Roles of estrogen receptor α and β in the regulation of proliferation in endometrial carcinoma

Endometrial carcinoma (EC), an estrogen-dependent gynecological malignancy, is prevalent worldwide. Estrogen receptor α (ERα) and estrogen receptor β (ERβ) are two main estrogen receptor isoforms, which mediate estrogen-induced proliferation in EC. However, the dynamic changes of ERα and ERβ subtype expression and their functions on proliferation in EC remain elusive. In this study, we aimed to investigate the expression of ERα and ERβ in para-tumor eutopic endometrium, endometrial atypical hyperplasia and EC by immunohistochemistry and then analyse their clinical significance. Subsequently, Ishikawa cells with ERα or ERβ knockdown by lentivirus transfection were used to explore the relationship between ERα/ERβ and cell proliferation, and preliminarily evaluate whether metformin’s inhibitory effect on estrogen-induced cell proliferation was mediated by ERα and ERβ. We found that the expression of ERα and ERβ were markedly changed in endometrial hyperplasia and EC compared with that in para-tumor eutopic endometrium and exhibited different expression trends. Through further analysis, we discovered that ERα presented higher expression in endometrial atypical hyperplasia and early stage of EC than that in para-tumor eutopic endometrium, while the expression of ERβ gradually decreased from para-tumor eutopic endometrium to EC. Additionally, the cell cycle-related protein, CyclinD1 was gradually increased but p21 decreased. Furthermore, knockdown of ERα and ERβ severally in Ishikawa cells either inhibited or promoted estrogen-induced cell proliferation through regulating CyclinD1 and p21 expression. Meanwhile, the inhibitory effect of metformin on estrogen-induced cell proliferation was respectively blunted or partly reversed by knockdown of ERα or ERβ. Altogether, ERα and ERβ have different expression patterns in the progression of EC either facilitating or suppressing cell proliferation through regulating the expression of CyclinD1 and p21 in EC cells, and may also mediate the inhibitory effect of metformin on estrogen-induced EC cells proliferation.     

Evolution of the term and definition of dysplasia of the hip – a review of the literature

There is no consensus on the definition of dysplasia of the hip (DH). Past and present concepts used to describe DH do not form a complete view of the pathology. Moreover, some authors still present the disease as congenital, not developmental. This prompted authors to analyze the evolution of the definition of DH. Based on the biomedical databases 500 articles and books in the field of hip dysplasia were found and analyzed. Fifteen definitions of hip dysplasia met inclusion criteria, subsequently were analyzed and presented in chronological order. The analysis revealed that currently there is no single, universal definition of hip dysplasia in the aspect of morphological, clinical, and radiological studies. Despite the widely-used term of DH, it is described imprecisely and in different ways. Therefore, it is necessary to develop a multidisciplinary definition of this pathology covering all aspects of hip disorders considered valid in modern orthopaedics.     

Can immunohistochemistry enhance the detection of micrometastases in pelvic lymph nodes from patients with high-grade urothelial carcinoma of the bladder?

Immunohistochemistry for keratin has enhanced our ability to detect micrometastases in certain cancer patients with negative lymph nodes by routine histologic examination of H&E-stained sections. However, there is no information about micrometastasis of bladder cancer. We performed immunohistochemistry for keratins on 159 pelvic lymph nodes, which were negative for metastatic tumors on routine H&E-stained sections, from 19 patients with high-grade muscle invasive urothelial bladder cancer. In 1 man, 1 lymph node contained a keratin-positive micrometastasis that was not present on the original H&E-stained slide. However, the metastasis was seen readily on a new H&E-stained section prepared from the paraffin block adjacent to the keratin-stained section. Immunohistochemical analysis for keratins revealed no additional case of micrometastasis of urothelial carcinoma of the bladder. The perinodal fibroadipose tissue of a lymph node from a woman contained a few keratin-positive benign glands of endosalpingiosis. A thorough examination of the H&E-stained sections is the best method for detecting lymph node metastases of urothelial carcinoma from the bladder. There is a potential risk for misdiagnosis of metastases by using immunohistochemistry or polymerase chain reactions for keratins because of the occasional presence of benign epithelial cells in pelvic lymph nodes and associated connective tissue.     

Adenoid cystic carcinoma with dedifferentiation/expansion of the luminal cell component and preserved biphasic morphology – Early high-grade transformation

We present two patients (29 and 67 years) with histomorphologic and immunohistochemical evidence of early high-grade transformation of adenoid cystic carcinoma in the nasal cavity and floor of mouth, respectively. The component of early high-grade transformation was characterized by 1) selective expansion of the luminal (CK7+, c-kit+, p63-) cell component with severe cytologic atypia and significantly increased Ki-67 proliferation index, and 2) retained albeit attenuated abluminal (CK7-, c-kit-, p63+) cells, surrounding nests of high-grade luminal cells.     

Presence of tumor cells in the vagina during surgical treatment could be the source of vaginal recurrence in patients with endometrial carcinoma — A pilot prospective study

BackgroundThe commonest site of recurrence in endometrial cancer (EC) is the vagina, with a rate of 16%. The aim of this study was to determine if vaginal recurrences in EC patients could develop due to contamination of the vagina with glandular tumor cells dropping off on polypoid, large size EC or tumors involving the endocervix, through manipulation of the uterus during surgery.MethodsThis pilot prospective study included 10 consecutive patients with EC, surgically treated with hysterectomy and additional lymphadenectomy according to stage. In every case, 2 proximal vaginal smears were collected before and during the hysterectomy procedure. All smears underwent Papanicolaou staining and the presence of atypical glandular cells in the smears was correlated with clinico-pathological parameters.ResultsResidual tumor was identified on the surgical specimen in the 10 cases; the tumor characteristics were large size (median 6 cm), polypoid type (80%), infiltrating the cervix (70%), and infiltrating more than half of the myometrium (60%). The smears obtained from the vagina showed that five cases (50%) presented tumor cells of glandular type in all smears (before and during the surgery), while in 3 cases (30%) the smears were negative for tumor cells preoperatively, but positive in the perioperative smears.ConclusionsOur results suggest that the vagina is most often contaminated preoperatively due to bleeding; however, the vaginal wound may also be contaminated perioperatively. We propose a change in the surgical procedure, which is easy to perform and inexpensive compared to postsurgical vaginal radiotherapy.     

Is endometrial pre-treatment of value in improving the outcome of transcervical resection of the endometrium?

The aim of this study was to determine whether or not the use of medical pre-treatment of the endometrium improves the outcome of transcervical resection of the endometrium with regards to long-term operative outcome, histological findings and patient satisfaction. A prospective randomized trial comparing three endometrial pre-treatment agents (danazol, medroxyprogesterone acetate or nafarelin) with no pre-treatment was conducted. The main outcome measures were: (i) thickness of the endometrium and myometrium resected; (ii) histological stage of the endometrium at the time of operation; (iii) the presence or absence of menses and (iv) patient satisfaction 1 year post-operatively. Of the three pre-treatments studied, danazol produced a lower median endometrial thickness than the control, showed the greatest ability to induce atrophy of the endometrial glands and stroma (not statistically significant) and produced the highest rate of amenorrhoea (not different to the control). Danazol and nafarelin produced significantly lower median endometrial thickness than no pre-treatment. There were, however, no significant differences in the rates of amenorrhoea in any of the pre-treatment groups compared with that in the control group. No improvement in clinical outcome or patient satisfaction is conferred by the use of medical pre-treatments if transcervical resection of the endometrium is performed in the proliferative phase of the menstrual cycle.     

Expression of angiogenesis-related genes in ovarian carcinoma – A clinicopathologic study

Angiogenic factors play a role in tumor growth and spread. The object of this study was to analyze the correlation between mRNA expression of angiogenesis-related genes and disease outcome in advanced-stage ovarian carcinomas. Sections from 66 primary ovarian carcinomas and metastatic lesions from 41 patients diagnosed with advanced stage ovarian carcinoma (FIGO stages III-IV) were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA In Situ Hybridization (ISH). Patients were divided in two groups based on disease outcome. Long-term survivors (17 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 116 and 133 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Expression of bFGF mRNA, most often intense, was detected in tumor and stromal cells in the majority of cases. Weak expression of IL-8 mRNA was detected in both cell compartments, while VEGF mRNA expression was limited to few cases. Primary tumors displayed higher bFGF and IL-8 mRNA expression. However, these differences did not reach statistical significance (P>0.05). bFGF, IL-8 and VEGF mRNA expression in both tumor and stromal cells was comparable in tumors of long-term and short-term survivors, and showed no correlation with disease outcome in survival analysis (P>0.05). bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma. This revised version was published online in July 2006 with corrections to the Cover Date.     

Gastric-type mucinous carcinoma of the cervix and its precursors – historical overview

The emerging concept of gastric-type mucinous carcinoma (GAS) of the uterine cervix has been accepted worldwide because of its aggressive clinical behaviour and the absence of high-risk human papillomavirus (HPV). GAS is included as a variant of mucinous carcinoma in the 2014 World Health Organization classification, and its recognition has provoked a discussion on endocervical adenocarcinoma as a single entity such that endocervical adenocarcinoma is now divided into HPV-associated and HPV-independent groups. This article reviews historical and conceptual aspects of GAS and its precursors, starting with minimal deviation adenocarcinoma (MDA), through the ensuing confusion, up to the recent paradigm shift in cervical adenocarcinoma subclassification. The gastric immunophenotype of MDA was demonstrated by a Japanese group in 1998 using the HIK1083 antibody, which recognises gastric pyloric gland mucin, and this elucidated the pathogenesis of this particular tumour. However, this information resulted in overdiagnosis of lobular endocervical glandular hyperplasia (LEGH), first described in 1999 and which represents pyloric gland metaplasia (PGM), as malignant. In the early 2000s the relationship between MDA and LEGH/PGM became a matter of controversy. In 2007 HIK1083 immunohistochemistry extended the morphological spectrum of endocervical adenocarcinoma showing gastric differentiation beyond MDA, which resulted in the proposal of GAS as a distinct entity including MDA as its very well-differentiated subtype. GAS is now considered to be an aggressive and chemoresistant neoplasm that is not related to high-risk HPV. The LEGH/PGM–GAS sequence is currently regarded as an HPV-independent pathway of carcinogenesis. Understanding the underlying molecular events in this process is key to the development of biomarkers for early detection and molecular targeted therapy.     

Changes in the expression of syndecan-1 in the colorectal adenoma–carcinoma sequence

 Syndecan-1, a transmembrane heparan sulphate proteoglycan (HSPG), functions as a matrix receptor on the basal surface of epithelial cells. It also co-localizes with E-cadherin at the lateral cell surface where its function is uncertain. Tumour development in the large bowel is associated with loss of normal epithelial adhesion and altered patterns of expression of cell adhesion molecules, possibly including syndecan-1. To evaluate changes in syndecan-1 expression during the development of colorectal neoplasia, 59 adenomas and 20 carcinomas arising from adenomas were investigated by immunohistochemistry. The staining intensity and distribution of syndecan-1 and E-cadherin in sequential sections was examined, semi-quantified and compared. Staining of syndecan-1 and E-cadherin was uniform in normal colorectal epithelial cells, and located at the basolateral surface. No significant change was seen in either molecule in mildly or moderately dysplastic adenomas. A significant reduction in expression of both syndecan-1 and E-cadherin was seen in severely dysplastic epithelium as compared to moderate dysplasia (P=0.001 and P=0.004 respectively). Similarly, there was a significant reduction of both molecules in carcinomas compared with associated adenomas (syndecan-1 P=0.00003; E-cadherin P=0.002). In both cases the loss of syndecan-1 expression was more striking than that of E-cadherin. Previous in vitro studies have shown that epithelial cells made deficient in syndecan-1 cease to express E-cadherin, suggesting a causal association. Our results support these findings and indicate that disruption of cell-matrix adhesion is critical in colorectal carcinogenesis, probably preceding changes in the purely homotypic cell-cell adhesion mediated by E-cadherin. Received: 11 May 1998 / Accepted: 14 September 1998     

Cell adhesion molecules in endometrial cancer – A systematic review

Adhesive molecules are responsible for the cell-cell interaction and the surrounding intercellular environment creating normal tissue architecture. The role of adhesion proteins in cancer refers to angiogenesis, loss of tissue continuity, and deprivation of intercellular contact with the extracellular matrix, promoting the spread of cancer through the formation of metastases. The integrity of the epithelium is disturbed – with disturbances in the whole mechanism of cell connections, thanks to which cancer cells infiltrate surrounding tissues, and move to lymphatic and blood vessels. Adhesive molecules are divided into five main families: cadherin, catenins, integrins, the immunoglobulin superfamily and non-classical adhesion molecules. In the present review we describe the role of all five families of adhesive molecules in endometrial cancer.     

Transmission and clearance of human papillomavirus infection in the oral cavity and its role in oropharyngeal carcinoma – A review

The majority of sexually active individuals becomes infected with human papillomavirus (HPV) at least once in their lifetime. Pathways for HPV transmission vary across different mucosal sites per individual. They include autoinoculation within one host, direct transmission between individuals (including perinatal transmission and transmission during sexual activity), and indirect transmission through contact with hands. The authors aim to clarify the prevalence and route of transmission per anatomic site, inter- and intra-individually, using a narrative review of the literature. In conclusion, transmission of HPV to the oral cavity and oropharynx is hypothesised to occur mainly through sexual contact. Transmission of particles through saliva has not been proven and daily living activities are not a documented source of HPV infection. Oropharyngeal HPV related cancer survivors and their partners do not show increased risk of infection during sexual intercourse. Transmission of HPV to the oral cavity (autoinoculation with fingers or transmission through saliva in deep kissing) is probably of limited importance.     

Cytopathologic diagnosis of bronchioloalveolar carcinoma: does it correlate with the 1999 World Health Organization definition?

We identified 29 bronchial washing, bronchoalveolar lavage, sputum, and fine-needle aspiration specimens with corresponding surgical pathology specimens with features of bronchioloalveolar carcinoma (BAC). Surgical pathology correlates were reclassified according to the 1999 World Health Organization classification into pure BAC, mixed adenocarcinoma-BAC (AD-BAC), and papillary adenocarcinoma (PAP-AD). Twelve cases of invasive pulmonary adenocarcinoma (INV-AD) without a bronchioloalveolar component were reviewed for comparison. The cytology slides were evaluated for 12 features of BAC. No statistically significant feature permitted separation of BAC from AD-BAC or from PAP-AD. However, comparison of BAC with INV-AD identified 9 statistically significant cytologic features: clean background, absence of 3-dimensional clusters, neoplastic cells in flat sheets, orderly arrangement of cells with round uniform nuclei, predominance of mucinous cells, absence of nuclear overlap, absence of irregular nuclear membranes, fine granular chromatin, and nuclear grooves that were features of BAC cases. Although cytologic evaluation cannot prospectively diagnose BAC, the bronchioloalveolar pattern may be recognized and suggests in situ proliferation that is present in BAC, AD-BAC, or PAP-AD. The bronchioloalveolar pattern must be correlated with clinical, radiographic, and histologic parameters to determine whether the tumor is localized, multifocal, or diffuse and whether there is parenchymal invasion.     

Increasing use of cognitive measures in the operational definition of frailty—A systematic review

Ageing is associated both with frailty and cognitive decline. The quest for a unifying approach has led to a new concept: cognitive frailty. This systematic review explores the contribution of cognitive assessment in frailty operationalization.PubMed, Web of Knowledge and PsycINFO were searched until December 2016 using the keywords aged; frail elderly; aged, 80 and over; frailty; diagnosis; risk assessment and classification, yielding 2863 hits. Seventy-nine articles were included, describing 94 frailty instruments. Two instruments were not sufficiently specified and excluded. 46% of the identified frailty instruments included cognition. Of these, 85% were published after 2010, with a significant difference for publication date (X² = 8.45, p < .05), indicating increasing awareness of the contribution of cognitive deficits to functional decline. This review identified 7 methods of cognitive assessment: dementia as co-morbidity; objective cognitive-screening instruments; self-reported; specific signs and symptoms; delirium/clouding of consciousness; non-specific cognitive terms and mixed assessments.Although cognitive assessment has been increasingly integrated in recently published frailty instruments, this has been heterogeneously operationalized. Once the domains most strongly linked to functional decline will have been identified and operationalized, this will be the groundwork for the identification of reversible components, and for the development of preventive interventional strategies.     

Poorly differentiated oxyphilic (Hürthle cell) carcinoma arising in lingual thyroid: a case report and review of the literature

Clinically significant lingual thyroid is an unusual developmental anomaly, and carcinoma arising in lingual thyroid, an extremely rare entity. Here we describe the cytologic, histologic, immunohistochemical, and ultrastructural findings of the first poorly differentiated oxyphilic (Hürthle cell) carcinoma described in lingual thyroid along with a review of the literature. Carcinoma arising in lingual thyroid was reported in 12 males and 21 females age 12 to 86 yr (mean age: 40). Because in nonneoplastic lingual thyroid there exists an intimate and irregular relationship of normal follicles with the surrounding skeletal muscle fibers, unequivocal infiltration, with desmoplastic response, and/or vascular invasion should be demonstrated before making a diagnosis of carcinoma. Immunostain for thyroglobulin is the most useful marker for the differential diagnosis. Although, in some older cases, the precise histologic type is difficult to determine, follicular carcinoma seems to be prevalent. This contrasts with the predominance of the papillary type in thyroglossal duct-associated carcinoma. This fact is probably related to the history of hypothyroidism and compensatory hyperplasia secondary to the absence of the orthotopic gland, like that occurring in areas of endemic goiter.     

Complement in removal of the dead – balancing inflammation

Recognition and removal of apoptotic and necrotic cells must be efficient and highly controlled to avoid excessive inflammation and autoimmune responses to self. The complement system, a crucial part of innate immunity, plays an important role in this process. Thus, apoptotic and necrotic cells are recognized by complement initiators such as C1q, mannose binding lectin, ficolins, and properdin. This triggers complement activation and opsonization of cells with fragments of C3b, which enhances phagocytosis and thus ensures silent removal. Importantly, the process is tightly controlled by the binding of complement inhibitors C4b-binding protein and factor H, which attenuates late steps of complement activation and inflammation. Furthermore, factor H becomes actively internalized by apoptotic cells, where it catalyzes the cleavage of intracellular C3 to C3b. The intracellularly derived C3b additionally opsonizes the cell surface further supporting safe and fast clearance and thereby aids to prevent autoimmunity. Internalized factor H also binds nucleosomes and directs monocytes into production of anti-inflammatory cytokines upon phagocytosis of such complexes. Disturbances in the complement-mediated clearance of dying cells result in persistence of autoantigens and development of autoimmune diseases like systemic lupus erythematosus, and may also be involved in development of age-related macula degeneration.