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Transcriptional silencing by CpG island hypermethylation plays a critical role in endometrial carcinogenesis. In a collection of benign, premalignant and malignant endometrial lesions, a methylation profile of a complete gene panel, such steroid receptors (ERα, PR), DNA mismatch repair (hMLH1), tumor-suppressor genes (CDKN2A/P16 and CDH1/E-CADHERIN) and WNT pathway inhibitors (SFRP1, SFRP2, SFRP4, SFRP5) was investigated in order to demonstrate their pathogenetic role in endometrial lesions. Our results indicate that gene hypermethylation may be an early event in endometrial endometrioid tumorigenesis. Particularly, ERα, PR, hMLH1, CDKN2A/P16, SFRP1, SFRP2 and SFRP5 revealed a promoter methylation status in endometrioid carcinoma, whereas SFRP4 showed demethylation in cancer. P53 immunostaining showed weak-focal protein expression level both in hyperplasic lesions and in endometrioid cancer. Non-endometrioid cancers showed very low levels of epigenetic methylations, but strong P53 protein positivity. Fisher exact test revealed a statistically significant association between hMLH1, CDKN2A/P16 and SFRP1 genes methylation and endometrioid carcinomas and between hMLH1 gene methylation and peritumoral endometrium (p < 0.05). Our data confirm that the methylation profile of the peritumoral endometrium is different from the altered molecular background of benign endometrial polyps and hyperplasias. Therefore, our findings suggest that the methylation of hMLH1, CDKN2A/P16 and SFRP1 may clearly distinguish between benign and malignant lesions. Finally, this study assessed that the use of an epigenetic fingerprint may improve the current diagnostic tools for a better clinical management of endometrial lesions.

Background: Endocrine gland-derived vascular endothelial growth factor (Prok1) and prokineticin 2 (Prok2) are involved in the organ-specific regulation of angiogenesis, which is a crucial step toward cancer progression in most tumors, including those of thyroid gland. The oncogene BRAF V600E mutation is associated with poor clinical outcome of papillary thyroid cancer (PTC) and can independently predict its recurrence., Design: Our hypothesis was that Prok1 and Prok2 expression levels associated with BRAF mutations can be prognostic factors for PTC outcome. Prok1 and Prok2 were examined in PTC, a cell line derived from a human PTC (designated FB-2), euthyroid multinodular goiter (MNG), Graves' disease (GD), and contralateral normal thyroid (NT) tissues from PTC cases. We evaluated BRAF mutation and its relationship with Prok1 expression pattern in PTC., Methods: We studied Prok1 and Prok2 mRNAs by real-time polymerase chain reaction and BRAF mutation by mutant allele-specific polymerase chain reaction amplification. Formalin-fixed, paraffin-embedded blocks of PTC and NT were used for the immunohistochemical determination of Prok1 using anti-endocrine gland vascular endothelial growth factor primary antibody., Results: Prok1 and Prok2 transcripts were both present in thyroid tissues, and Prok1 was differentially expressed in PTC compared to MNG, GD, and NT. Prok1 mRNA levels were very low in NT and MNG and significantly higher in PTC, FB-2, and GD (p<0.05). Prok1 protein was almost undetectable in NT but was highly expressed in all PTC samples having an infiltrative pattern of growth and lymph node metastases ( p<0.05). Further, the expression of Prok1 in PTC was associated with 60% of the samples being positive for the BRAF mutation ( p<0.05)., Conclusions: We found that Prok1 is significantly increased in PTC, and its expression in PTC is related to BRAF mutation. These results suggest that Prok1 could be a new useful marker for thyroid cancer progression. Prok1 therefore could also be a potential target for novel therapeutic strategies, although the lack of functional data suggests caution against generalization of this assumption

Cancer statistics report an increased incidence of OSCC and OPSCC around the world. Though improvements in screening and early diagnosis have dramatically reduced the incidence of this neoplasm in recent years, the 5-year-disease-free survival, is still poor, specially for oropharyngeal cancer, despite the great scientific and financial efforts. Recently, several papers showed that HPV may be involved at least in the pathogenesis of a subgroup of oral and cervical SCC, leading to distinct molecular characteristics compared with HPV-negative ones. Nevertheless, OPSCCs associated with HPV infection seem to show a better prognosis and affect younger patients (< 40 yrs.), especially females. Therefore, there is the need to properly assess oropharyngeal SCC subgroups: 1) not HPV associated/classic oral SCC: less responsive to anticancer drugs: needs novel post-surgical treatment; 2) HPV associated/oral SCC: needs several management options and suitable "target" therapy against the virus, and/or immune-stimulating therapy. Further issues are: 1) the disclosure of putative targets for more efficient molecular therapy, which may work as cervical cancer post-surgical treatment, in anticipation of the effects of "global prevention" performed by WHO anti-HPV vaccination programs; 2) careful identification of precancerous lesions in both sites; dysplasia is currently treated by excisional or ablative procedures, which don't consider the concept of field carcinogenesis. In fact, it is probable that near or far from an excised precancerous lesion new foci of cell transformation may exist, which are not yet macroscopically evident, but, if detected, would put the patient into a high risk subgroup.Comparing findings reported in the recent literature, the data of this state of the art about HPV might add useful informations concerning oropharyngeal carcinogenesis. Moreover, our review would be useful in order to define novel perspectives of treatment choice for Head & Neck cancer patients, by combining well known chemotherapeutical drugs with new molecular "target" therapy.

Introduction: Endosalpingiosis is a disorder of Mullerian system characterized by benign glands lined by tubal type epithelium and involves the peritoneum, subperitoneal tissues, and retroperitoneal lymph nodes. Endosalpingiosis is almost an incidental finding on microscopic examination. Seldom it appears as a cyst and it can be confused clinically for an ovarian tumor., Design: A case report and a systematic review about pelvic mass-like florid endosalpingiosis of the uterus from PUB MED database were performed., Patient(s): We describe a case report of a 50-year-old woman with a pedunculated uterine neoformation, for which the preoperative exams could be compatible with an adnexal mass. Twelve patients with similar clinical history were discussed in the review., Treatment: Laparoscopy with radical exeresis was performed., Results: Microscopic exam revealed florid cystic endosalpingiosis of the uterus., Conclusions: Endosalpingiosis is a rare mullerian disorder and the main problem is that the symptomatology is not specific and it may be initially misinterpreted. In relation to the papillary aspect of the lesion and focal calcifications, the histological differential diagnosis could include serous adenocarcinoma, but the lack of cellular stratification in absence of mitotic activity, and the presence of slight nuclear atypia contradict the diagnosis of carcinoma. The differential diagnosis for endosalpingiosis also includes multiple peritoneal inclusion cysts (benign cystic mesothelioma). The aim of this case report has not been only to describe the rarity of this pathology, but it contributes to consider endosalpingiosis as a possible diagnostic hypothesis for which may be indicated a conservative surgical treatment.

Objective: To study the main processes involved in oral squamous cell carcinoma (OSCC): apoptosis and inflammation., Study Design: The immunohistochemical expression of bcl-2, CD3, CD20, CD45 and CD68 were studied by standard linked streptavidin-biotin horseradish peroxidase technique in 21 paraffin-embedded OSCC specimens in order to establish their possible correlation with the degree of tumoral differentiation., Results: A trend was observed for the association of inflammatory infiltrate with the degree of tumor differentiation: well and moderately differentiated tumors tend to be associated to a dense inflammatory infiltrate (57.9% of cases), while poorly differentiated cancers seem to be associated to a low inflammatory infiltrate in 85.7% of cases. The most expressed molecule was CD68, followed by CD45, CD20 and CD3. Bcl-2 was low or moderately expressed, and immunostaining was more diffuse in moderately or poorly differentiated oral cancers., Conclusion: Inflammatory infiltrate and the degree of OSCC differentiation may be linked, but the specific role still remains unclear.

Objective: To evaluate beta-catenin expression in human tooth germ development., Study Design: Specimens of 7 human fetuses aged between the ninth and sixteenth week were examined for beta-catenin expression by immunohistochemistry., Results: In the bud stage, we observed catenin membranous positivity for all primitive dental lamina and dental ridge cells, cytoplasmic positivity for tooth bud and intense nuclear positivity for early-condensed dental mesenchyme. The cap stage was marked by intense cytoplasmic and nuclear positivity in the outer and inner enamel epithelium and the dental papilla and by moderate cytoplasmic positivity in the enamel knot. In the early bell stage, we noted strong cytoplasmic and nuclear staining in the inner and outer enamel epithelium, only moderate membranous and cytoplasmic staining in the stellate reticulum, a high percentage of intense nuclear positivity in the dental papilla and strong focal nuclear and cytoplasmic positivity in the dental sac., Conclusion: All areas with close contact between epithelial structures and ectomesenchymal cells showed increased expression of delocalized cytoplasmic and nuclear beta-catenin. Nuclear localization, tissue expression pattern and timing suggest a pivotal role for beta-catenin in the transcriptional activation of genes probably involved in the mesenchyme-epithelial interactions on which human tooth development is based.

Purpose: Survivin, an inhibitor of apoptosis protein and a cell cycle regulator, has been detected in the majority of human cancers. Five splice variants (survivin, survivin-2alpha, survivin-2B, survivin-3B, and survivin-DeltaEx3) have been identified; their expressions have been investigated here., Methods: By means of RT real-time PCR and immunohistochemistry, we have evaluated survivin isoform expressions at both mRNA and protein levels in human normal oral tissue, precancerous lesions, and oral squamous cell carcinoma (OSCC). Their correlations with the pathological findings have also been analyzed., Results: Expression levels of all survivin transcript variants were markedly elevated in OSCC when compared to normal tissues. One-way analysis of variance (ANOVA) revealed highly significant up-regulation of survivin (P = 0.001), survivin-DeltaEx3 (P = 0.001) and survivin-2B (P = 0.004), whereas survivin-3B showed a minor increase in OSCC compared to normal mucosa., Conclusions: Our findings suggest that survivin isoforms deregulation may have significant implications in tumor aggressiveness and prognosis.

Deregulated expression of inhibitors of apoptosis may contribute to cancer by aberrantly extending cell viability and facilitating the insurgence of resistance to chemo- and radiotherapy. In this study, we have investigated, by immunohistochemical technique, the expression and potential prognostic significance of survivin in a series of 49 clear cell type renal cell carcinoma (ccRCC). Survivin expression was significantly associated with poorly differentiated, advanced stages and more aggressive ccRCCs (p < 0.05). Patients with low survivin expression had statistically significant better survival rates than patients with high survivin expression (p < 0.05). This may be relevant for follow-up protocols design and/or alternative therapeutic approaches.

Background: A large number of renal cancer patients shows poor or partial response to chemotherapy and the mechanisms have not been still understood. Multi-drug resistance is the principal mechanism by which many cancers develop resistance to chemotherapic drugs. The role of the multi-drug resistant transporter (MDR-1/P-glycoprotein), the gene product of MDR-1, and that one of the so-called multi-drug resistance associated protein (MRP), two energy-dependent efflux pumps, are commonly known to confer drug resistance. We studied MDR-1 expression in selected cases of renal cell carcinoma (RCC), clear cell type, with long-term follow-up, in order to establish its prognostic role and its possible contribution in the choice of post-surgical therapy., Methods: MDR-1 has been studied by standard LSAB-HRP immunohistochemical technique, in paraffin embedded RCC samples. Protein expression has been compared to clinical and histopathological data and to disease specific survival of RCC patients, by Kaplan-Meier curve and Cox multivariate regression analyses., Results: Two groups of RCCs were obtained by esteeming MDR-1 expression and disease specific survival (obtained with Kaplan-Meier curve and Cox multivariate regression analyses): the first one presents low or absent MDR-1 expression and good survival; the second one is characterized by high MDR-1 expression and significant poor outcome (p < 0.05). Afterwards, we have found disease specific survival, adjusted for stages and independent of therapy: this difference of survival rates was statistically significant (p < 0.05). Stage adjusted disease specific survival rate, according to MDR-1 expression and therapy in patients affected by RCC in early stage (stage I), has revealed that the group of patients with high MDR-1 expression and without adjuvant therapy showed poor survival (p < 0.05). Cox multivariate regression analysis has confirmed that, in our cohort of RCC (clear cell type) patients, the strong association between MDR-1 and worse outcome is independent not only of the adjuvant therapy, but also of the other prognostic parameters (p < 0.05)., Conclusion: In our opinion, the results of this study well prove the relationship between MDR-1 expression and worse clinical prognosis in RCC, because MDR-1 over-expressing RCCs can be considered a group of tumours with a more aggressive behavior. This finding outlines a possible role of MDR-1 as prognostic factor, dependent and independent of multidrug resistance. These results could be useful to predict cancer evolution and to choose the appropriate treatment: this is another step that can stimulate further promising and interesting investigations on broader study population.

We evaluated the efficacy of office hysteroscopic treatment of benign intrauterine pathologies using 5F mechanical instruments (scissors, grasping forceps). Subjects were 4863 women who underwent the procedure without analgesia or anesthesia. We treated cervical and endometrial polyps (0.2-3.7 cm), intrauterine adhesions, and anatomic impediments. At 3 months postoperatively, pathology persisted in 364 women (5.6%). Many operative procedures may be performed in the office setting with simple instruments, provided that correct indications are observed.