The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions

Objectives To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. Methods Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. Results A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. Conclusions Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development (AU)

The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions.

OBJECTIVES: To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. METHODS: Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. RESULTS: A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. CONCLUSIONS: Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development.

Feasibility Study of a Variant Procedure of Radical Breast Ductectomy (Dolichectomy) with a Perinipple Incision.

Papillomatosis and recurrent duct ectasia could be treated with terminal lactiferous ducts excision. In this study we describe a modified miniinvasive procedure of terminal lactiferous ducts excision with a perinipple approach to the lower or upper half of the nipple. This technique avoids the much more extensive periareolar incision and has excellent aesthetic results.

Inguinal endometriosis: A systematic review.

Inguinal endometriosis is a very rare entity with uncertain pathophysiology, that poses several diagnostic and therapeutic challenges. This study aimed to summarize published literature on the diagnosis and treatment of this condition. Thus, a systematic literature search was conducted in PubMed/MEDLINE, Scopus and the Cochrane Library. An effort was made to numerically analyze all parameters included in case reports and retrospective analyses, as well. The typical and atypical features of this condition, investigations used, type of treatment and histopathology were recorded. More specifications about the surgical treatment, such as operations previously performed, type of surgery and treatment after surgery have been acknowledged. Other sites of endometriosis, the presence of pelvic endometriosis and the follow-up and recurrence have been also documented. Overall, the search yielded 61 eligible studies including 133 cases of inguinal endometriosis. The typical clinical presentation includes a unilateral inguinal mass, with or without catamenial pain. Transabdominal or transvaginal ultrasound was typically used as the first line method of diagnosis. Groin incision and exploratory surgery was the treatment indicated by the majority of the authors, while excision of part of the round ligament was reported in about half of the cases. Chemotherapy and radiotherapy were initiated in cases of coexisting endometriosis-related neoplasia. Inguinal recurrence or malignant transformation was rarely reported. The treatment of inguinal endometriosis is surgical and a long-term follow-up is needed. More research is needed on the effectiveness of suppressive hormonal therapy, recurrence rate and its relationship with endometriosis-associated malignancies.

The Expression of NRIP1 and LCOR in Endometrioid Endometrial Cancer.

BACKGROUND: The aim of the study was to analyze the expression of nuclear receptor interacting protein 1 (NRIP1) and its partner ligand-dependent nuclear receptor co-repressor (LCOR) in endometrioid endometrial cancer and to investigate their association with estrogen receptor (ER), progesterone receptor (PR), Ki-67, clinicopathological parameters and patient survival. MATERIALS AND METHODS: Immunohistochemical evaluation was carried out to investigate the subcellular expression of NRIP1 and LCOR in endometrioid endometrial cancer samples. Statistical analysis was used to identify the correlations of NRIP1 and LCOR expression with clinicopathological variables and to estimate the survival rates. RESULTS: Endometrial cancer tissues exhibited higher expression of NRIP1 and LCOR in comparison with the normal tissues. Cytoplasmic LCOR expression was positively associated with ER and PR expression, while cytoplasmic NRIP1 expression was positively associated with ER expression. Moreover, cytoplasmic expression of NRIP1 was positively associated with Ki-67. CONCLUSION: Our study demonstrated that high cytoplasmic expression of LCOR may predict a longer overall survival of patients with endometrioid endometrial cancer. Patients with tumors expressing low levels of LCOR showed a worse survival compared to those expressing high levels.

Ductoscopy Coupled to Duct Lavage and Duct Brushing in Pathologic Nipple Discharge: Our Experience.

PURPOSE: to present our experience in the management of pathological nipple discharge using the procedure D.DL.DB: "ductoscopy" (D) coupled to "duct lavage" (DL) plus "duct brushing" (DB) for etiologic diagnosis. Also to compare the diagnosis obtained with D.DL.DB to the final histology. MATERIAL AND METHOD: Eighty-five patients with organic unilateral nipple discharge were enrolled in two Breast Units. 82 of 85 patients were investigated successfully with D.DL.DB. Results:: The final histological results were: papilloma 46.3%, duct ectasia 36.5%, breast cancer 8.5%, precancer lesions 4.9%, and mixed benign lesions 3.8%. Pyramidectomy and radical ductectomy were performed in 76 and 6 cases respectively. In 80% of the cases, DLDB cytology results were identical to the final histology. (Kappa=0;69 CI=[0.56 -0.82]. The sensitivity of D.DL.DB versus pathology, for cancer or precancer lesions was 81.8% (CI=0.59 -1) and the specificity was 97.1% (CI=0.93 -1). Using Koch scale, the concordance between the two methods D.DL.DB and surgery was high and the sensitivity was in the upper range regarding the literature (58% to 90%). CONCLUSION: Our experience confirms the high value of D.DL.DB in the management of organic nipple discharge.

Management of malignant and borderline phyllodes tumors of the breast: our experience.

PURPOSE: Phyllodes breast tumors (PT) range from benign lesions to malignant ones that may give distant metastasis. Preoperative diagnosis is difficult, while the treatment of borderline and malignant disease remains controversial. METHODS: Eighteen patients in 3 clinics were included in the study. Lumpectomy with large margins was performed in 15 patients, while mastectomy was performed in 3 patients. Lymph node excision was carried out in 3 patients with malignant tumors. Radiation therapy (RT) was delivered after a second lumpectomy in cases of local recurrence. Chemotherapy was used only in 2 patients with aggressive recurrent tumors. RESULTS: Borderline behavior was reported in 4 patients. Lumpectomy was performed in these cases, with local recurrence in 2 of them. Malignant behavior was reported in 14 patients. Lumpectomy was performed in 10 patients and mastectomy in 3. Local recurrence was reported in 5 cases and in 2 patients recurrence after a 2nd operation was also reported. CONCLUSIONS: Borderline PT were treated conservatively and the prognosis was excellent, while malignant subtypes needed mastectomy in about 25% of the cases, The local recurrence rate was high, but the disease free survival (DFS) and the overall survival (OS) were also very high (94%).

CRH Receptors in Human Reproduction.

BACKGROUND: Corticotropin releasing hormone (CRH), the main peptide-mediator of stress, has been found in the female reproductive system. OBJECTIVE: Herein, the role of CRH receptors in the female reproductive system is presented. RESULTS: It is clear that CRH receptors are involved in the regulation of the hypothalamic-pituitaryovarian axis, while locally are associated with decidualization, embryonic implantation, early fetal development and triggering of parturition. CONCLUSION: Abnormal CRH signaling may contribute to obstetrical pathophysiology, such as preeclampsia, abnormal placenta invasion, endometrial growth retardation and preterm delivery.

Alpha tocopherol transfer protein (αTTP) is expressed in endometrial carcinoma and is correlated with FIGO stage and 5-year survival.

BACKGROUND: Increased oxidative stress plays an important role in cancer development. Vitamin E is considered a potent anti-oxidant and its transfer protein αTTP facilitates its cellular delivery. We hypothesize that αTTP could be present in and have an impact on endometrial cancer. MATERIALS AND METHODS: Ishikawa endometrial cancer cells were treated with BSO and AAPH to mimick oxidative stress conditions. αTTP was detected by immunocytochemistry and western blot. αΤΤP expression was then assessed in 191 endometrioid endometrial carcinomas. Immunopositivity was correlated with grade, FIGO stage, and 5-year survival. Immuno-reactivity was assessed with a semi-quantitative score. RESULTS: AAPH- and BSO-induced αTTP expression in Ishikawa cells. Immunohistochemical assessment of the 191 endometrial cancer cases showed that αTTP expression correlated with FIGO stage (p = 0.014) but not with grade. Five-year survival was significantly better in cases of lower αTTP expression compared to cases with higher expression (p = 0.041). CONCLUSIONS: The current results show that αTTP plays a role in endometrial carcinoma. Possibly endometrial cancer cells attempt to protect themselves from increasing oxidative stress by up-regulating αTTP. Selective molecular interventions targeting oxidative stress escape strategies, e.g., by overexpression of αTTP, could, therefore, allow oxidative stress to damage cancer cell membranes and thus restrict cancer progression.

Hysteroscopy in women with abnormal uterine bleeding: a meta-analysis on four major endometrial pathologies.

PURPOSE: To determine the accuracy of hysteroscopy in diagnosing endometrial cancer, hyperplasia, polyps and submucous myomas. METHODS: Relevant articles were retrieved from the MEDLINE and the Cochrane Library (1986-2011). Studies were selected blindly. Results for diagnostic accuracy were extracted to form separate 2 × 2 tables (for endometrial cancer, hyperplasia, polyps and submucous myomas). A summary sensitivity and specificity point reflected the average accuracy observed. Summary ROCs (SROCs) were also calculated according to the HSROC model. RESULTS: For endometrial cancer, the estimated sensitivity was 82.6% (95% CR 66.9-91.8%) and the specificity was 99.7% (95% CR 98.1-99.9%). For endometrial hyperplasia, sensitivity was 75.2% (95% CR 55.4-88.1 %), while specificity was 91.5% (95% CR 85.7-95.0%). For endometrial polyps, sensitivity was 95.4% (95% CR 87.4-98.4%) and specificity was 96.4% (95% CR 93.7-98.0%). Finally, for submucous myomas, sensitivity was estimated to 97.0% (95% CR 89.8-99.2%) and specificity to 98.9% (95% CR 93.3-99.8%). CONCLUSIONS: Diagnostic accuracy for hysteroscopy is high for endometrial cancer, polyps and submucous myomas, but only moderate for endometrial hyperplasia.

Hypoxia-induced factor-1α in endometrial carcinoma: a mini-review of current evidence.

Despite the well-established role of hypoxia in cancer biology, the literature on its effects on endometrial cancer is scarce; it mainly refers to experimental settings rather than patient-derived results. Herein, an overview of the hypoxia inducible factor 1α (HIF-1α) biology, focusing on endometrial cancer, is presented. The molecular mechanisms possibly involved in endometrial cancer progression are presented, followed by a systematic approach to the current literature on immunohistochemistry evaluation of HIF-1α expression in endometrial carcinoma. Since no consensus has been made regarding HIF-1α evaluation, the evidence of possible involvement of HIF-1α in endometrial carcinoma prognosis is weak. After a consensus has been made, properly powered studies may be able to clarify whether HIF-1α can act as a prognosticator in endometrial carcinoma.

Decidual macrophages are significantly increased in spontaneous miscarriages and over-express FasL: a potential role for macrophages in trophoblast apoptosis.

Decidual macrophages (DM) are the second most abundant population in the fetal-maternal interface. Their role has been so far identified as being local immuno-modulators favoring the maternal tolerance to the fetus. Herein we investigated tissue samples from 11 cases of spontaneous miscarriages and from 9 cases of elective terminations of pregnancy. Using immunohistochemistry and dual immunofluorescence we have demonstrated that in spontaneous miscarriages the DM are significantly increased. Additionally, we noted a significant up-regulation of macrophage FasL expression. Our results further support a dual role for DM during pregnancy and miscarriages. We hypothesize that the baseline DM population in normal pregnancy is in line with an M2 phenotype supporting the ongoing gestation. In contrast, during spontaneous miscarriages, the increased FasL-expressing population could be a part of an M1 phenotype participating in Fas/FasL-related apoptosis. Our results highlight a new aspect of macrophage biology in pregnancy physiology and pathophysiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact.

Immunohistochemical study of the angiogenetic network of VEGF, HIF1α, VEGFR-2 and endothelial nitric oxide synthase (eNOS) in human breast cancer.

BACKGROUND: The role of Nitric Oxide (NO) in angiogenesis has not been fully clarified yet. A dual role for NO, either inductive or inhibitory, has been proposed on the basis of different effects that high or low concentrations of NO may exert on the angiogenic process. Additionally, it has been referred that NO may induce VEGF production, while VEGF may induce NO production via up-regulation of the endothelial nitric oxide synthase (eNOS), the two pathways being reverse. The aim of the current study was to investigate the expression of key molecules involved in these opposite pathways in primary breast cancer. METHODS: Representative tumor samples from 242 patients with early-stage breast cancer (invasive ductal breast carcinomas) were investigated for the expression of VEGF, VEGFR-2, HIF1α, iNOS, and eNOS using immunohistochemistry. RESULTS: Endothelial NOS was found in 159 cases, VEGF in 131 cases, HIF-1α in 139 cases, VEGFR2 in 185 cases and inducible NOS (iNOS) in 22 cases. There was a significant correlation between the expression of VEGF and VEGFR-2, eNOS and VEGF, eNOS and VEGFR-2, eNOS and HIF1α. No statistically significant correlation was found between iNOS and the rest of the studied molecules. CONCLUSIONS: In breast cancer cases, the major molecules regulating NO and VEGF production can be co-expressed in the individual carcinomas implying a possibility for the relevant pathways to be active; however appropriate functional experiments remain to be conducted to prove such a hypothesis.

A systematic review and meta-analysis of randomized studies comparing misoprostol versus placebo for cervical ripening prior to hysteroscopy.

OBJECTIVE(S): Hysteroscopy is an effective method for examining the uterine cavity but has some limitations, including the occasional need for cervical dilatation. Misoprostol is routinely used for cervical dilatation in various procedures but has not gained wide acceptance for use before hysteroscopy. STUDY DESIGN: This review includes randomized controlled trials which compare the use of misoprostol versus placebo by different routes and doses before diagnostic or operative hysteroscopy. The MEDLINE database and the Cochrane Central Register of Controlled Trials were searched for articles published from January 1970 to April 2010. The outcome measures studied were related either to the facilitation of the hysteroscopic procedure (need for cervical dilatation, cervical width at the beginning of hysteroscopy, duration of the procedure and complications such as cervical tear and uterine perforation) or to the medication side-effects. With regard to side-effects, we studied the incidence of nausea, diarrhea, abdominal pain, bleeding, and fever. RESULTS: Vaginal misoprostol reduced the need for cervical dilatation in the total population of pre- and post-menopausal women to a statistically significant degree. In the subgroup of operative hysteroscopy the need for dilatation and the duration of the procedure were also significantly reduced. Most other outcomes relating to the facilitation of the procedure did not reach statistical significance. The side effects in the misoprostol group were significantly more frequent than in the placebo group. CONCLUSION(S): There is insufficient evidence to recommend the routine use of misoprostol before every hysteroscopy. As the lack of serious benefit from misoprostol is unlikely to be due to type II error, its use should be reserved for selected cases.

Primary atypical carcinoid of the breast: a case report and brief overview of evidence.

Primary atypical carcinoid of the breast is rare. Herein we present a case of atypical carcinoid of the breast treated with surgery. The management plan is commented. Moreover an overview of the current evidence is presented. All the evidence is classified as level IV (opinion-based evidence) since there is no satisfactory case series to support a certain therapeutic decision. The treatment for an atypical carcinoid of the breast is the same one offered in patients diagnosed with primary infiltrating breast cancer. A multi-centric approach is needed in order to gather enough data to confidently support a certain management plan for these patients.

Reproduction after breast cancer.

Breast cancer is the most frequently occurring cancer in women of developed countries, and as a result of new developments in breast cancer treatment, more women are cured after being diagnosed with this disease. It is important that fertility preservation strategies are addressed before chemotherapy, because chemotherapy may induce premature ovarian failure (depending on the woman's age, the drugs used, the dosage and duration of treatment). Among possible solutions are embryos or oocytes cryopreservation, ovarian tissue cryopreservation-freezing with a subsequent orthotopic and heterotopic autotransplantation, whole ovary cryopreservation, ovarian suppression with gonadotropin-releasing hormone (GnRH) analogues, which inhibit ovarian follicular depletion induced by chemotherapeutic agents and in vitro fertilisation (IVF) after ovulation induction with aromatase inhibitors or tamoxifen.

Nipple discharge screening.

Nipple discharge is a common complaint among women. It is classified as normal or abnormal depending on features such as laterality, cycle variation, quantity, color or presentation (i.e., induced vs spontaneous). It can be related to benign conditions, such as intraductal papilloma, duct ectasia, plasma cell mastitis or galactorrhea; or to malignant conditions such as ductal, lobular or papillary carcinoma. Techniques used in nipple discharge evaluation include mammography, ultrasound, cytology (which could be assisted by a mammary pump), duct endoscopy, ductography, immunochemical methods and at least surgical excision of the pathological ducts for diagnosis and treatment in the same procedure.

Management and evolution of cervical intraepithelial neoplasia during pregnancy and postpartum.

OBJECTIVE: To investigate the evolution of cervical intraepithelial neoplasia (CIN), and to evaluate the safety of cytological and colposcopical surveillance of women with CIN during pregnancy. STUDY DESIGN: Ninety-eight women with antenatal cytological and/or colposcopical impression of CIN were followed up during pregnancy with cytology and colposcopy every 2 months. A cytological and colposcopical reevaluation 2 months postpartum was done, and large loop excision of the transformation zone (LLETZ) was performed if appropriate. Punch or loop biopsies were only taken if there was suspicion of microinvasion. RESULTS: In 14 of 39 (35.9%) and in 25 of 52 (48.1%) women with antenatal impression of CIN I and CIN II-III, respectively, there was postnatal impression of regression. Seven women with findings suspicious of microinvasion underwent small loop biopsies during pregnancy, but early stromal invasion (< 1 mm) was seen in just one case. There was one more case of microinvasion (1.5 mm) diagnosed postnatally in which the antenatal impression was of CIN III. 84.6% of the women with regression compared to 67.3% of the women with stable disease or progression had a vaginal delivery (P = 0.057). CONCLUSION: There is a considerable regression rate of CIN after pregnancy possibly attributable to the loss of the dysplastic cervical epithelium during cervical ripening and vaginal delivery. Frequent cytological and colposcopical evaluation seems to be safe. Small loop biopsies are recommended in cases of possible microinvasion.