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[Photodynamic therapy of early squamous epithelial carcinomas and severe squamous epithelial dysplasias of the esophagus with 5-aminolevulinic acid].

INTRODUCTION: Photodynamic therapy (PDT) is a new local, endoscopically controlled therapeutic concept based on the selective sensitization of malignant and precancerous lesions prior to light-induced tissue destruction. 5-aminolaevulinic acid (5-ALA) appears to be a promising alternative photosensitizer with a high mucosa specificity without phototoxic side effects on the skin. We report on our experience with this new form of PDT in 24 patients. PATIENTS AND METHODS: Five females and 19 males (aged 50 to 79 years) with histologically proven high-grade dysplasia (n = 9) and early cancer (normal EUS or uTlNOMO, n = 15) of the esophagus were included in this study. Four to six hours after oral ingestion of 5-ALA (dosage of 60 mg/kg b.w.) laser light irradiation was conducted with a dye laser system (XP 800 KTP/YAG, Laserscope, San José, USA) at a wavelength of 635 nm. With a light dose of 150 J/cm2. RESULTS: The length of the segment with severe dysplasia or mucosal cancer varied between 0.5 and 9 cm (mean length: 3.6 cm). High-grade dysplasia was eradicated in all patients (9/9). In addition, 16 mucosal carcinomas in 15 patients were successfully treated in 8/16 cases with an average of 1.8 treatment sessions and a mean follow-up of 14.5 months (range: 3-31 months). A method-related mortality and morbidity was not observed. CONCLUSIONS: Severe dysplasia and superficial (< or = 2 mm) mucosal cancer of the esophagus can be completely ablated by 5-ALA-PDT. Patients with early carcinoma thicker than 2 mm are not suitable for 5-ALA-PDT. PDT with 5-ALA has few side effects and might offer an alternative to esophagectomy or radio-chemotherapy.

Administration, Oral↗

Evidence for heterogeneity in a small squamous cell type ('light' cells) in the rabbit corneal epithelium--a scanning electron microscope study. Corneal epithelial squamous cells.

The rabbit corneal epithelial surface, as viewed by scanning electron microscopy (SEM), is composed of a mosaic of polygonal cells with different appearances (light, medium and dark) with the lighter cells having a characteristically high density of microplicae. From the central zone of the corneal epithelial surface of 16 female New Zealand White rabbits (2 kg), the lighter-appearing cells had an average area of 108 +/- 47 microns2 (n = 567, +/-SD). A subgroup of atypical lighter cells had an average area of 294 +/- 67 microns2 (n = 53) compared to typical light cells of 88 +/- 12 microns (n = 514). These atypical lighter cells had fused microplicae at their periphery (instead of a uniform arrangement of densely packed microplicae), tended to be rounder in shape (as opposed to being angular), could show signs of desquamation and were not decorated with the epithelial craters found on almost all (92%) other light cells. All of these features are suggestive of these atypical lighter cells being the terminal phenotype of the light cells just prior to desquamation from the ocular surface. The observation of the desquamation of lighter cells supports a hypothesis that they constitute a distinct sub-population of cells at the corneal epithelial surface.

Animals↗

Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases.

Noninvasive squamous lesions are distinctively uncommon in biopsies of the urinary bladder with the exception of nonkeratinizing squamous metaplasia. The clinical significance of these squamous lesions in the bladder remains to be explored. A total of 29 cases of transurethral biopsies and resections of the bladder containing noninvasive squamous lesions (excluding nonkeratinizing metaplasia) were studied from the consult files of one of the authors. These cases included keratinizing squamous metaplasia (5), verrucous squamous hyperplasia (5), squamous papilloma (5), condyloma acuminatum (3), and squamous cell carcinoma in situ (CIS) (11). Immunohistochemistry for epithelial growth factor receptor (EGFR) and in situ hybridization for wide-range human papillomavirus was performed on 23 cases. The follow-up period ranged from 2 months to 3 years with an average of 1.5 years. After the initial diagnoses in biopsies of the bladder, 10 patients received cystectomies, and 7 patients received repeat tissue sampling of the bladder. Of the 5 patients with keratinizing squamous metaplasia, 2 patients had invasive urothelial carcinoma with squamous features in their cystectomy specimens at intervals of 3 and 14 months, respectively, 1 had persistent keratinizing squamous metaplasia on rebiopsy. Of the 5 patients with verrucous squamous hyperplasia, 1 patient had invasive squamous cell carcinoma at cystectomy at an interval of 14 months, 1 had squamous cell CIS on rebiopsy, 1 had persistent verrucous squamous hyperplasia on rebiopsy, and 2 had no evidence of disease at 6 and 24 months. Of the 5 patients with squamous papilloma, 1 patient had low-grade urothelial carcinoma at cystectomy at an interval of 21 months (h/o low-grade urothelial carcinoma preceding papilloma diagnosis), 2 were free of lesions at rebiopsy. Of the 3 patients with condyloma acuminatum, 1 had squamous CIS at cystectomy at an interval of 3 months, 1 had invasive squamous cell carcinoma at 20 months. Of the 11 patients with squamous cell carcinoma in situ (CIS), 3 patients had invasive squamous cell carcinoma at intervals of 2, 3, and 4 months, respectively, 1 had invasive urothelial carcinoma with squamous features in cystectomies at an interval of 12 months, 1 had squamous cell CIS at 10 months, 1 had high-grade urothelial carcinoma (not otherwise specified) at rebiopsy at an interval of 6 months, and 1 had no evidence of disease at 8 months. Among the 9 patients with invasive carcinoma, 4 patients died in the period of 0.5 to 3 years after the diagnoses. Immunohistochemical study with EGFR demonstrated strong signals in 20 cases and no signals in 2 cases. Wide-range human papillomavirus DNA signal was detected in 1 case of condyloma acuminatum and 1 case of squamous cell CIS. Keratinizing squamous metaplasia, verrucous squamous hyperplasia, and condyloma acuminatum in the urinary bladder can be associated with subsequent or concurrent in situ, or invasive squamous carcinoma and should be closely followed. Squamous cell CIS in the urinary bladder is often associated with subsequent or concurrent invasive carcinoma with squamous differentiation. Enhanced expression of EGFR in these bladder squamous lesions suggests that EGFR may represent a logic therapeutic target in those squamous lesions that are difficult to manage clinically.

Adult↗

Angiogenesis, proliferation, and apoptosis in anal high-grade squamous intraepithelial lesions.

PURPOSE: Management of anal high-grade squamous intraepithelial lesions is controversial. Anal and cervical high-grade squamous intraepithelial lesions are similar in that they occur in transitional squamous epithelium, are associated with human papilloma virus infection, and have increased incidence in the immunocompromised population. Ablation of cervical high-grade squamous intraepithelial lesions is preferred, but similar ablation or excision of anal high-grade squamous intraepithelial lesions may compromise bowel control; thus, there is a need to define the malignant potential of anal high-grade squamous intraepithelial lesions. METHODS: We analyzed 50 paraffin sections of normal anoderm, anal low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and anal squamous-cell carcinoma. Microvessels were detected immunohistochemically with von Willebrand factor and counted manually along the epithelial-stromal junction. Proliferation and apoptosis were determined in the epithelial cells with MIB-1 antibody immunostaining and the terminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end labeling, respectively. RESULTS: Microvascular density was significantly greater in anal high-grade squamous intraepithelial lesions (mean, 0.50 vessels/cm) vs. normal anoderm (mean, 0.21 vessels/cm; P = 0.0017, Mann-Whitney U test). The proliferative percentages were greater in low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and squamous-cell carcinoma (mean, 20.4, 21.8, and 23.6 percent) vs. normal anoderm (mean, 14.4 percent), although not significantly (P = 0.06, Kruskal-Wallis statistic). Although the mean proliferative proportions were similar in low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions, the apoptotic proportion was lower for high-grade squamous intraepithelial lesions than low-grade squamous intraepithelial lesions (10.13 vs. 19.96 percent, respectively; P = NS, Mann-Whitney U test). CONCLUSIONS: Angiogenesis, increased proliferation, and decreased apoptosis occur in anal high-grade squamous intraepithelial lesions as they do in the cervix before the development of malignancy. These biologic markers support the importance of anal high-grade squamous intraepithelial lesions as a potential premalignant lesion warranting surgical intervention.

Anal Canal↗

Epithelial lesions associated with invasive penile squamous cell carcinoma: a pathologic study of 288 cases.

A heterogeneous spectrum of epithelial alterations and atypical lesions affect the squamous epithelium of penile mucosal anatomical compartments. Analogous to other genital sites, the terminology utilized to define the lesions is variable. The few pathologic studies of penile precancerous lesions are mostly related to carcinoma in situ and human papilloma virus (HPV), and the information on low-grade atypical lesions is limited. The objective of this study was to comprehensively describe the morphologic features of all epithelial alterations, benign and atypical, low grade and high grade, associated with invasive squamous cell carcinoma of the penis and to investigate their relation with each other and with subtypes of invasive carcinoma. We also propose herein a simple and reproducible nomenclature for penile precancerous abnormalities until more biological, molecular, or epidemiologic information on the lesions is available. Two hundred and eighty-eight penectomy and circumcision specimens with invasive squamous cell carcinoma were pathologically evaluated. Carcinomas were classified as usual, verrucous, papillary not otherwise specified, warty (condylomatous), basaloid, and mixed. Associated lesions were classified as squamous hyperplasia and squamous intraepithelial lesions of low and high grade (LGSIL and HGSIL). In LGSIL, atypia was confined to the lower third, and in HGSIL, atypical cells affected at least two thirds of the squamous epithelium. Subtypes of SIL were squamous, warty, basaloid, warty-basaloid, and papillary. Squamous hyperplasia, the most common lesion, was found in 83% of the cases, followed by LGSIL (59%) and HGSIL (44%). In 62% of the cases more than 1 associated lesion was present per specimen. A sequence from squamous hyperplasia to low-grade to high-grade SIL was seen frequently. Squamous hyperplasia was more commonly associated with usual squamous, papillary, and verrucous than with warty and basaloid invasive carcinomas. LGSIL was associated with all types of squamous cell carcinoma but was rarely present adjacent to basaloid or verrucous tumors. HGSIL was present in two thirds of invasive warty, basaloid, and mixed warty-basaloid tumors, in about half of usual squamous cell carcinomas, and was absent in papillary and verrucous carcinomas. Correlation of special types of invasive carcinomas with subtypes of SIL revealed morphologic correspondence of invasive tumor and the associated intraepithelial lesion. Squamous LGSIL was preferentially associated with verrucous, papillary, and usual squamous cell carcinomas; warty LGSIL, with invasive warty and mixed warty-basaloid carcinomas. High-grade SIL of the squamous type was frequently found in squamous cell carcinoma of usual type but was rarely present with warty or basaloid carcinomas. Basaloid HGSIL was associated with basaloid carcinoma, and HGSIL of warty type, with either warty or mixed warty-basaloid carcinomas. The high frequency of squamous hyperplasia and LGSIL and preferential association with usual, verrucous, and papillary carcinomas plus the subtle morphologic differences of the 2 lesions suggest that, despite its benign appearance, squamous hyperplasia is a precursor of the aforementioned carcinomas. The association and histologic similarities between high-grade SIL of the basaloid, warty, or mixed forms with their invasive counterparts indicate these lesions are their likely precursors.

Carcinoma in Situ↗

Urinary bladder carcinoma with a neoplastic squamous component: a mapping study of 31 cases.

A mapping study of cystectomy specimens in three cases of pure squamous cell carcinoma and 28 cases with transitional cell carcinoma with squamous differentiation is described, with an emphasis on the histogenesis of pure squamous cell carcinoma. Two of the three cases of pure squamous cell carcinoma had extensive benign keratinizing mucosa and an atypical squamous metaplastic mucosa contiguous with the tumour. These pure squamous cell carcinomas seemed to be derived from the squamous metaplasia. On the other hand, in all except one of the cases of transitional cell carcinoma with squamous differentiation, there was neither benign keratinizing nor atypical squamous metaplastic mucosa in the bladder. The quantitative amounts of both the transitional cell and squamous components differed from case to case in 28 cases with transitional cell carcinoma with squamous differentiation. Five of the 28 had a tumour composed predominantly of a squamous component with minute transitional cell components at the margin. In another two cases, transitional carcinoma in situ or satellite tumours of transitional cells were present adjacent to the main tumour which was composed of squamous cell carcinoma alone. We think these seven tumours originated as a result of extensive squamous differentiation in the transitional cell carcinomas. These features may indicate two forms of histogenesis of pure squamous cell carcinoma. The first is malignant transformation on the basis of squamous metaplasia of the bladder mucosa and the second is extensive squamous differentiation in a pre-existing transitional cell carcinoma.

Aged↗

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.

Carcinoma, Adenosquamous↗

Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.

There are approximately 200,000 new cases of cutaneous squamous cell carcinoma diagnosed each year in the United States, with between 1300 and 2300 deaths per year from metastatic disease. The tumor suppressor p16, encoded by the CDKN2/INK4a locus, has been reported mutated in >or=24% of squamous cell carcinomas. Mutations of the p16 gene have also been found in actinic keratoses, the first identifiable lesion in the continuum from normal skin to squamous cell carcinoma. We hypothesized that there may be an appreciable difference in expression of p16 between normal skin, actinic keratoses, squamous cell carcinoma in situ, and invasive squamous cell carcinoma. Ten actinic keratoses, 10 in situ squamous cell carcinomas, and 10 invasive squamous cell carcinomas were examined using the immunoperoxidase method with antigen retrieval for anti-p16(INK4a) antibody. All 10 actinic keratoses were positive for weak to moderate p16 staining in the lower third to lower half of the epidermis (especially the basal keratinocytes). This staining was significant when compared with the lack of staining seen in normal skin controls. Twenty percent of in situ squamous cell carcinomas had moderate to strong staining in only the lower half to lower two thirds of the epidermis, whereas 70% of the in situ squamous cell carcinomas exhibited full-thickness p16 staining, with no staining in the dermis. Thirty percent of invasive squamous cell carcinomas had full-thickness staining of the in situ component of the lesion, and 100% of invasive squamous cell carcinomas exhibited moderate to strong staining of the invasive component of the lesion. These findings indicate correlation between the increased expression of p16 during the progression of skin from actinic keratosis to in situ squamous cell carcinoma to invasive squamous cell carcinoma. These data may lend further support to the view of the actinic keratosis as a precursor lesion to squamous cell carcinoma.

Carcinoma, Squamous Cell↗

Cross-linked envelope-related markers for squamous differentiation in human lung cancer cell lines.

Lung carcinoma cell lines were analyzed in culture and in nude mouse xenograft for both morphological appearance and expression of specific proteins that participate in cross-linked envelope formation during normal squamous cell terminal differentiation. Cross-linked envelope formation, induced by artificial influx of millimolar Ca2+ into the cultured cells, was an exclusive trait of squamous, adenosquamous, and mucoepidermoid carcinomas. Small cell lung carcinoma and non-squamous non-small cell lung carcinoma lines, such as adenocarcinoma and large cell carcinoma, were uniformly negative for cross-linked envelope formation. Involucrin, which is incorporated into the cross-linked envelope by the enzyme transglutaminase, was expressed at highest levels in squamous tumors, but several of the non-squamous non-small cell lung carcinoma lines also expressed comparable amounts. On the other hand, transglutaminase activity was consistently higher in squamous as opposed to non-squamous lines, so that in cell culture, a clear contrast between the groups could be observed. A Mr 195,000 protein that is incorporated into cultured human epidermal cell cross-linked envelopes was also observed in some but not all of the squamous lines. Two forms of transglutaminase are expressed in cultured keratinocytes. One of them, tissue transglutaminase, was expressed in the majority of squamous cell lines even though it is not a normal product of squamous differentiation in vivo. Keratinocyte transglutaminase, which is distinct from the tissue form and is normally expressed during terminal differentiation in squamous epithelia. was measurably present in only one of the six squamous cell lines tested. In nude mouse xenografts, keratinocyte transglutaminase, localized immunohistochemically with a biotinylated mouse monoclonal antibody, was again present only in a minority of the squamous lines whereas involucrin was expressed in all. In contrast to involucrin, keratinocyte transglutaminase is not an obligatory component of squamous differentiation in the pulmonary carcinoma cell lines tested. Its expression may be of value in further refining their classification.

Animals↗

Distribution of proliferating-cell nuclear antigen and epidermal growth factor receptor in intraepithelial squamous cell lesions of human bronchus.

Distribution of proliferating-cell nuclear antigen and epidermal growth-factor receptor was studied by immunohistochemistry in intraepithelial squamous cell lesions of human bronchus. Ten biopsy specimens were examined for each of the following categories of lesions (50 specimens altogether): normal bronchial epithelium, benign squamous metaplasia, dysplastic squamous metaplasia, and squamous cell carcinoma in situ, in addition to invasive squamous cell carcinoma. The percentage positivity of immunoreactive cells and their localization in the epithelium were examined in formalin-fixed, paraffin-embedded tissues of bronchial biopsy specimens retrieved from the surgical pathology file. Proliferating-cell nuclear antigen positivity ranged from 3.2% (normal bronchial epithelium), to 7.6% (benign squamous metaplasia), 51.8% (dysplastic squamous metaplasia), and 85.0% (squamous cell carcinoma in situ). The difference between the groups was statistically significant (p < 0.01). The percentage positivity for invasive squamous cell carcinoma was 56.9%. Epidermal growth-factor receptor positivity ranged from 7.3% (normal bronchial epithelium), to 38.7% (benign squamous epithelium), 67.5% (dysplastic squamous metaplasia), and 91.3% (squamous cell carcinoma in situ). The difference between the groups was statistically significant (p < 0.01). Invasive squamous cell carcinoma positivity was 49.7%. Both proliferating-cell nuclear antigen-positive and epidermal growth-factor receptor-positive cells showed zonal distribution in the bronchial epithelium. They were located in the basal cell layer in normal bronchial epithelium and expanded upward as the morphologic changes advanced. In squamous cell carcinoma in situ, both proliferating-cell nuclear antigen-positive and epidermal growth-factor receptor-positive cells covered the entire thickness of the bronchial epithelial layer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗