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The prognostic value of p53 in predicting recurrence and progression of superficial transitional cell carcinoma of the bladder (TCCB) is still uncertain. Materials and methods P53 expression was retrospectively assessed in 160 patients. At a median follow-up of 45 months, (up to years) 84 patients (53%) recurred and 13 (8%) progressed. Adjuvant intravesical chemotherapy after TUR was adopted in 51 patients (32%). The correlations between p53 and G-grade, T-category, risk of recurrence and progression, and intravesical chemotherapy were investigated. Similarly, the correlations between variations in grade and stage at recurrence and modifications in p53 expression were also studied. Results Seventy-nine patients (49%) were negative for p53. P53 was expressed in 84% of G3 tumors and in 65% of T1 lesions. A significant correlation between p53 expression and G-grade (pConclusion According to our experience, p53 expression is not independent from grade and stage of superficial TCCB. A significant correlation between p53 expression and progression, not independent from G-grade, was detected only in T1 tumors.

In this study, 32 pleomorphic adenomas (PAs) and seven adenoid cystic carcinomas (ACCs) were analysed for the evaluation of proliferating cell nuclear antigen (PCNA) indices and flow cytometric variables. Our aim was to assess any possible relationship between these parameters and the clinico-pathological variables and to clarify their histogenesis and reasons for their biological differences. The tumours were divided into three groups, mainly epithelial (E), myxoid (M) and chondroid (C); PCNA labelling index (LI) and weighted mean index (WI) and the WI/LI ratio were analysed in the predominant components; a single PCNA index, weighted by the percentage of each component, was also calculated. Only WI/LI was found to be significantly different in the three components, while PCNA single index did not show either significant differences by sex, age, site and size, or any correlation with the S phase fraction. A significant difference was found between PAs and ACCs by site (P < 0.01) and DNA ploidy (P < 0.05); furthermore, all PCNA indices (single index) were significantly lower in PAs than in ACCs.

It is essential to reach a better understanding of "flat epithelial atypia/columnar cell lesions" (FEA/CCLs) in breast core biopsies. Our aim was to explore their biological nature, in order to predict the likelihood of an upgrade to carcinoma. "Cytological grading" has been specially focused, in view of its possible utility in the choice of management. One hundred thirty of a total of 900 cases core needle (CN)/vacuum-assisted biopsies (VABs), with diagnoses of "hyperplasia" and "atypia" were retrospectively re-evaluated. Pathological findings of further excision biopsies (FEBs) performed in 40/75 patients with follow-up were compared with the previous diagnoses. In all cases, both Ki-67 and c-kit immunoreactivities were explored and compared with both normal breast tissues and subsequently documented cancers, with special reference to the hyperplastic FEA/CCLs, with "mild" atypia (FEA/CCHAm). Sixteen cases were re-diagnosed as "usual ductal hyperplasia" (UDH), 60 as "columnar cell hyperplasia" (CCH), and 54 as FEA/CCHA, 30 of which FEA/CCHAm and 24 FEA/CCHAh (with high atypia). Significantly, the Ki-67 index proved to be on the increase and c-kit expression on the decrease in FEA/CCHA lesions, mainly in the FEA/CCHAh group and in the subsequently observed cancers, compared with either benign tissues or the FEA/CCH cases. It was also significant that most of the carcinomas were found in FEBs within the FEA/CCHAh group. In this study cytological grading, together with Ki-67 and c-kit indices, proved to be helpful in FEA/CCLs evaluation. With regard to FEA/CCHAm lesions, an adequate surveillance appears to be a more appropriate management tool than FEB, as a result of their biological nature and behavior.

A striking feature of cellular blue nevus consists in the presence, in its histologic picture, of numerous hypertrophic nerves and nerve-like figures, positive for histochemical and immunohistochemical methods for nerve fibers and myelin sheaths. These findings, first described in Masson's original article and repeatedly highlighted in the past for their possible histogenetic significance, are currently considered as merely coincidental. However, the thin conventional histologic sections, catching only short tracts of the nerves, preclude a correct observation of their route and do not allow us to verify if there is an architectural relationship between them and the nevus as a whole. With this aim, we observed a few specimens of cellular blue nevus on digitally overlapped images of contiguous 25-microm-thick sections, processed with Winkelmann's technique of silver impregnation for nerve fibers, which supplied an overall, 3-dimensional view of the lesions and the nerves running through them. In these images, the lobular form of the nevus could be seen gathering around a branching hypertrophic nerve, whose stem stretched vertically from the depth to the most superficial tract of the lesion. The nevus cell aggregates invested the stem and the limbs individually, and these followed the curvilinear contour of the nevus lobules. Our images represent evidence of a preferential perineural aggregation of cellular blue nevus, at least in its lobular form. This indicates that the numerous nerves and the neuroid figures, observed in detail-but within a limited perspective- in the conventional sections, are not merely coincidental and they could indeed be a sign of neural differentiation and/or a clue to the possible neural origin of the nevus.

A retrospective histological and immunohistochemical study has been carried out in 25 cases of tick bites recorded in our Departments. The samples that included an attached tick showed a cement cone anchoring the mouthparts to the skin and a blood-soaked, spongiform appearance of the superficial dermis, with a mild neutrophilic and eosinophilic infiltration. The vessels displayed a loose multilayered endothelial proliferation, with plump endothelia, permeated with erythrocytes. A few of them were severed, allowing copious blood extravasation. The established lesions included the following: erythema chronicum migrans-like cases, foreign body granulomas-sometimes containing remnants of the mouthparts-cutaneous lymphoid hyperplasia, either of the T-cell or the B-cell type, and tick-bite alopecia. In both the T-cell and B-cell pseudolymphomas, several vessels showed concentric endothelial and perithelial proliferation similar to that seen in the acute lesions. In the tick-bite alopecia, a lymphocytic infiltrate attacked the permanent portion of the hair follicles, whose reaction was a noticeable hyperplasia of the fibrous sheaths, although only a minority of the hairs was destroyed. The observed alterations are specific in the acute lesions and in the alopecia, where they directly arise as a result of the interactions between the host's tissues and the antihemostatic, anti-inflammatory, and immunomodulatory chemicals contained in the tick saliva. In the other lesions, the changes seem less characteristic, although the fragments of mouthparts and the special vascular changes provide a clue to their etiology.

Reelin is a glycoprotein that plays a critical role in the regulation of neuronal migration during brain development and, since reelin has a role in the control of cell migration, it might represents an important factor in cancer pathology. In this study, 66 surgical specimens of prostate cancer were analyzed for reelin expression by immunohistochemical method. The reelin expression was correlated with Gleason score and individual Gleason patterns. Reelin expression was found in 39% prostate cancers. Stromal tissues, normal epithelial cells and prostate intraepithelial neoplasia (PIN) of any grade around and distant from cancer were always negative for reelin. Reelin was found in malignant prostatic epithelial glands of 50% cases Gleason score 10, 52% Gleason score 9, 56% Gleason score 8, 18% Gleason score 7, while no sample of prostate cancers with Gleason score 6 showed reelin expression (P=0,005). As reelin staining is frequently found in high Gleason score prostate cancers, we explored whether reelin expression is influenced by single Gleason patterns. While Gleason 3 pattern did not show reelin immunoreactivity, reelin expression was found in 35% Gleason 4 patterns and 45% Gleason 5 patterns (P

BACKGROUND: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients. PATIENTS AND METHODS: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay. RESULTS: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P

Background Methylation of the p16 promoter is one of the most frequent mechanisms of gene inactivation; its incidence is extremely variable according to the type of tumor involved. Our purpose was to analyze the hypermethylation of the p16 promoter in laryngeal squamous cell carcinomas (LSCC), salivary gland (SG) tumors and in colorectal cancer (CRC), to detect any possible association with the clinicopathological features and to determine the prognostic significance of the p16 gene in the tumors analyzed. Patients and methods The hypermethylation of the p16 promoter was prospectively analyzed, by MSP, in a consecutive series of 64 locally advanced LSCC patients, in a consecutive series of 33 SG tumor patients and in a consecutive series of 66 sporadic CRC patients. Results Hypermethylation was observed in 9% of the LSCC cases, in all cases of SG cancer and in 21% of the CRC cases. No significant association was observed between p16 hypermethylation and clinicopathological variables in all the tissue samples analyzed. Moreover at univariate analysis p16 mutations were not independently related at disease relapse and death in LSCC and CRC. Conclusions The results of this study suggest that the lack of p16 function could happen in advanced stage of SG tumors.

The gene Nm23, which encodes for a nucleoside diphosphate kinase, has been defined as a metastasis-suppressor gene because of the inverse correlation between its expression and the metastatic capacity of the tumor cells. For colorectal cancer, however, the findings are equivocal. The aim of our study was to assess, in 160 patients undergoing surgery for colorectal cancer (CRC), the expression of the Nm23-H1 protein and to evaluate its possible associations with traditional clinicopathologic variables, with DNA-ploidy and proliferative activity (S-phase fraction, SPF), and with disease-free and overall survival of patients. Nm23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry; DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. The median follow-up time in our study group was 71 months (range 34-115 months). No association was observed between Nm23-H1 protein expression and clinicopathological variables, S-phase fraction and DNA-ploidy. Furthermore, no significant differences were observed in the survival of patients with either moderate or strong Nm23-H1 expression. The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA aneuploid tumors and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. Our results indicate that Nm23-H1 activity is tissue-specific and that in CRCs the expression of the protein is not associated with tumor progression and patient prognosis, although further studies are required in order to throw more light on the possible clinical significance of the overexpression of the protein Nm23-H1 in such tumors.

To study GP-170 in superficial bladder cancer at initial diagnosis and at recurrence and to evaluate if intravesical chemoprophylaxis modifies the expression of GP-170 in tumor recurrences. GP-170 was retrospectively assessed in 160 patients affected by primary superficial transitional cell carcinoma of the bladder and followed for up to 10 years. Eighty-four patients (52.5%) recurred after transurethral resection (TUR). Adjuvant intravesical chemotherapy after TUR was adopted in 52 patients. The correlations between GP-170 and G-grade, T-category, risk of recurrence and of progression, and adoption of adjuvant intravesical chemotherapy were investigated. The correlations between variations in grade and stage at recurrence and modifications in GP-170 expression were also studied. No significant correlation between GP-170 expression and G-grade and T-category was found. A significant correlation was detected between GP-170 expression and recurrence (P=0.0383). It showed a biphasic pattern, i.e., tumors that did not express GP-170 had a higher recurrence rate, but high GP-170 levels were also associated with an increasing risk of recurrence. Intravesical chemotherapy did not induce significative variations in GP-170 expression. No correlation was found between progression and GP-170. GP-170 seems to be an independent prognostic factor for recurrence in superficial bladder tumors. A negative GP-170 pattern and high levels of GP-170 are associated with an increasing risk of recurrence but have no impact upon progression. In our experience, GP-170 is neither induced nor modified by intravesical chemotherapy, although it might represent a factor of chemoresistance when strongly expressed.

Extramammary Paget disease of the axilla with underlying apocrine carcinoma has been reported only in six cases until now. This report deals with a seventh case characterized by the unique finding of comedo-like features evocative of large cell ductal breast carcinoma within an otherwise typical in situ apocrine carcinoma. This is characterized by spiral-shaped foci of epithelial proliferation with decapitation secretion and central masses of necrotic debris. A possible connection between the solid neoplasm and the overlying Paget disease is illustrated by a few apocrine-follicular units colonized by both the Paget cells and the structured adenocarcinoma. Here, although they display the same immunohistologic pattern of glandular differentiation, the two populations seem to be cytologically different and do not show signs of gradual transition to one another. Thus, they give the impression of parallel but distinct processes, which is consistent with the hypothesis of proliferative induction of a preexisting intraepidermal scattered population from the underlying adnexal carcinoma. The observed resemblance between apocrine carcinoma and comedo carcinoma of the breast, with its ontogenetic and phylogenetic implications, links not only the two neoplasms and the corresponding glands of origin but also mammary and extramammary Paget disease. This reinforces the unifying conception of Paget disease.

Purpose: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. Methods: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. Results: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P < 0.05) and DNA aneuploid tumors (P < 0.05) tumors. DNA-aneuploidy was associated with distal tumors (P < 0.01), histological grade (G3) (P < 0.05), advanced Dukes' stage (C and D) (P < 0.01), lymph node metastases (P < 0.01) and high SPF (> 18.3%) (P < 0.01). The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA-aneuploidy, and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. Conclusions: Our results indicate that DNA aneuploidy and high SPF are associated in CRC with a poor clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23-H1 expression is still to be clarified.

BACKGROUND The prognostic value of DNA ploidy, S-phase fraction (SPF) and K-ras-2 mutations in gastric carcinoma (GC) has not yet been clearly defined. The aim of this study was to clarify the association between biomolecular variables, tumor characteristics, and clinical outcome in GC patients. METHODS Resected specimens from a consecutive series of 69 patients with GC who underwent potentially curative surgery were studied prospectively. DNA ploidy and SPF were assessed by flow cytometry on multiple frozen tumor samples, whereas K-ras-2 mutations were detected by polymerase chain reaction followed by single-strand conformation polymorphism. All the patients involved in this study were followed up for a mean of 95 months. RESULTS DNA aneuploidy was present in 72% of the cases (50 of 69), whereas 10% of these (5 out of 50) showed multiclonality. Mutations of K-ras-2 were detected in 8% of the tumors (5 of 63). Both DNA ploidy and SPF were associated with TNM stage (American Joint Committee on Cancer [AJCC] staging system) and node status. Moreover, DNA aneuploidy was significantly related to high SPF. K-ras-2 mutations were not associated with clinicopathologic variables or flow cytometric indicators. At univariate analysis, advanced TNM stage, node involvement, diffuse histotype, depth of invasion, DNA aneuploidy, and high SPF proved to be significantly related to quicker tumor relapse and to shorter overall patient survival. With multivariate analysis, DNA aneuploidy, high SPF, and depth of invasion were related to risk of tumor relapse and patient death, whereas diffuse histotype was independently related to patient risk of tumor relapse. CONCLUSIONS DNA ploidy and SPF, when associated with clinicopathologic staging, might be useful for the identification of GC patients who have different risks for death or relapse of disease. Cancer 2001;92:294–302. © 2001 American Cancer Society.

In this paper we study the development of chick embryo retina cultured in vitro and the effects exerted by insulin. Retinas were removed from 7-day embryos and cultured in serum- and hormone-free medium for 7 additional days. Under these conditions retinal cells survived and underwent cholinergic differentiation, as previously ascertained by Hausman et al. (Dev. Brain Res., 1991, 59: 31-37). However, a great retardation of development was noted compared to uncultured control, 14-day retina. In fact both wet weight and DNA and protein content increased much slower than in ovo and the tubulin content decreased below even the starting value. In addition, although after 7 days in culture retinal cells were organized in identifiable layers, nevertheless the typical organization equivalent to 14-day in ovo retina was absent. The addition of insulin in the medium markedly increased the wet weight of cultured retinas, their protein content and the level of tubulin pools, particularly that of non-assembled fraction. Nevertheless insulin did not modify DNA synthesis and did not induce the increment of both neuron specific enolase and actin. Morphological observations show that insulin markedly increased the number and the thickening of the fiber layers. These results, together with the facts that retina synthesizes and secretes insulin and possesses specific insulin receptors suggest that insulin can have autocrine or paracrine regulatory functions in retinal development by exerting a general effect on retinal growth and a more specific one on tubulin production.

A series of 20 cases of pleomorphic adenoma and 19 cases of adenoid-cystic carcinoma of the salivary glands, and one case in the mammary location, were investigated regarding immunohistochemical reactivity for Tissue Polypeptid Antigen (TPA), Pre-Keratins, Vimentin, S-100 Protein, and their arrangement pattern of fibronectin. As a whole, the results support the hypothesis of morpho-structural and mainly, onto-histogenetic similarities between these tumours, but they also underline the need for great care in outlining their morpho-functional features, in relation to their different prognoses.

A series of 65 cases of different histological types of breast carcinoma was investigated for the immunohistochemical location of the estrogen receptor-related, 29 kD phosphoprotein using the ER-D5 monoclonal antibody.The ER-D5 response is heterogeneous in relation to some therapeutic limitations and is correlated with histopathological features of the tumors and survival. The main parameters for evaluation of breast cancers are reviewed, both those that are statistically correlated and those that are not apparently always correlated but are known to have considerable biological meaning, such as the ER-status of tumors.