Histology and histopathology Vol.30, nº9 (2015)
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- PublicationOpen AccessImpact of tumor angiogenic profile on the outcome of patients with metastatic breast carcinoma treated with weekly docetaxel. A Hellenic Cooperative Oncology Group (HeCOG) study(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Kourea, Helen P.; Kotoula, Vassiliki; Koutras, Angelos; Alexopoulou, Zoi; Papaspirou, Irene; Skarlos, Dimosthenis V.; Efstratiou, Ioannis; Bobos, Mattheos; Zagouri, Flora; Papakostas, Pavlos; Pectasides, Dimitrios; Chrisafi, Sofia; Varthalitis, Ioannis; Aravantinos, Gerasimos; Kosmidis, Paris; Bafaloukos, Dimitrios; Scopa, Chrisoula D.; Fountzilas, GeorgeBackground: Metronomic taxane administration has putative antiangiogenic properties. Herein, we examined the baseline tumor angiogenic profile of patients with metastatic breast carcinoma (MBC) in a prospective-retrospective translational research study. The interplay between the angiogenic factors expressed in the tumors and their prognostic value in MBC were investigated. Patients and Methods: Tumor tissues from patients with MBC treated with weekly docetaxel (n=159) were examined by immunohistochemistry for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, VEGFR-3 and osteopontin (OPN) and by mRNA analysis for expression of VEGF-A, VEGFxxxa, VEGFxxxb, VEGFC, thrombospondin-1 (THBS-1), hypoxia-inducible factor-1α (HIF-1α) and von Hippel-Lindau (VHL) genes. Associations between these parameters and outcome were statistically analyzed. Results: Statistically significant correlations were identified between almost all biomarkers examined in continuous form, particularly at the mRNA level: VEGFA with VEGFxxxa (rho=0.70); VEGF-C with VEGFxxxa, VEGFxxxb and VHL (rho=0.51, 0.60 and 0.44 respectively); HIF-1α with VEGF-C and THBS1 (rho=0.48 and 0.45). High VEGF-A mRNA was associated with worse survival (p=0.0279) and marginally with progression free survival (PFS). Intratumoral co-expression of VEGFR-1 and VEGFR-2 proteins was associated with more favorable survival (p=0.0337). In multivariate analysis, only high VEGF-A mRNA levels retained their prognostic role for worse PFS and survival (PFS: HR=2.34, 95% CI=1.25-4.40, p=0.0080; survival: HR=3.15, 95% CI=1.48-6.72, p=0.0029). Conclusions: In MBC, this study confirms the adverse prognostic effect of high intratumoral VEGF-A mRNA and reveals the combined VEGFR-1/VEGFR-2 protein expression as a potentially favorable prognosticator, which merits further evaluation in larger studies.
- PublicationOpen AccessHistological grading in colorectal cancer: new insights and perspectives(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Barresi, Valeria; Bonetti, Luca Reggiani; Leni, Antonio; Caruso, Rosario Alberto; Tuccari, GiovanniPoor histological differentiation is currently considered among the adverse histopathological factors associated with unfavourable clinical course of colorectal carcinoma (CRC). At present, the histological grade of CRC is assessed based on the percentage of glandular differentiation in the tumor according to the World Health Organization (WHO) criteria. However the prognostic value of the WHO grading system is limited by significant inter-observer variability in its assessment. In addition, the prognostic significance of WHO grading seems to depend on the microsatellite instability (MSI) status of the tumor. Finally, this grading does not apply to rarer histotypes of colorectal adenocarcinomas, such as the micropapillary, medullary, mucinous and signet ring cell variants. Recently a novel grading system based on the counting of clusters of five or more cells lacking a glandular structure (poorly differentiated clusters) and set in the tumor stroma or at invasive edge has been proposed in CRC. There is evidence that grading based on poorly differentiated clusters (PDC) is more reproducible and has more robust prognostic significance compared to WHO grading in CRC. In the present review we discuss the morphological features, criteria for the assessment, prognostic significance and correlation with biomolecular profiles of grading based on PDC counting in CRC.
- PublicationOpen AccessFunctional histopathology of keloid disease(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Jumper, N.; Paus, R.; Bayat, A.Keloid disease is a benign, yet locally aggressive and recurrent cutaneous fibroproliferative condition characterised by excessive scarring. Unique to humans, keloids represent the end-point of a spectrum of abnormal wound healing, are aesthetically disfiguring and can cause major functional impairment. Its heterogeneous phenotype can confound clinical diagnosis leading to mismanagement. This review examines the histological morphology of keloid disease relative to the underlying pathobiology, places it in the context of other cutaneous fibroses and highlights gaps within the literature that hinder differential diagnosis. The pathological similarity to hypertrophic scarring, dermatofibrosarcoma protuberans, dermatofibroma and scleroderma emphasise the importance of detailing the architectural and cellular components of this unique entity. In the papillary dermis keloid tumours show a tongue-like advancing edge that resembles invasive tumour growth. A thickened but flattened epidermis, hyalinised haphazardly arranged collagen bundles that dominate the dermis with subsequent obliteration of the papillary-reticular boundary along with displacement and eventually destruction of skin appendages, exemplify additional hallmark findings associated with keloid disease. Compared to healthy skin, keloid scars show an increased type I/III collagen ratio, decreased fibrillin-1 and decorin expression, increased dermal cellularity and increased expression of fibronectin, versican, elastin and tenascin in the reticular dermis and hyaluronan and osteopontin in the epidermis. We illustrate these “pathognomonic” features of keloid disease by representative micrographs and discuss them in the context of inflammation, hypoxia and tension - as key elements of keloid disease. Finally, we highlight deficits within the keloid research literature as well as discuss important areas for future research in keloid histology.
- PublicationOpen AccessThe influence of immunosuppressants on the morphology, proliferating cell nuclear antigen (PCNA) and apoptosis in the rat ventral prostate(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Grabowska, Marta; Słuczanowska-Głąbowska, Sylwia; Kram, Andrzej; Teresiński, Leszek; Piasecka, Małgorzat; Podhorska-Okołów, Marzenna; Rotter, Iwona; Kędzierska, Karolina; Sporniak-Tutak, Katarzyna; Ciechanowski, Kazimierz; Laszczyńska, MariaAim: Analysis of the impact of immunosuppressants on apoptosis and PCNA in the rat ventral prostate. Method: The studies were performed on 48 male Wistar rats. The animals were divided into a control group and 7 experimental groups. For 6 months, the rats were administered drugs such as: rapamycin (Rapa), cyclosporin A (CsA), tacrolimus (Tac), mycophenolate mofetil (MMF) and glucocorticosteroids (GS). During section of the rats, prostate ventral lobes were obtained. Morphological evaluation (HE, PAS), TUNEL assay, PCNA expression analysis and quantitative image computer analysis were performed. Results: The highest percentage of apoptosis in epithelial cells was observed in groups which received two combinations of drugs: (V) CsA, MMF, GS and (VII) Tac, MMF, GS. A much lower percentage of apoptotic epithelial cells was found in the groups where the treatment schemes included rapamycin throughout the duration of the study. Interestingly, the conversion of the treatment to rapamycin caused a significant reduction of apoptosis in epithelial cells as well as in proliferation in both epithelial and stromal cells. Conclusions: On one hand, the obtained results may explain the anticancer activity of rapamycin in reducing the proliferation of epithelial cells, and on the other hand the adverse effect of rapamycin in the form of reduced regeneration of these cells. Taking into account the prostate in isolation from other organs/systems, the dosage scheme with Rapa, Tac and GS would appear to be the most favorable, due to the smallest morphological changes.
- PublicationOpen AccessImmunohistochemical localization of LLC1 in human tissues and its limited expression in non-small cell lung cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Chandra, Vishal; Choi, Yong-Bock; Hwang, Hai-Li; Lee, Jeong-Hwa; Park, Seong-Yeol; Kim, Hyun-Kyoung; Poojan, Shiv; Koh, Jae-Soo; Kim, Han-Seong; Hong, Kyeong-ManWe have shown both LLC1 expression in the lung epithelium by in situ hybridization and its inactivation in lung cancer by epigenetic modification. However, LLC1 protein’s cellular localization or its role in normal lung or cancer tissues has not yet been evaluated. In the present study, a monoclonal antibody against recombinant LLC1 was produced, and immunohistochemical staining was performed on arrays including various human tissues, normal lung and nonsmall cell lung cancer (NSCLC) tissues for LLC1 localization. The immunohistochemical results showed LLC1 expression in the cilia of normal-airway epithelial cells and in the cytoplasm of type II pneumocytes in bronchiectatic patients, but no expression in most of the NSCLC tissues, which is consistent with our previous report positing LLC1 as a tumor suppressor. However, LLC1 over-expression in NSCLC cell lines NCI-H1299 and NCI-H23 did not show any change in proliferation or migration, which does not indicate any LLC1 tumorsuppressor role. As for the other human tissues, LLC1 was localized in renal tubular cells, pancreatic acinar cells, and epithelial cells of the stomach, duodenum, and gallbladder. In summary, our findings suggest that LLC1 is not a tumor suppressor, and that it is localized in the cilia of the normal lung epithelium but is absent in most NSCLC cases, probably due to the loss of cilia during lung carcinogenesis.
- PublicationOpen AccessHyaluronic acid injections protect patellar tendon from detraining-associated damage(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Frizziero, Antonio; Salamanna, Francesca; Giavaresi, Gianluca; Ferrari, Andrea; Martini, Lucia; Marini, Marina; Veicsteinas, Arsenio; Maffulli, Nicola; Masiero, Stefano; Fini, MilenaIntroduction: Having previously demonstrated that detraining affects patellar tendon (PT) proteoglycan content and collagen fiber organization, we undertook the present study with two aims: to improve knowledge on the adaptation of PT and its enthesis to detraining from a histological and histomorphometric point of view, and to investigate the hypothesis that repeated peri-patellar injections of hyaluronic acid (HA) on detrained PT may reduce and limit detrained associated-damage. Methods: Twenty-four male Sprague-Dawley rats were divided into 3 groups: Untrained (n=6), Trained (n=6) (10 wks-treadmill) and Detrained (n=12). In the detrained rats, the left tendon was untreated while the right tendon received repeated peri-patellar injections of either HA or saline (NaCl). Structure and morphology of PTs (modified Movin score, tear density, collagen type I and III) and enthesis (cell morphology, chondrocyte cluster formation, tidemark integrity, matrix staining and vascularization) were evaluated. Results: The left PT and enthesis of the Detrained groups showed altered structure and morphology with the highest Movin score values, the highest percentage of collagen III and the lowest of collagen I; the lowest score values were observed in the Trained and Detrained-HA groups. Detrained-NaCl PTs showed the highest collagen III and the lowest collagen I values with respect to Detrained-HA PTs. Conclusion: This study strengthens previously published data showing the alteration in tendon and enthesis morphology due to discontinuation of training, and provides new data showing that treatment with HA is effective in the maintenance of the structural properties of PT and enthesis in Detrained rats. Such beneficial effects could play a significant role in the management of conservative and rehabilitation strategies in athletes that change type, intensity and duration of training.
- PublicationOpen AccessHistopathological findings in the peritumoral edema area of human glioma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Wang, Xingfu; Liu, Xueyong; Chen, Yupeng; Lin, Guoshi; Mei, Wenzhong; Chen, Jianwu; Liu, Ying; Lin, Zhixiong; Zhang, ShengPeritumoral brain edema (PTBE) is considered to be one of the main biological behaviors of brain glioma. However, the histopathological features of PTBE remain imprecisely defined. We analyzed the histopathological characteristics in the PTBE area of 22 cases of glioma. Microscopically, the pre-existing basic structure in the edema area was still preserved but there were varying degrees of loose tissue. The main components of the edema tissue were scattered invasive tumor cells, reactive cells, and various blood vessel patterns. Invasive tumor cell density was significantly higher in high-grade glioma than in low-grade glioma, and the density was significantly higher in the area near compared to the area far from the glioma. The Ki-67 proliferative index of the invasive tumor cells was higher in high-grade glioma than in low-grade glioma, but the index was not different in the area near compared to the area far from the glioma. The microvessel pattern in PTBE was primarily branching capillary. The microvessel densities (MVDs) of CD34+ and CD105+ were higher in high-grade glioma and the area near the glioma than in low-grade glioma and the area far from the glioma. Compared to CD34+, the MVD of CD105+ exhibited a more significant downward trend in terms of distance from the glioma. The most obvious types of reactive cells were reactive astrocytes and activated microglia. The reactive astrocytes were positive for nestin. The activated microglia emerged in the area near the glioma in most cases and in the area far from the glioma in more than half of the cases. In addition, several cases displayed focal collections of small lymphocytes around small blood vessels and tumor cells arranged around a neuronal cell, and a limited number of cases displayed giant dysmorphic neurons in an edematous cortex. Our data indicate that PTBE is a consequence of tissue reconstruction resulting from tumor cell invasion and is an appropriate niche for the growth and spread of glioma cells.
- PublicationOpen AccessDiameter of involved nerves is a valuable prognostic factor for gastric cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Zhou, Zhi-hua; Zhang, Jian-dong; Zhao, Hai-Bin; Wu, Yao-yiThe prognostic role of perineural invasion (PNI) in gastric cancer remains unclear. We hypothesized that the diameter of the tumor-involved nerves might be a useful indicator for prognosis. By labeling nerves and cancer cells in 204 cases of gastric cancer with single or double immunochemistry, we found that 146 cases were PNI positive and that 58 were PNI negative. For each case with PNI, the maximum diameter of the involved nerve was measured microscopically. Then, we correlated this parameter with the patients’ 5-year overall survival, and receiver operating curves were used to determine the cutoff value. We found that the optimal cutoff value for predicting 5-year survival was 65 µm (sensitivity 76.9%, specificity 70.0%). Next, all 204 patients were classified into two groups as follows: Group A, PNI-positive cases in which the largest involved nerves were ≥65 µm in diameter (110 cases); Group B, PNI-positive cases in which the largest involved nerves were <65 µm and all PNI-negative cases (94 cases). Compared with Group A, Group B had a better 5-year survival (74.5% vs 27.3%) and a better 5-year disease-free survival (63.8% vs 23.6%). Multivariate analysis suggested that a ≥65 µm maximum diameter of the involved nerves was an independent risk factor for both recurrence (P<0.001) and gastric cancer-related death (P<0.001) within 5 years. However, if all patients were classified simply based on whether PNI existed (regardless of the nerve size), this did not provide more information than traditional clinicopathological variables. In conclusion, the presence of cancer-involved nerves with a diameter ≥65 µm was a valuable prognostic factor for gastric cancer.
- PublicationOpen AccessLymphovascular invasion: assessment and prognostic impact in melanoma and breast cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Thompson, Nicola; Storr, Sarah; Zhang, Siwei; Martin, StewartThe presence of lymphovascular invasion is a recognised poor prognostic factor in a wide range of tumour types. Vascular invasion was historically identified through haematoxylin and eosin staining, however this technique is non-specific and differentiates poorly between blood and lymphatic vessels. Newer techniques using immunohistochemistry allow more sensitive and specific identification of lymphovascular invasion and are able to accurately differentiate between lymphatic and blood vessels. This review will discuss the current methods available for the assessment of lymphovascular invasion. Additionally, it will focus on the role of lymphovascular invasion in breast cancer and melanoma, discussing the relative importance of lymphatic and blood vessel invasion in each tumour type.
- PublicationOpen AccessHepatic myofibroblasts and fibrogenic progression of chronic liver diseases(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Novo, Erica; Cannito, Stefania; Morello, Elisabetta; Paternostro, Claudia; Bocca, Claudia; Miglietta, Antonella; Parola, MaurizioLiver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process that during the course of a chronic liver disease (CLD) leads progressively to an excess deposition of extracellular matrix (ECM) components in an attempt to limit the consequences of chronic parenchymal injury. Irrespective of etiology, liver fibrogenesis is sustained and modulated by an intense cross talk occurring between different hepatic cell populations that involves the synthesis and release of several mediators, including growth factors, cytokines, chemokines, reactive oxygen species, adipokines, vasoactive agents and plasma proteins. In this scenario a major pro-fibrogenic role is played by a heterogeneous population of α-smooth muscle actin (α-SMA) positive cells defined as hepatic myofibroblasts (MFs). Hepatic MFs are highly proliferative and contractile cells, primarily responsible for excess deposition of ECM components and involved in ECM altered remodeling observed in CLDs. MFs also represent a unique and critical cellular crossroad able to integrate incoming paracrine or autocrine signals, released from all hepatic cell populations involved or available in the microenvironment, as well as to synthetize and release mediators which sustain and perpetuate fibrogenesis, chronic inflammatory response and neo-angiogenesis. This review has been designed to offer critical knowledge on hepatic MFs, including terminology, essential definitions and characterization of MFs, with a focus on the origin of these cells (mainly from hepatic stellate cells and portal fibroblasts or, to a lesser extent, bone marrow-derived cells), the process of activation and the functional responses that these cells can operate in the fibrogenic progression of CLDs.
- PublicationOpen AccessImmunohistochemical changes and atrophy after chronic ethanol intoxication in rat salivary glands(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Fernandes, Luanna Melo Pereira; Teixeira, Francisco Bruno; Junior, Sergio Melo Alves; Pinheiro, João de Jesus Viana; Maia, Cristiane Socorro Ferraz; Lima, Rafael RodriguesAlcoholism in humans is a chronic and progressive disease, characterized by loss of ethanol consumption control. Previous studies have reported that prolonged exposure to ethanol was responsible for alterations in glandular tissues of human and rodents. However, the interrelationship between ethanol and the glandular system is still the subject of numerous investigations, including the possible resistance of the submandibular gland (SG). In the present study, we investigated whether chronic ethanol exposure during adolescence may affect the parotid gland (PG) and SG in female rats. Female rats (n=16) were treated with distilled water or ethanol (dose of 6.5 g/kg/day, 22.5% w/v) through gavage for 55 days. Glands were collected, weighed and submitted to histological processing. Morphometric analysis was assessed by parenchymal and stromal area measurements. Smooth muscle actin (α-SMA), cytokeratin-19 (CK19) and apoptotic caspase3 (CAS) were measured using ImageJ® software. Chronic ethanol administration did not alter the body weight of rats after treatment, although it increased glandular weight (p<0.001), reduced the parenchyma area (p<0.001) and decreased CK19 and α-SMA immunostainning in the PG. Besides, ethanol induced CK19 and CAS overexpression, and the occurrence of duct-like structures in SG. These results suggest that ethanol induces histological and morphometric changes in salivary glands of female rats intoxicated with ethanol during adolescence. Furthermore, the mechanism underlying these alterations needs to be investigated but may be not related to the inflammatory process.