Metaplastic Squamous Epithelium Research Articles

Atypical squamous epithelium in cytologic specimens from the pancreas: cytological differential diagnosis and clinical implications.

Atypical squamous epithelium is an uncommon finding in cytologic specimens obtained from pancreatic lesions. A variety of pathologic conditions can result in the presence of these cells, including primary or metastatic carcinomas, chronic pancreatitis, and squamous metaplasia related to pancreatic or biliary duct stent placement. Primary adenosquamous and squamous-cell carcinomas of the pancreas are rare, representing 3.4% and 1.4 % of pancreatic carcinomas, respectively. Cytologic separation of these malignancies from less ominous metaplasias has immense clinical importance. We reviewed Indiana University Hospital's and Duke University's experiences with atypical squamous epithelium occurring within pancreatic aspirates. Study cases were identified using a computer to search the cytology records of these two institutions. Nine cases with a diagnosis of squamous-cell carcinoma, adenosquamous carcinoma, or atypical squamous epithelium were retrieved from the two institutions' Department of Pathology files. One case of pure squamous-cell carcinoma occurred in a patient with a known pulmonary primary; a single case of adenosquamous carcinoma was diagnosed in a patient with a coexistent endometrial primary; a single sample of adenocarcinoma with squamous differentiation was diagnosed in a patient without other known disease; and four primary squamous-cell carcinomas of the pancreas were detected. In addition, a single case of atypical squamous metaplasia associated with a stent was identified, and one case of atypical squamous epithelium associated with chronic pancreatitis was diagnosed. Despite the reactive atypia present in the examples of metaplastic squamous epithelium, separation of these cases from true squamous-cell carcinoma and adenosquamous carcinoma was achievable by cytologic evaluation. No cytologic criteria aided in separating primary pancreatic carcinomas with squamous differentiation from metastatic lesions. In this study, we report our findings in a series of nine cases where cytology disclosed atypical squamous epithelium in the aspirates derived from pancreatic lesions.

Identification of a Basal/Reserve Cell Immunophenotype in Benign and Neoplastic Endometrium: A Study with the p53 Homologue p63

Background. Metaplastic differentiation, including squamous, mucinous, and tubal (ciliated), is common in both benign and neoplastic endometrium, and the cell of origin for this pathway is poorly understood. In this study, expression of a marker for basal and reserve cells in cervical squamous mucosa, designated p63, was investigated in a spectrum of endometrial alterations.Methods. One hundred ninety different endometria from 132 patients were examined, including fetal (6), premenarchal (3), benign cyclic (29) and noncyclic (54), hyperplastic (14), and neoplastic (93) endometrial glandular epithelia. The latter included conventional endometrioid carcinomas with and without mucinous, ciliated, and squamous metaplasia, and uterine papillary serous carcinoma (UPSC).Results. p63 expression was identified in basal/subcolumnar cells in the fetal endometrium in a distribution similar to that in basal/reserve cells of the cervix. Staining was confined to individual scattered basal and suprabasal cells in cycling endometrium. In polyps and postmenopausal endometria, focal clusters of p63-positive cells were identified in inactive glands or surface epithelium. Metaplastic (squamous or mucinous) epithelia, either alone or in conjunction with hyperplasias or carcinomas, exhibited the most intense staining, primarily in basal or subcolumnar cells. In some cases, immediately adjacent nonmetaplastic columnar epithelium also stained positive. UPSCs contained only rare scattered p63-positive cells.Conclusions. Cells with a basal or reserve cell phenotype exist in the endometrium during fetal life, are not conspicuous during the reproductive years, but may emerge during shifts in differentiation. Whether these cells signify specialized multipotential endometrial cells is not clear, but the similarity of these cells to basal/reserve cells of the cervix and their association with neoplasia merit further study.

Proliferation and number of Clara cell 10-kDa protein (CC10)-reactive epithelial cells and basal cells in normal, hyperplastic and metaplastic bronchial mucosa.

Clara cell 10-kDa protein (CC10) is an inhibitor of phospholipase A2 and binds to phosphatidylinositol. It may therefore interfere with intracellular signal transduction. Bronchial CC10-reactive cells have been described by several authors. In contrast to the bronchiolar CC10-containing Clara cell, which is a progenitor cell of terminally differentiated airway epithelium, the role of bronchial CC10-reactive cells remains to be elucidated. We assessed the number of bronchial CC10-reactive cells in relation to cytokeratin (CK) expression and proliferative activity in normal, hyperplastic and squamous metaplastic epithelium. Sixty-five human bronchial mucosal specimens were investigated immunohistochemically for CK expression (CK7, CK13 and CK5/6), proliferative activity (MIB-1) and number of CC10-reactive epithelia. The proliferation fraction of CC10-reactive cells was assessed with double staining for MIB-1 and CC10. The proliferation index of the epithelium differed significantly between normal, hyperplastic and metaplastic epithelium. The number of CC10-reactive cells was inversely related to the epithelial proliferation. Bronchial CC10-reactive cells showed no proliferative activity as assessed using immunohistochemical double staining for CC10 and MIB-1. In contrast to normal and hyperplastic epithelium, squamous metaplasia disclosed CK5/6 in all epithelial layers, a loss of CK7 and a gain of CK13. We conclude that CC10-reactive cells have no progenitor role in the bronchial mucosa. However, because the proliferative activity is inversely related to the number of CC10-reactive cells, the CC10 protein may play a role in the regulation of epithelial repair. Squamous metaplasia most likely originates from basal cells.

Parathyroid hormone-related protein (1-34) and urothelial redifferentiation in the neuropathic urinary bladder.

A comparative study of immunostaining for parathyroid hormone-related protein (1-34) (PTHrP (1-34)) in the vesical epithelium of biopsies obtained from patients with non-neuropathic bladder and those with neuropathic bladder. To investigate the immunostaining for PTHrP (1-34) in the control cases and in neuropathic bladders showing (1) normal transitional epithelium, (2) hyperplastic transitional epithelium, and (3) squamous metaplasia. Regional Spinal Injuries Centre, and Department of Cellular Pathology, Southport & Ormskirk Hospitals NHS Trust, Southport, Department of Pathology, Royal Liverpool University Hospital and the Departments of Clinical Chemistry and Cell Biology, The University of Liverpool, Liverpool, England. Cold cup biopsies of bladder mucosa were taken from patients suffering from neuropathic urinary bladder when they were undergoing a therapeutic procedure in the urinary tract. Immunohistochemistry was performed on these biopsy specimens using a rabbit polyclonal antibody raised to a synthetic peptide corresponding to human PTHrP (1-34). Control group (n=10) consisted of archival biopsies taken from non-neuropathic bladders. In the control group, the transitional epithelium showed no immunostaining, or at the most, very faint positive staining was seen in the transitional epithelium of non-neuropathic bladder. Positive immunostaining to PTHrP (1-34) was seen in the normal transitional epithelium of neuropathic bladder in nine of 13 cases. Hyperplastic transitional epithelium showed positive immunostaining for PTHrP (1-34) in 11 of 13 biopsies from patients with neuropathic bladder. Immunostaining for PTHrP (1-34) was observed in the metaplastic squamous epithelium in 14 of 17 cases with neuropathic bladder. The transitional epithelium of non-neuropathic bladder showed no immunostaining, or at the most, very faint positive staining for PTHrP (1-34). In contrast to this, positive immunostaining for PTHrP (1-34) was observed more frequently in the vesical epithelium of neuropathic bladder. This observation opens up avenues for innovative therapy with PTHrP or its analogues for possible modulation of urothelial differentiation in the neuropathic bladder.

Métaplasie de tissu aortique en tissu trachéal. Perspectives chirurgicales

Tracheal reconstruction after extensive resection remains an unsolved surgical problem. Numerous attempts have been made using tracheal grafts or prosthetic conduits with disappointing results. In this study, we propose a new alternative using an aortic autograft as tracheal substitute. In a first series of experiments, a half circumference of two rings was replaced with an autologous carotid artery patch. In a second series, a complete segment of trachea was replaced with an autologous aortic graft supported by an endoluminal tracheal stent. No dehiscence or stenosis was observed. Microscopic examinations at 3 and 6 months showed the replacement of the aortic tissue by tracheal tissue comprising neoformation of cartilage and mucociliary or non-keratinizing metaplastic polystratified squamous epithelium. Although these results need to be confirmed by a larger series of experiments, they showed that a vascular tissue placed in a different environment with a different function can be submitted to a metaplastic transformation which tends to restore a normal structure adapted to its new function. These remarkable findings offer new perspectives in tracheal reconstruction in human.

K-ras gene point mutation in neogenetic lesions of subpleural fibrotic lesions: either an early genetic event in lung cancer development or a non-specific genetic change during the inflammatory reparative process.

In the present study, K-ras mutation was investigated in 156 neogenetic epithelia that appeared in the lesion of subpleural fibrosis in order to elucidate the close relationship of lung cancer development with pulmonary interstitial pneumonia. The neogenetic epithelia were histologically subclassified into six types: (i) ciliated bronchial epithelium (CBE); (ii) squamous metaplastic epithelium (SME); (iii) cuboidal immature epithelium (CIE); (iv) stratified immature epithelium (SIE); (v) mucus cell epithelium (MCE); and (vi) intestinal metaplastic epithelium (IME). K-ras mutation was detected in 9.6% of neogenetic epithelia overall; 21% of CIE, 12% of SIE, 16% of SME, but not in other types of neogenetic epithelia. Immunohistochemically, CIE and SIE frequently expressed surfactant apoprotein and SME was characteristic to carcinoembryonic antigen expression. According to Ki-67 immunostain, CIE, SIE and SME are likely to grow faster than other histological types of epithelia. K-ras mutation was seen exclusively in codon 12 with predominant G to A and G to C substitutions without any G to T transversions, results which are somewhat different to previous studies in lung cancers. The present study clearly demonstrated that K-ras mutation appeared in certain histological types of neogenetic epithelia, but raised the question of whether K-ras mutation in neogenetic epithelia during the inflammatory reparative process might be an early genetic event in lung carcinogenesis.

Human papilloma virus (HPV) is possibly involved in laryngeal but not in lung carcinogenesis

Data on human papilloma virus (HPV) involvement in preneoplastic and neoplastic lesions of the larynx and lung are limited and conflicting. The presence of HPV was investigated in a series of laryngeal specimens and non-small cell lung carcinomas (NSCLCs). The laryngeal samples (154) comprised 14 cases with hyperplasia without dysplasia, 49 with dysplasia, and 91 squamous cell carcinomas (SqCCs). The NSCLCs included 31 SqCCs, 32 adenocarcinomas, and 5 undifferentiated large cell carcinomas. Furthermore, we examined, for HPV DNA sequences, 14 bronchial metaplastic squamous lesions located next to cancerous areas. We used a sensitive nested polymerase chain reaction assay (NPCR), dot blotting, and in situ hybridization. The findings were correlated with clinicopathologic features of the patients. In the laryngeal specimens, NPCR analysis showed HPV DNA in 20 (13%) of the 154 specimens. Notably, 19 of 20 HPV-positive cases were carcinomas and only one was a mild dysplastic lesion. Typing of the carcinomas showed single HPV 6, 16, 18, and 33 infection in 1 (1.1%), 12 (13.2%), 2 (2.2%), and 1 (1.1%) samples, respectively, and HPV 6 33 , 16 33 , and 6 18 coinfection in three carcinomas. In situ hybridization findings were in agreement with PCR results, with the exception of two cases in which HPV 18 DNA was detected only by PCR. HPV was more frequently observed in heavy smokers than in patients with low daily cigarette consumption and nonsmokers ( P = .03). There was no correlation between virus infection and gender, grade, and lymph node status of the carcinomas. None of the NSCLCs or adjacent metaplastic squamous epithelium contained HPV DNA sequences. The presented data suggest a contributory role of HPV in late stages of laryngeal carcinogenesis, because all premalignant lesions were negative but one. This study does not support a potential role of HPV in the development of NSCLCs.

Nasal epithelium as a sentinel for airborne environmental pollution.

A wide range of chemicals, particulate matter, and gaseous air pollutants are present in urban atmospheres and may pose a significant health risk for human populations. Nasal passages are the first site of contact of the respiratory tract with the environment and offer significant protection to the lower respiratory tract by conditioning the inspired air. This activity, which includes removal of certain pollutants, places the nose at risk of pathological changes, including cancer. Mexico City residents are exposed to a complex mixture of air pollutants. Based on predicted nasal air flow characteristics, four nasal biopsy sites were selected for study in adult male volunteers from a control low polluted town (n = 12) and southwest metropolitan Mexico City permanent residents (n = 54). Clinical data with emphasis on nasal symptoms and histopathological changes including basal and goblet cell hyperplasia, squamous metaplasia, epithelial dysplasia, and neovascularization were evaluated. Immunohistochemical staining was used to assess accumulation of p53 protein. Control individuals had no respiratory symptoms and their biopsies were unremarkable. Mexico City residents complained of epistaxis, rhinorrea, nasal crusting, dryness, and nasal obstruction. Their biopsies showed patchy shortening of cilia, deciliated areas, basal cell hyperplasia, and squamous metaplasia. Dysplastic lesions were predominantly located on antral squamous epithelium and in squamous metaplastic epithelium of the posterior inferior turbinates and they exhibited p53 nuclear accumulation. Individuals with > 10 h of daily outdoor exposure for 5 years or more had the highest rate of dysplasia. Subjects with epistaxis were more likely to have dysplasias and neovascularization. Results of this study suggest: (a) Nasal lesions in Mexico City residents are likely the result of many potentially toxic and/or carcinogenic pollutants, including ozone, aldehydes, particulate matter, and unmeasured pollutants; (b) the alteration of the nasal mucociliary defense mechanisms and the effects of reactive and/or water-soluble materials and particulates could be playing a major role in the nasal pathology; (c) the accumulation of p53 protein in dysplastic nasal lesions in the context of prolonged exposure to air pollutants raises the possibility that p53 mutations are already present and are providing the squamous cells with a selective advantage for clonal expansion; and (d) the nasal passages provide a valuable sentinel tissue for the detection of toxic air pollutants.

Human papillomavirus and mixed epithelial tumors of the endometrium

Strong epidemiological evidence links human papilloma viruses (HPV) with the development of cervical intraepithelial neoplasia (CIN) and invasive cancers of the uterine cervix. The localization of HPV DNA sequences high up in the female genital tract (in benign and malignant lesions) is not that uncommon, but its precise significance is uncertain. In particular, the detection of HPV DNA sequences by polymerase chain reaction (PCR) needs careful interpretation, because the source of the amplicon may emanate from tumor cells, direct contamination from the cervix, or possibly from extratumoral sites in the endometrium. We have previously reported the identification of koilocyte-like changes in the squamous epithelium of some endometrial adenoacanthomas. Adenoacanthomas (adenocarcinoma with squamous metaplasia) are mixed epithelial tumors arising in the endometrium composed of malignant glandular areas admixed with benign metaplastic squamous epithelium. The rarer adenosquamous carcinoma containing both malignant glandular and squamous areas is also described. The origin of benign/malignant squamous epithelial islands in endometrial tumors has been the subject of speculation, with some investigators considering an origin from metaplastic glandular endometrial cells. In this study, we examined 10 normal endometrial samples, 20 adenocarcinomas, 41 adenocarcinomas with squamous metaplasia, and two adenosquamous carcinomas, (including control cervical material where possible) for the presence of HPV DNA sequences using nonisotopic in situ hybridization (NISH), type-specific HPV PCR, general primer PCR (to detect sequenced and unsequenced HPVs), and PCR in situ hybridization (PCR-ISH). We did not identify HPV DNA sequences in normal endometrial tissue. In adenocarcinomas (endometrioid type), HPV was only identified in 2 of 20 cases by PCR, both of which were HPV 11 positive. We were unsuccessful in identifying HPV in endometrial carcinomas by NISH or by PCR-ISH, raising the possibility of contamination from the cervix in the two positive cases. In adenoacanthomas, a low-risk HPV type (HPV 6) was found in 19 of 41 cases. NISH signals were intranuclear in location in squamous regions of adenoacanthomas. Additional positive nuclei were uncovered using PCR-ISH, which increases the sensitivity of standard NISH detection. HPV DNA sequences were located in some malignant endometrial glandular epithelial cells, but this accounted for a minority of samples. HPV DNA sequences were not detected in extraepithelial sites. Mixed infection by two different HPV types was identified in two cases. Most cases showed similar HPV types in cervical and endometrial lesions, although discordant cases were uncovered. In adenosquamous carcinomas, one case showed mixed infection with HPV 6 and 33 by PCR. The apparent segregation of low-risk HPV type (HPV 6) with benign squamous metaplastic epithelium in adenocarcinoma with squamous metaplasia, and high-risk type (HPV 33) with malignant squamous epithelium in adenosquamous carcinoma, raises important questions in relation to the role of HPVs in mixed epithelial tumors of the endometrium and their interplay in the pathogenesis of squamous metaplasia at extracervical sites.

Inter- and intra-observer variation in the histopathological reporting of cervical squamous intraepithelial lesions using a modified Bethesda grading system.

1. To assess inter- and intra-observer variation in the histopathological reporting of cervical colposcopic biopsies using a histologic modification of the cytological Bethesda grading system; 2. to determine the histologic profile of those cases which resulted in diagnostic disagreement. Consecutive cervical colposcopic biopsies (n = 125) were assessed independently by six experienced histopathologists. Cases were classified as normal, low grade squamous intraepithelial lesion or high grade squamous intraepithelial lesion. Six months later the process was repeated. The degree of inter and intra-observer variation was assessed by kappa statistics. All cases in which there was less than perfect inter and intra-observer agreement were reviewed by the coordinator of the study. In the first round of the study inter-observer agreement was generally poor, with unweighted and weighted kappa values ranging from 0.15 to 0.58 (average 0.30) and from 0.21 to 0.61 (average 0.36) respectively. In the second round inter-observer agreement was better, with unweighted and weighted kappa values ranging from 0.08 to 0.55 (average 0.33) and from 0.22 to 0.59 (average 0.42). Ten of the 15 pairs of observers achieved fair inter-observer agreement using weighted kappa analysis. The degree of intra-observer agreement was better, unweighted and weighted kappa values ranging from 0.26 to 0.61 (average 0.47) and from 0.34 to 0.62 (average 0.51) respectively. Two of the six participants achieved fair intra-observer agreement and two achieved good intra-observer agreement using weighted kappa analysis. There were marked difficulties in the separation of normal squamous epithelium from low grade squamous intraepithelial lesion and in the separation of low grade from high grade squamous intraepithelial lesions. Histopathological review revealed that many of the difficulties in the separation of normal and low grade squamous intraepithelial lesion were in the distinction between superficial vacuolated cells and true koilocytes. Difficulties also resulted in the separation of basal cell hyperplasia, inflammatory associated changes and immature squamous metaplasia from low grade squamous intraepithelial lesion. Conditions which resulted in difficulty in the separation of low grade and high grade squamous intraepithelial lesions included florid koilocytotic change and immature metaplastic squamous epithelium with atypia. In some cases, there was a full spectrum of diagnoses from normal to high grade squamous intraepithelial lesion. These were largely cases of immature metaplastic squamous epithelium with atypia and of thin or atrophic squamous epithelium with atypia. Most pairs of observers can achieve fair inter-observer agreement in the reporting of cervical colposcopic biopsies using a modified Bethesda system. Intra-observer agreement is also generally fair to good using this system. It may be that a two tier grading system is more appropriate for the histopathological reporting of these biopsies than the traditional three-tier intraepithelial neoplasia (CIN) system.

Nasal Epithelium as a Sentinel for Airborne Environmental Pollution

A wide range of chemicals, particulate matter, and gaseous air pollutants are present in urban atmospheres and may pose a significant health risk for human populations. Nasal passages are the first site of contact of the respiratory tract with the environment and offer significant protection to the lower respiratory tract by conditioning the inspired air. This activity, which includes removal of certain pollutants, places the nose at risk of pathological changes, including cancer. Mexico City residents are exposed to a complex mixture of air pollutants. Based on predicted nasal air flow characteristics, four nasal biopsy sites were selected for study in adult male volunteers from a control low polluted town (n = 12) and southwest metropolitan Mexico City permanent residents (n = 54). Clinical data with emphasis on nasal symptoms and histopathological changes including basal and goblet cell hyperplasia, squamous metaplasia, epithelial dysplasia, and neovascularization were evaluated. Immunohistochemical staining was used to assess accumulation of p53 protein. Control individuals had no respiratory symptoms and their biopsies were unremarkable. Mexico City residents complained of epistaxis, rhinorrea, nasal crusting, dryness, and nasal obstruction. Their biopsies showed patchy shortening of cilia, deciliated areas, basal cell hyperplasia, and squamous metaplasia. Dysplastic lesions were predominantly located on antral squamous epithelium and in squamous metaplastic epithelium of the posterior inferior turbinates and they exhibited p53 nuclear accumulation. Individuals with > 10 h of daily outdoor exposure for 5 years or more had the highest rate of dysplasia. Subjects with epistaxis were more likely to have dysplasias and neovascularization. Results of this study suggest: (a) Nasal lesions in Mexico City residents are likely the result of many potentially toxic and/or carcinogenic pollutants, including ozone, aldehydes, particulate matter, and unmeasured pollutants; (b) the alteration of the nasal mucociliary defense mechanisms and the effects of reactive and/or water-soluble materials and particulates could be playing a major role in the nasal pathology; (c) the accumulation of p53 protein in dysplastic nasal lesions in the context of prolonged exposure to air pollutants raises the possibility that p53 mutations are already present and are providing the squamous cells with a selective advantage for clonal expansion; and (d) the nasal passages provide a valuable sentinel tissue for the detection of toxic air pollutants.

The problem of replacement and differentiation of the intestinal epithelium: its relation to squamous metaplasia in the uterine cervix.

The problem of replacement and differentiation of the intestinal epithelium: its relation to squamous metaplasia in the uterine cervix.

Colposcopic regression patterns in high-grade cervical intraepithelial neoplasia

To evaluate the serial changes in colposcopic and cervicographic findings of women with cervical intraepithelial neoplasia (CIN) II and III enrolled in a phase III randomized comparison of oral beta carotene and placebo. All subjects treated with beta carotene or placebo for at least 6 months were included if they met the criteria of persistent or progressive disease (no change or worsening of CIN grade) or disease regression (improvement of two grades or more). These two groups were compared for changes in colposcopic and cervicographic patterns. Colposcopically directed biopsies and cervicography were done at enrollment and after 6 months. Quarterly Papanicolaou smears and colposcopic assessments also were performed. Findings of mosaic pattern, punctation, and white epithelium were graded and diagrammed at colposcopic examinations. Cervicographic measurements of the centripetal movement of metaplastic epithelium were recorded. Data were analyzed by chi 2 analysis and Fisher exact tests. Data were available for 23 subjects with regression and 16 with persistent lesions. Small lesions were significantly more likely to regress than large ones. Lesions without coarse punctation were significantly more likely to regress than lesions with coarse punctation, and lesions with mild acetowhite changes were more likely to regress than those with dense white epithelium. A pattern of centripetal movement of the metaplastic epithelium toward the cervical os was noted in lesions that regressed, but not in those that persisted or progressed. This study describes the centripetal growth of metaplastic squamous epithelium associated with the regression of CIN II and III. This observation contributes to our understanding of the process of disease regression in CIN and may be useful in identifying individuals for conservative management. Failure to identify this pattern correlates with persistent or progressive disease.

Immunohistochemical analysis of estrogen receptors in cystic-endometritis-pyometra complex in the bitch

Monoclonal antibodies to human estrogen receptor were used with an indirect immunohistochemical technique to localize in formalin-fixed, paraffin-embedded sections of the genital tract of the bitch. The presence of estrogen receptors in the uterus of dogs with cystic hyperplasia endometritis complex (CHE) was compared with normal uteri from dogs at the same stage of estrous cycle. Lower estrogen receptor expression was found in the squamous metaplastic epithelium covering the luminal surface of the endometrium from dogs with CHE than in the columnar epithelium from normal dogs. In contrast, the basal glands from uteri of CHE group dogs contained more estrogen receptor than glands from normal dogs at the same stage of estrous cycle. This was most pronounced and statistically significant in the late secretary stage of the estrous cycle. When the glands presented cystic degeneration, the estrogen receptor labeling was less pronounced. The highest estrogen receptor score was present in normal glands from dogs treated with progestins. In this group even cystic degenerated glands contained high estrogen receptor concentrations compared with those of the other groups. From this study it was concluded that the down regulation of estrogen receptor expression in the endometrial glands under the influence of rising progesterone concentrations is defective in dogs with CHE. Therefore it is suggested that the regulation of estrogen receptor expression in endometrial glands may play an important role in the pathogenesis of CHE in the bitch.

Progressing imbalance between proliferation and apoptosis with increasing severity of cervical intraepithelial neoplasia.

The equilibrium between cell proliferation and protection against apoptosis was studied immunohistochemically using monoclonal antibodies against Ki-67-Ag and bcl-2, respectively, in consecutive sections from normal and metaplastic cervical epithelia and cervical intraepithelial neoplasia (CIN) lesions and cervical carcinomas. A high percentage of Ki-67-Ag positive cells was seen in the parabasal cells of normal ectocervical and mature squamous metaplastic epithelium, although the basal cells were virtually negative. In preneoplastic lesions, however, the basal cells showed high proliferative activity and an increasing frequency of Ki-67-Ag positive cells was observed in the higher epithelial layers with increasing severity of CIN. In squamous cell carcinomas, variable numbers of Ki-67-Ag positive cells were observed and in adenocarcinomas expression increased with the degree of anaplasia. bcl-2 expression was observed only in the basal cells of normal endo- and ectocervix including reserve cells. With increasing severity of CIN, staining intensity and number of bcl-2 positive cells gradually increased. Five of eight squamous cell carcinomas were variably positive. All five adenocarcinomas showed extensive bcl-2 expression. Increased expression of both Ki-67-Ag and bcl-2 with increasing severity of CIN indicates an increasing imbalance between cell proliferation and protection from apoptosis. It is therefore proposed that an increasing proliferative fraction combined with a higher number of cells protected from apoptotic cell death contributes to progression of CIN. This phenotype may identify premalignant lesions with the potential to transform to cervical cancer.

Transitional (urothelial) cell metaplasia of the uterine cervix: morphological assessment of 31 cases.

Thirty-one cases of transitional cell metaplasia (TCM) of the uterine cervix were studied. The mean age of patients was 62 years (range 30-87); 25 (81%) were postmenopausal and six premenopausal. In 24 of 25 postmenopausal patients, TCM was an incidental finding at operation for a variety of gynecological lesions, and in such patients the distribution of TCM included the endocervical canal, transformation zone, native ectocervix and vagina. In five of six premenopausal patients, TCM was identified in the cervices of women investigated for abnormal Papanicolaou smears. In all six premenopausal patients, as well as in the remaining postmenopausal patient who also presented with an abnormal Papanicolaou smear, TCM was confined to the endocervical canal and transformation zone. TCM was typified by a multilayer epithelium, clearly distinguishable from the atrophic ectocervical epithelium of most postmenopausal patients by its thickness (averaging 12 cells thick). TCM was identified on the surface epithelium or in sequestered endocervical glands resembling Walthard cell nests of the fallopian tube serosa. There was loss of the usual basal "picket fence" layer seen in cervical squamous epithelia; the cells had crowded nuclei oriented vertically and swirling to give a superficial appearance of disorder. Although lack of "differentiation" from the basal to superficial layers was characteristic, in many examples there was an obvious surface umbrella layer. Intraepithelial glandular differentiation and lesions resembling cystitis glandularis of the urinary bladder were occasionally noted on the ectocervix and vagina. Cellular detail included large pale oval nuclei, oriented vertically, with finely stippled chromatin, small inconspicuous nucleoli, and frequently a deep longitudinal groove. Although the nuclear/cytoplasmic ratio was high, cell-to-cell variation was negligible, and mitoses were rare and never atypical, which, with the nuclear details, distinguished TCM from high-grade squamous dysplasias. The nature of the metaplasia and its biological function are unclear. In postmenopausal patients, it presumably arises occasionally as a consequence of the altered hormonal environment of the cervix and vagina and is of interest only for the possibility of misinterpreting it as a high-grade squamous intraepithelial lesion. In premenopausal patients, it may represent a cellular variation of either physiologic or atypical metaplastic squamous epithelium of the cervical transformation zone.

Neoangiogenesis: a putative marker of malignancy in non-small-cell lung cancer (NSCLC) development.

Several studies have documented a relevant prognostic role of microvessel count (MC) in non-small-cell lung carcinomas (NSCLC). However, no evidence has been reported about the involvement of neo-angiogenesis in the development of bronchial cancers. The aim of this study was to analyze microvessel density both in normal and in pathological features of the bronchial tree detected concomitantly with carcinomas. In a group of 34 patients resected for NSCLC, 48 bronchial lesions (hyperplasia, squamous metaplasia, moderate dysplasia and in situ carcinoma) were identified. In addition, 20 samples of normal bronchial epithelium from the same patients were analyzed. A monoclonal antibody was used in order to identify microvessels in the most intense areas of neovascularization from the bronchial specimens. MC was also analyzed in invasive components. An increased number of microvessels was observed from normal to dysplastic epithelium, including in situ carcinoma. Mean MC was significantly lower in normal, hyperplastic and squamous metaplastic epithelium than in dysplastic epithelium and in situ carcinoma. In particular, no differences were observed between normal and hyperplastic/metaplastic components, whereas a statistically significant difference appeared between the latter and dysplastic lesions. Moderate dysplasia and in situ carcinoma showed a number of microvessels in the lamina propria of their mucosa which were not significantly different from the invasive component, whereas hyperplastic/metaplastic lesions presented a much lower number of microvessels than invasive cancer. From these data it appears that normal bronchial epithelium and lesions associated with cancers of the bronchial tree show neovascularization in their stromal component. Hyperplasia and squamous metaplasia, unlike dysplasia and in situ carcinoma, show a low microvessel count, and they cannot represent precursor or incipient changes in the bronchial epithelium before the fully developed in situ stage has also been reached.

BCL‐2 IMMUNOREACTIVITY INCREASES WITH SEVERITY OF CIN: A STUDY OF NORMAL CERVICAL EPITHELIA, CIN, AND CERVICAL CARCINOMA

The presence of the BCL-2 protein, a marker for inhibition of programmed cell death, was studied in a series of routinely processed cervical tissues, consisting of normal endocervical (n=40) and ectocervical epithelium (n=27), squamous metaplastic epithelium (n=30), CIN (cervical intraepithelial neoplasia) lesions (n=32), and cervical carcinomas (n=13). BCL-2 was strongly expressed in the basal cell compartment of normal ectocervical squamous epithelium and in nearly all reserve cells, while in endocervical columnar cells it was moderately expressed. In immature squamous metaplastic epithelium, BCL-2 expression varied. Half of the cases showed only basal cell staining, while the other half showed staining also in suprabasal layers. BCL-2 could be detected in all premalignant lesions, showing a striking increase in the number of positive cells with increasing severity of CIN, in combination with a mild increase in staining intensity. All adenocarcinomas were positive (n=5), while five of eight squamous cell carcinomas expressed BCL-2. Based on these results, it is hypothesized that both the larger number of cells staining with BCL-2 in higher grades of CIN and the increase in staining intensity imply an increasing protection of these neoplastic conditions against programmed cell death. This protection facilitates not only continuing proliferation, but also the induction of genetic instability in dysplastic epithelial cells; it may thus reflect the greater capacity of the more severe CIN lesions to evolve into cervical carcinoma.

BCL-2 immunoreactivity increases with severity of CIN: a study of normal cervical epithelia, CIN, and cervical carcinoma.

The presence of the BCL-2 protein, a marker for inhibition of programmed cell death, was studied in a series of routinely processed cervical tissues, consisting of normal endocervical (n = 40) and ectocervical epithelium (n = 27), squamous metaplastic epithelium (n = 30), CIN (cervical intraepithelial neoplasia) lesions (n = 32), and cervical carcinomas (n = 13). BCL-2 was strongly expressed in the basal cell compartment of normal ectocervical squamous epithelium and in nearly all reserve cells, while in endocervical columnar cells it was moderately expressed. In immature squamous metaplastic epithelium, BCL-2 expression varied. Half of the cases showed only basal cell staining, while the other half showed staining also in suprabasal layers. BCL-2 could be detected in all premalignant lesions, showing a striking increase in the number of positive cells with increasing severity of CIN, in combination with a mild increase in staining intensity. All adenocarcinomas were positive (n = 5), while five of eight squamous cell carcinomas expressed BCL-2. Based on these results, it is hypothesized that both the larger number of cells staining with BCL-2 in higher grades of CIN and the increase in staining intensity imply an increasing protection of these neoplastic conditions against programmed cell death. This protection facilitates not only continuing proliferation, but also the induction of genetic instability in dysplastic epithelial cells; it may thus reflect the greater capacity of the more severe CIN lesions to evolve into cervical carcinoma.

扁平上皮化生粘膜上皮内のLangerhans cellの動態

Langerhans cells (LCs) in the squamous metaplastic epithelium of the trachea and the urinary bladder of vitamin A-deficient rats were examined. Both round, immature cells which were considered to be precursor LCs, and mature LCs with prominent dendritic processes, were recognized in the present study. Both cells were positive for anti-protein kinase type II antibody (PKC-II), and although the former did not have Birbeck granules (BGs), the latter did. The precursor LCs without BGs first appeared in the early stage of squamous metaplasia. As the differentiation of squamous metaplasia progressed, the number of BG bearing LCs increased, and the precursor cells became mature LCs in the later stage of squamous metaplasia of both the trachea and the urinary bladder. In the later stage of squamous metaplasia of the urinary bladder, LCs with BGs also appeared in the lamina propria. These findings indicate that precursor cells which probably migrate from the bone marrow, disperse into the metaplastic squamous epithelium in morphologically immature forms, and mature into BG bearing LCs as a result of contact with squamous epithelium.