methylation in NSCLC. Methylation status of the FHIT gene was examined using Methylation-Specific PCR. All statistical analyses were two-sided, with a 5% type I error rate. Hypermethylation of the FHIT gene occurred more frequently in squamous cell carcinoma than adenocarcinoma. For 93 adenocarcinomas there was no statistically significant association between FHIT methylation and age, gender, smoking history, pathologic stage and p16 methylation. However, FHIT methylation in 125 squamous cell carcinomas was associated with exposure to tobacco smoke and p16 methylation, but not with age, gender and pathologic stage. Hypermethylation of FHIT in squamous cell carcinomas occurred more frequently in current smokers (45%) than in never-smokers (13%). FHIT methylation was significantly associated with p16 methylation in current- and ex-smokers (P = 0.02 and P = 0.01, respectively) with squamous cell carcinoma and in patients with pathologic stage I squamous cell carcinoma (P = 0.001). Patients with p16 methylation were 3.74 times [95% confidence interval (CI) = 1.62 - 7.95; P = 0.001] more likely to have FHIT methylation in squamous cell carcinoma. FHIT methylation in squamous cell carcinoma occurred at a 4.62 times (95% CI = 1.26 - 34.97; P = 0.02) higher prevalence in current smokers than in never-smokers. No prognostic effect of FHIT methylation was observed in stage I and stage II NSCLCs. In conclusion, hypermethylation of the FHIT gene did not have a prognostic significance in early stage NSCLCs. The FHIT methylation is associated with the p16 methylation and smoking in squamous cell carcinoma, suggesting that FHIT may cooperate with p16 for the development of squamous cell carcinoma of lung in individuals exposed to tobacco smoke.

Acid Anhydride Hydrolases↗

PubMed2004

A genomic predictor of oral squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: The objective was to identify a genomic profile that predicts the likelihood of oral squamous cell carcinoma compared with normal oral mucosa in unknown tissue samples. STUDY DESIGN: Using a training set of tissue samples that were histologically classified as oral squamous cell carcinoma or normal mucosa, the authors used principal component analysis to develop a genomic predictor for oral squamous cell carcinoma. On a separate test set of unclassified samples, the authors used the predictor to classify the samples, then evaluated the performance of the predictor using histological diagnosis. METHODS: The authors used a data set consisting of messenger RNA extracted from 29 oral squamous cell carcinoma and 19 normal oral mucosa tissue samples and hybridized to Affymetrix oligonucleotide microarrays containing probe sets for 7070 genes and expressed sequence tags. The samples were divided into a training set of 15 oral squamous cell carcinoma and 10 normal samples and a test set consisting of the remaining samples. Using principal component analysis on the training set, the authors found a composite gene expression vector (principal component vector), which they used to compute likelihood ratios for oral squamous cell carcinoma on the test set. By calculating the contribution of each gene to the principal component vector, the authors identified genes with the greatest predictive value. RESULTS: Using the likelihood ratio, the authors correctly classified all 23 samples in the test set as either oral squamous cell carcinoma or normal. The authors found that many of the most predictive genes are known to be markers of squamous cell carcinoma or normal mucosa. CONCLUSION: Principal component analysis can be used with genomic microarray data to correctly predict the presence of oral squamous cell carcinoma in unknown tissue samples.

Biomarkers, Tumor↗

PubMed2003

Analysis of promoter hypermethylation of death-associated protein kinase and p16 tumor suppressor genes in actinic keratoses and squamous cell carcinomas of the skin.

Death-associated protein kinase is a serine/threonine protein kinase implicated in promoting apoptosis and tumor suppression, whereas p16 is a tumor suppressor gene that inhibits cyclin-dependent kinase 4 and 6 activity and arrests the cell cycle in the G1 phase. Hypermethylation of death-associated protein kinase or p16 gene with resultant gene inactivation has been described in a wide variety of human cancers. Promoter methylation of the death-associated protein kinase and p16 gene has been found in about 55% and 30% cases of head and neck squamous cell carcinoma respectively but has not yet been analyzed in cutaneous premalignant and malignant lesions. A total of 33 cases were examined for evidence of death-associated protein kinase and p16 hypermethylation and these consist of 9 cases of spongiotic dermatitis as nonneoplastic skin control, 9 cases of actinic keratosis, 8 cases of squamous cell carcinoma in situ, and 7 cases of invasive squamous cell carcinoma. Death-associated protein kinase promoter methylation was detected in 1 case of squamous cell carcinoma in situ and 1 case of nonneoplastic skin control but none of the cases of invasive squamous cell carcinoma or actinic keratosis. P16 promoter methylation was detected in 1 case of invasive squamous cell carcinoma and 1 case of nonneoplastic skin control but none of the cases of squamous cell carcinoma in situ or actinic keratosis. Promoter hypermethylation of the death-associated protein kinase and p16 genes does not appear to play an important role in the development of cutaneous squamous cell carcinoma. The data thus suggest that the mechanisms of ultraviolet-induced cutaneous carcinomas differ from those involved in the development of head and neck squamous cell carcinoma, a malignant disease induced by tobacco and alcohol exposure.

Apoptosis Regulatory Proteins↗

PubMed2003

Induced expression of syndecan-1 in the stroma of head and neck squamous cell carcinoma.

Syndecan-1 (CD138), a cell-surface heparan sulfate proteoglycan, is involved in cell-cell, cell-matrix interaction and growth factor binding. Loss of expression of syndecan-1 in tumor cells leads to decreased intercellular cohesion, increased potential for tumor invasiveness, and metastatic spread. Furthermore, induction of syndecan-1 expression in the tumor stroma has been postulated to promote tumor angiogenesis via its binding to growth factors such as basic fibroblast growth factor. Although syndecan-1 expression within tumor cells has been investigated in head and neck squamous cell carcinoma, stromal expression has not been studied in detail. We analyzed 38 cases of head and neck squamous cell carcinoma by immunohistochemical staining for syndecan-1 expression within the stroma. The expression of syndecan-1 within tumor cells of various histologic grades of differentiation, squamous cell carcinoma in situ cells, and benign squamous epithelium was also determined. Variable levels of diminished syndecan-1 expression were noted within the dysplastic cells of 9 of 16 (60%) squamous cell carcinoma in situ lesions and in all 38 (100%) invasive squamous cell carcinoma. In general, higher levels of syndecan-1 expression were observed in the well-differentiated tumors, in contrast to significant reduction of expression seen in poorly differentiated tumors. Syndecan-1 expression was observed within the stroma (in fibroblasts) surrounding infiltrating carcinoma cells in 28 of 38 (74%) cases. The intensity of syndecan-1 staining within the stroma showed generally an inverse correlation with the degree of tumor cell differentiation. Syndecan-1 expression was not detected in the stroma beneath normal squamous epithelium or adjacent to areas of squamous cell carcinoma in situ. We conclude that induced expression of syndecan-1 in the stroma surrounding tumor cells of invasive head and neck squamous cell carcinoma is a frequent event. The increased stromal syndecan-1 expression, coupled with its loss from the surface of carcinoma cells, may contribute to tumor cell invasion and the development of metastases.

Aged↗

PubMed2005

Diagnostic utility of cell cycle and apoptosis regulatory proteins in verrucous squamous carcinoma.

A major problem in the diagnosis of verrucous squamous cell carcinoma is the lack of readily reproducible objective criteria for distinguishing this malignant lesion from reactive epithelial hyperplasia. Both lesions are characterized by thickened (well-differentiated) squamous epithelium without cellular atypia and subjacent stroma densely infiltrated by lymphocytes and plasma cells. This study was carried out to evaluate the use of cell cycle and apoptosis-related regulatory proteins in the diagnosis of verrucous carcinoma. The study materials consisted of representative formalin-fixed and paraffin-embedded tissue blocks from 19 cases of verrucous carcinoma, 18 classic squamous cell carcinoma, and 14 squamous epithelial hyperplasia (acanthosis). The immunohistochemical expression of the following of cell cycle and apoptosis-related regulatory proteins was evaluated using avidin-biotin complex detection technique: p16, p21, p53, Ki67, and retinoblastoma gene product (RBGP) (also known as retinoblastoma protein [pRb]). Expression of Ki67 was detected only in the single basal layer of the epithelium in all 14 cases of acanthosis. In verrucous carcinoma, Ki67 was detected in basal and suprabasal cells in the lower third of the neoplastic epithelium in 19 of 19 cases (100%). In neoplastic squamous epithelium with frankly invasive squamous cell carcinoma, Ki67 was diffusely expressed throughout the entire thickness of the epithelium as well as in the underlying invasive tumor nests. The pattern of p53 expression was similar to that of Ki67 in all the experimental groups, with a Pearson correlation coefficient of 0.98. In addition, immunohistochemical expression of p53 in the hyperplastic squamous epithelium was very weak, in contrast to the more intense immunoreactivity observed in verrucous carcinoma and classic squamous cell carcinoma. There was an overlapping in the expression of p16, p21, and RGBP in all the experimental groups, being present in more than half the thickness of the epithelium in 50% to 100% cases in each study group. We therefore conclude that the pattern of Ki67 and p53 expression in verrucous carcinoma is readily reproducible and distinctly different from that observed in epithelial hyperplasia and that seen in invasive squamous cell carcinoma. Thus Ki67, and p53 immunostains are reliable adjuncts that may be helpful in resolving diagnostic problems associated with verrucous carcinoma.

Adult↗

PubMed2005

High recurrence rates of squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic leukemia.

BACKGROUND: Cutaneous cancers exhibit a much higher incidence in patients with chronic lymphocytic leukemia than in nonleukemic patients. Squamous and basal cell carcinomas also exhibit greater subclinical tumor extension in patients with chronic lymphocytic leukemia. OBJECTIVE: The purpose of this study was to estimate and compare the recurrence rates of squamous cell carcinoma after Mohs' surgery in patients with chronic lymphocytic leukemia compared with those in controls and to evaluate differences among squamous cell carcinoma size and histologic grade. METHODS: We retrospectively assessed the clinical histories, postoperative notes, and surgical photographs of patients with chronic lymphocytic leukemia and controls matched (2:1) for age, sex, and surgical year. Both patients and controls underwent Mohs' surgery for squamous cell carcinoma of the head and neck at the Mayo Clinic between March 1988 and April 1999. RESULTS: Twenty-eight patients who underwent Mohs' surgery for 57 squamous cell carcinomas had 7 recurrences. The cumulative incidence of recurrence on a per-tumor basis was 4.3% at 1 year, 14.8% at 3 years, and 19.0% at 5 years. Squamous cell carcinoma was seven times more likely to recur in patients with chronic lymphocytic leukemia than in controls (p = .003). The distribution of tumor histologic grade was not significantly different between patients and controls (p = .39). Maximum preoperative tumor diameters were clinically similar between patients and controls (median 15 mm vs 14 mm; p = .04). CONCLUSION: The recurrence rates of squamous cell carcinoma were significantly higher in patients with chronic lymphocytic leukemia. Squamous cell carcinomas in patients with chronic lymphocytic leukemia did not exhibit a significant difference in histologic grade or clinical difference in preoperative tumor size. Close surveillance for squamous cell carcinoma recurrence is warranted in patients with chronic lymphocytic leukemia.

Aged↗

PubMed2005

Critical role of peroxisome proliferator-activated receptor gamma on anoikis and invasion of squamous cell carcinoma.

PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a important role in various physiological functions. We examined whether PPARgamma is expressed in primary squamous cell carcinoma and lymph node metastasis and whether PPARgamma is a potential target for tumor therapy. EXPERIMENTAL DESIGN AND RESULTS: A high-level expression of PPARgamma was observed in tumor cells of human primary squamous cell carcinoma, lymph node metastasis, and squamous cell carcinoma cell lines. Treatment with PPARgamma-specific antagonists, but not agonists, caused apoptotic cell death on squamous cell carcinoma cell lines in a concentration-dependent manner. Small interfering RNA for PPARgamma also inhibited cell adhesion and growth of squamous cell carcinomas. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with PPARgamma antagonists, and resulted in decreases in phosphorylation of Erk and mitogen-activated protein kinase. Furthermore, PPARgamma antagonists decreased the adhesion of squamous cell carcinomas into fibronectin-coated plates, indicating the inhibition of interaction between squamous cell carcinomas and fibronectin. Expression of integrin alpha5, a counter adhesion molecule for fibronectin, was inhibited by the treatment with PPARgamma antagonists. These results indicate that the decrease in integrin alpha5 and following inhibition of cell adhesion may cause the inhibition of FAK signaling pathways. PPARgamma antagonists also strongly inhibited invasion of squamous cell carcinoma via down-regulation of CD151 expression. CONCLUSIONS: The cell death caused by the PPARgamma antagonists was a result of direct interference with cell adhesion "anoikis" involving intracellular FAK signaling pathways. These results imply a potentially important and novel role for the inhibition of PPARgamma function via the use of specific antagonists in the treatment of squamous cell carcinoma and the prevention of tumor invasion and metastasis.

Adult↗

PubMedDate not supplied

Significance of squamous cells in fine needle aspiration cytology of the breast. A review of cases in a seven-year period.

OBJECTIVE: To delineate the significance of detecting squamous cells in fine needle aspiration biopsy of breast lesions. STUDY DESIGN: The authors reviewed 15 cases of fine needle aspiration cytology of the breast with a discernible number of squamous cells from the files of Pamela Youde Nethersole Eastern Hospital, Hong Kong, during a seven-year period from the start of 1994 to the end of 2001. The cytologic features were correlated with clinical, radiologic and histologic findings, if any. RESULTS: Among the 15 fine needle aspirates of the breast with a discernible number of squamous cells, 5 of them represented metaplastic carcinoma. The remaining consisted of 3 cases of fibroepithelial tumors, 1 case of duct ectasia, 3 cases of subareolar abscess, 2 cases of sclerosed intraduct papilloma and 1 case of benign breast cyst. In general, benign squamous cells were bland looking and often associated with anucleated squames. They were mitotically inactive and could show a good maturation pattern. Tumor cell cannibalism was rare. The presence of abundant, foamy macrophages in the background suggested a benign lesion. The primary diagnosis could be deduced by recognition of other features, such as the presence of myxoid stromal tissue and papillary structures. In contrast, malignant squamous cells in metaplastic carcinoma were more pleomorphic and mitotically active. Dyskeratosis and tumor cell cannibalism were obvious. Tumor diathesis and bizarre-shaped cells were sometimes found. CONCLUSION: Squamous cells occur in fine needle aspirates from a number of benign and malignant breast lesions. Benign conditions with abundant squamous cells may sometimes mimic malignant squamous lesions and vice versa. Careful assessment of the cytologic features of squamous cells and background appearance is crucial for achieving a correct diagnosis.

Abscess↗

PubMedDate not supplied

Keratinized squamous cells in fine needle aspiration of the brain. Cytopathologic correlates and differential diagnosis.

OBJECTIVE: To analyze the differential diagnosis when keratinized squamous cells are found in a brain aspirate. STUDY DESIGN: Twenty cases of brain aspirates with keratinized squamous cells were retrieved (1982-2001). Diagnoses included craniopharyngioma (CP) (n = 11), metastatic squamous cell carcinoma (SCC) (n = 5), epidermoid cyst (EC) (n = 3) and Rathke cleft cyst (RCC) (n = 1). Aspirates were obtained under stereotactic radiologic (CT) guidance. Smears were stained with Diff-Quik or Papanicolaou stain, and cell block sections were stained with hematoxylin and eosin. Radiologic and histopathologic correlation with subsequent resection specimens was performed in selected cases. RESULTS: CP showed cellular smears with numerous keratinized squamous cells in a background of degenerated cellular and keratinaceous debris. Also noted were clusters of anucleate squamous cells, multinucleated giant cells, histiocytes, calcified debris and characteristic fragments of basaloid epithelial cells. Metastatic SCC showed single cells and tissue fragments of markedly atypical and focally keratinized cells with enlarged, hyperchromatic nuclei; prominent pleomorphism in a background of necrotic cellular debris and acute inflammatory exudate. EC showed numerous isolated keratinized squamous cells often with prominent keratohyaline granules and occasional parakeratotic cells in a relatively clean background. RCC showed single cells and aggregates of benign-appearing squamous cells admixed with numerous anucleate squames and hemosiderin-laden macrophages. Glandular-type epithelium was present only rarely. CONCLUSION: Squamous cell-containing lesions in the brain present a spectrum of pathologic entities. Although they all display the common morphologic denominator of keratinizing squamous cells, subtle cytomorphologic differences exist in these lesions, permitting an accurate cytopathologic diagnosis. Clinicardiologic features and anatomic location of the tumor in the brain are additionally helpful.

Adolescent↗

PubMed2005

Remarkably high frequency of EGFR expression in breast carcinomas with squamous differentiation.

The human epidermal growth factor receptor (EGFR) is reportedly overexpressed in 15-20% of breast carcinomas. EGFR overexpression is associated with reduced survival and is inversely correlated with expression of estrogen receptor (ER). This study assessed EGFR expression in breast carcinomas with squamous differentiation. The immunohistochemical (IHC) expression of EGFR was evaluated in 39 breast carcinomas with squamous differentiation (30 pure squamous, 6 adenosquamous, 3 carcinosarcomas) by use of the pharmDx assay (clone 2-18C9, DakoCytomation). Cases were considered positive if at least 10% of the cells showed 1+ positivity in the squamous component. Squamous differentiation was confirmed with IHC for CK5-6 (clone D5/16B4, DakoCytomation). ER, PR, and HER2 status as well as clinical information regarding treatment and outcome were correlated. As a control, a tissue microarray comprising 280 lymph node positive breast carcinomas was evaluated with the same EGFR assay. The 39 patients ranged in age from 33 to 77 years (mean 52). The tumors measured 1.3-30 cm (mean 4.8). Sentinel or full axillary lymph node dissection was performed in 28 patients. Fourteen patients had positive lymph nodes. At the time of initial diagnosis, 3 patients had distant metastasis. Follow-up was available for 16 patients (mean 45 months). Disease-free survival at 3 years was 70%. Among the 39 tumors 87% (34) were positive for EGFR (p<0.0001). Sixty-nine percent (27 of 39) showed >50% 2+ EGFR staining. EGFR-positive tumor cells (showing squamous morphology) were also found in 1 bone, 1 lung, and 8 of 11 lymph node metastases available for evaluation. All 11 lymph nodes showed squamous differentiation. All but 1 of the EGFR+ tumors examined were ER and PR negative. Six EGFR-positive tumors were HER2 positive. No statistically significant differences in HER2 status, size, lymph node status and disease-free survival were observed between EGFR+ and EGFR- cases, but the number of EGFR-negative tumors was quite small. Nine of 280 (3%) of lymph node-positive invasive carcinomas on the tissue microarray were EGFR+; review of the initial diagnostic slides failed to reveal squamous features in all but 1 of the 9 EGFR+ tumors. Breast carcinomas with squamous differentiation are a distinct subgroup of breast tumors with a very high frequency of EGFR positivity. Breast carcinomas of this type would be ideal candidates for a trial with EGFR inhibitors.

Adult↗

PubMed2006

Pattern of development of basal versus squamous cell carcinoma.

BACKGROUND: Basal cell and squamous cell carcinomas both arise in the epidermis of fair-skinned people in response to ultraviolet light, with the overall frequency of basal cell carcinoma being 4 times that of squamous cell carcinoma. Despite the similarities in the population at risk, and the presumed etiology of these tumors, it is unclear if any one individual has a proclivity to develop only one type of tumor. OBJECTIVE: The study explores whether or not there is a pattern of expression of basal versus squamous cell carcinoma among people with these cancers. METHODS: This case-control study involved patients with a total of more than 3 and fewer than 10 basal or squamous cell carcinomas. Patient age and gender, as well as number and location of diagnosed basal and squamous cell carcinomas were gathered and patterns within these values were sought. RESULTS: Patients found to have at least one basal cell carcinoma tended to produce more basal cell carcinomas and patients found to have at least one squamous cell carcinoma tended to produce more squamous cell carcinomas. CONCLUSION: The study supports the possibility that people who develop basal cell carcinoma are more likely to develop more basal cell carcinomas. Similarly, people who develop squamous cell carcinoma are more likely to develop more squamous cell carcinomas.

Adult↗

PubMed1975

Unique immunobiological aspects of head and neck squamous carcinoma.

The immune reactivity of patients with squamous carcinoma of the head and neck region was compared with that of patients with squamous carcinoma of the female pelvic organs and patients with adenocarcinomas, melanomas, and sarcomas. The reactivity of patients with clinically localized tumors was compared with that of cured patients and a large normal population. Patients with squamous carcinomas of the head and neck region and female pelvic organs displayed higher incidences of impaired cellular immune competence than patients with malignancies of other histologic types. Among cured patients, those previously treated for squamous carcinoma were unique in that they displayed cellular immune defects and serum suppressants of in vitro immune reactivity similar to tumor-bearing patients. Antibodies to herpes simplex virus nonvirion antigen was found in high incidence only among patients with squamous carcinomas, and the incidences in tumor-bearing and cured patients were similar. The persisting immune defects in cured squamous carcinoma patients give importance to the determination of the role of genetic and environmental factors in the induction of these tumors. The associations made between herpes virus and squamous carcinoma offer an explanation for the defects and also an approach for the definition of the factors involved in squamous carcinogenesis. The findings are clinically relevant to the isolation of population groups at high risk for the development of squamous carcinoma, as a rational basis for the development of prophylactic measures, and as a basis for more effective therapeutic regimens.

Antibody Formation↗

PubMed1986

Altered expression in squamous carcinoma cells of an orientation restricted epithelial antigen detected by monoclonal antibody A9.

The monoclonal IgG2a antibody A9 was raised to the UM-SCC-1 human squamous cell carcinoma cell line. Hemadsorption assays using monolayer cultures as target cells revealed a restricted range of A9 reactivity with human cell lines. The A9 antibody was reactive with 29 of 34 squamous cell carcinoma cell lines and with 5 epithelial cancer cell lines of non-squamous origin. In contrast, no antibody binding was detected with twelve malignant melanoma, two fibrosarcoma, two malignant lymphoid, two transitional cell carcinoma, or four adenocarcinoma cell lines. Similarly, normal lymphoid cells, RBC, and fibroblasts from multiple donors were negative. The relative expression of the A9 antigen varied greatly among positive squamous cancer lines such that the 50% endpoint titer of A9 ascites fluid ranged from less than 10(1) for low antigen expressor lines to 10(6) for strong antigen expressors. Hemadsorption tests with secondary passage cultures of normal squamous cells failed to detect A9 binding to the cell surface. However, in experiments with intact colonies in primary cultures of normal squamous cells, antibody binding was observed at the periphery of individual colonies. Mechanical detachment of such colonies revealed A9 antigen bound to the plastic surface underneath the cells, but the newly exposed surface of the cells, like the upper surface, was negative. In contrast, when cells of similar cultures were detached by trypsinization prior to testing no antigen remained on the plastic, but approximately 30% of the trypsinized cells were positive. Similar experiments with the five surface-negative squamous cell carcinoma cell lines revealed that cryptic A9 antigen could also be detected underneath mechanically detached cells and on the surface of 100% of trypsinized cells. Trypsinization of melanomas and fibroblasts did not reveal A9 antigen. Immunoperoxidase assays on frozen sections of normal epidermis localized A9 antigen to the basal cells and the basement membrane region. In frozen sections of squamous cancers, individual tumor cells and particularly the growing edge of the tumors were strongly stained by A9, while in basal cell cancers only very slight staining could be detected. Thus, in normal epithelial cells the A9 antigen appears to be expressed only by the stem cell subset. In squamous cancer cells, the expression of the A9 antigen is not only increased but appears to have escaped the orientation restriction characteristic of normal epithelial cells.

Adenocarcinoma↗

PubMed1992

Identification of a new squamous cell differentiation marker and its suppression by retinoids.

Rabbit tracheobronchial epithelial cells (RbTE) can undergo squamous cell differentiation under defined culture conditions and, therefore, have been used as a model to study the regulation of squamous cell differentiation markers. In the present study, we identified a 20-kDa protein, designated rSQ20, in the serum-free growth medium conditioned by RbTE cells undergoing squamous cell differentiation. The protein was also found in extracts of squamous differentiated cells. rSQ20 was labeled by cells incubated with [35S]methionine but not with [3H]glucosamine, suggesting that it is not a glycoprotein. Undifferentiated cells did not produce this protein. rSQ20 was detected in the conditioned medium of RbTE cells after they reached a confluent and growth-arrested state, and thereafter its level increased markedly and concurrently with an increase in type I (epidermal) transglutaminase, an established marker of squamous cell differentiation. rSQ20 found in concentrated conditioned medium of squamous differentiated RbTE cells was eluted from a gel filtration column as a protein of 20 kDa, similar to that found by gel electrophoresis under denaturing conditions, suggesting that it is not a multimeric protein. A protein with an apparent molecular weight of 16 kDa (rSQ16), probably the product of partial proteolysis of rSQ20, was often found in various amounts in the conditioned medium of differentiated RbTE cells. beta-All-trans retinoic acid and other vitamin A analogues (retinoids), which suppress squamous cell differentiation, inhibited the expression of rSQ20 in RbTE cells. RbTE cells immortalized by transfection with SV40 large T antigen as well as malignantly transformed derivatives obtained from the immortalized cells by further transfection with v-Ha-ras secreted SQ20 and SQ16 when grown to high cell densities although their squamous differentiation was impaired. An analogous protein with an apparent molecular weight of 16 kDa, designated hSQ16, was detected in the medium of differentiated normal human bronchial epithelial (NHBE) cells and normal human epidermal keratinocytes (NHEK). No such protein could be detected in the medium in which undifferentiated NHBE or NHEK cells were grown. These results suggest that rSQ20 and hSQ16 are new markers of squamous cell differentiation.

Animals↗

PubMed1998

Qualification of atypical squamous cells of undetermined significance in an independent laboratory: is it useful or significant?

OBJECTIVES: Correlation of cervical smears and biopsy samples emphasizes the significance of atypical squamous cells of undetermined significance as a diagnostic category. STUDY DESIGN: A retrospective study (October 1, 1995-March 21, 1997) was performed on all Papanicolaou smears diagnosed at DIANON Systems, Inc (Stratford, Conn). RESULTS: During this period 1551 patients with Papanicolaou smears had subsequent cervical biopsies performed within 90 days of cytologic sampling. There were 560 diagnoses of atypical squamous cells of undetermined significance. Tissue specimen results were positive in 203 cases (36.2%) and negative in 357 cases (63.8%). Of the positive biopsy results after a smear with atypical squamous cells of undetermined significance, 109 showed low-grade squamous intraepithelial lesions and 94 showed high-grade squamous intraepithelial lesions. CONCLUSIONS: This study, the largest cytologic and histologic correlation of atypical squamous cells of undetermined significance, demonstrates that a significant percentage of smears with atypical squamous cells of undetermined significance represent squamous intraepithelial lesions and that qualification of atypical squamous cells of undetermined significance as reactive or dysplastic is useful and should serve as a guide for patient management.

Cervix Uteri↗

PubMed1999

Ploidy in human papillomavirus positive and negative vulvar squamous cell carcinomas and adjacent skin lesions.

To better characterize the two clinicopathologic types of squamous cell carcinoma, human papillomavirus (HPV) positive and negative, and their adjacent skin changes, we performed cytomorphometric analysis on 12 HPV-positive squamous cell carcinomas and adjacent vulvar intraepithelial neoplasia and 22 HPV-negative squamous cell carcinomas and adjacent squamous cell hyperplasia and lichen sclerosis. Our results were that 83% (10 of 12) HPV-positive carcinomas and 78% (7 of 9) adjacent vulvar intraepithelial neoplasia were aneuploid, compared with 59% (13 of 22) HPV-negative carcinomas, 6% (1 of 16) squamous cell hyperplasias and 0% (0 of 20) lichen scleroses. Seventy-five percent (9 of 12) HPV carcinomas and 78% (7 of 9) vulvar intraepithelial neoplasias showed two aneuploid peaks, but no HPV-negative carcinoma or non-neoplastic epithelial lesion showed multiple aneuploid peaks. Fifty percent of squamous cell hyperplasias (8 of 16) and lichen scleroses (10 of 20) adjacent to HPV-negative carcinomas were hypodiploid. The mean DNA indices were: 1.70 for the dominant tumor cell population of HPV-positive carcinoma, 1.64 for the dominant population of vulvar intraepithelial intraepithelial neoplasia, 1.41 for HPV-negative carcinoma, 0.85 for squamous cell hyperplasia and 0.83 for lichen sclerosis. In conclusion, the higher rate of aneuploidy, higher mean DNA index, and presence of multiploid peaks in HPV-positive carcinomas and adjacent vulvar intraepithelial neoplasias compared with the lower rate of aneuploidy, lower mean DNA index, absence of multiploid peaks of HPV-negative carcinomas and tendency to hypodiploidy in squamous cell hyperplasia and lichen sclerosis support the hypothesis that there are two clinicopathologic types of vulvar carcinoma, with different pathogenetic mechanisms. The similarities in ploidy findings between vulvar HPV-positive carcinomas and vulvar intraepithelial neoplasia and those previously published for cervical carcinoma and cervical intraepithelial neoplasia support the view that these two cancers are analogous and have similar pathogenetic mechanisms. The frequent finding of hypodiploidy in squamous cell hyperplasia and lichen sclerosis next to HPV-negative carcinomas requires further investigation of the molecular pathogenesis of this cancer type.

Journal Article↗

PubMed1998

Squamous change in bladder cancer and its relevance to understanding clonal evolution in development of bladder cancer.

Using conventional morphological assessment, squamous change in bladder epithelium has been observed in 73% of bilharzial associated squamous cancers but only 28% of pure transitional cancers. However, more detailed studies of patients with TCC suggest that the latter figure may be an underestimate, since in one series it was reported to be more than 50%. The most significant risk factor for development of squamous carcinoma in the bladder is chronic persistent bacterial cystitis, although in the areas of the world where bilharzia is endemic this infestation also increases the risk of both squamous bladder cancer and chronic bacterial cystitis. Although it is clear that carcinogens are involved as co-factors in transformation from squamous metaplasia to cancer, the fact that in Zimbabwe one author has observed that TCC is more frequent in whites than squamous cancer is in bilharzia infected blacks is evidence that other unidentified risk factors are involved. This is increasing evidence for involvement of HPV subtypes in cervix, oropharynx and lung cancer. As all three of these tumours are associated with squamous metaplasia, there could be a case for investigation of bladder squamous tumours for HPV involvement. This is particularly so given the observation of the "hit and run" type of transient infection in cattle that develop BPV associated tumours and the tenfold difference (30% vs 3%) in frequency of HPV detection in squamous skin tumours developing in immunosuppressed individuals compared with those arising spontaneously. With new technology for cytological screening techniques using dot ELISA and evidence of differences in TP53 mutations that support the involvement of nitrous oxide, it is clear that there is more to learn from study of this tumour type that may be of general interest in understanding the clonal development of cancer.

Animals↗