WHO classification of tumors of the nervous system (2007) [8]
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"3128",leadTitle:null,fullTitle:"Tribology - Fundamentals and Advancements",title:"Tribology",subtitle:"Fundamentals and Advancements",reviewType:"peer-reviewed",abstract:"As the subject of tribology comprises lubrication, friction and wear of contact components highly relevant to practical applications, it challenges scientists from chemistry, physics and materials engineering around the world on todays sophisticated experimental and theoretical foundation to complex interdisciplinary research. Recent results and developments are preferably presented and evaluated in the context of established knowledge. Consisting of eleven chapters divided into the four parts of Lubrication and Properties of Lubricants, Boundary Lubrication Applications, Testing and Modeling, and Sustainability of Tribosystems, this textbook therefore merges basic concepts with new findings and approaches. Tribology Fundamentals and Advancements, supported by competent authors, aims to convey current research trends in the light of the state of the art to students, scientists and practitioners and help them solve their problems.",isbn:null,printIsbn:"978-953-51-1135-1",pdfIsbn:"978-953-51-6342-8",doi:"10.5772/3427",price:139,priceEur:155,priceUsd:179,slug:"tribology-fundamentals-and-advancements",numberOfPages:332,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"77f3ee5568b737c8d26a5eee991c9d34",bookSignature:"Jürgen Gegner",publishedDate:"May 22nd 2013",coverURL:"https://cdn.intechopen.com/books/images_new/3128.jpg",numberOfDownloads:50495,numberOfWosCitations:135,numberOfCrossrefCitations:71,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:194,numberOfDimensionsCitationsByBook:8,hasAltmetrics:1,numberOfTotalCitations:400,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 20th 2012",dateEndSecondStepPublish:"April 10th 2012",dateEndThirdStepPublish:"September 25th 2012",dateEndFourthStepPublish:"October 29th 2012",dateEndFifthStepPublish:"February 17th 2013",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"40520",title:"Dr.",name:"Jürgen",middleName:null,surname:"Gegner",slug:"jurgen-gegner",fullName:"Jürgen Gegner",profilePictureURL:"https://mts.intechopen.com/storage/users/40520/images/system/40520.jpg",biography:"Prof. Jürgen Gegner studied Physics at the University of Erlangen-Nuremberg and completed his first degree (“Dipl.-Phys.”) in 1989 with a diploma thesis on deuteron-deuteron scattering. He graduated his doctoral studies in Materials Science (“Dr. rer. nat.”) at the University of Stuttgart, where he defended his dissertation on interfacial oxygen segregation in 1994 at the Max Planck Institute for Metals Research. After postdoctoral research on ceramics and aluminum alloys at the Max Planck Institute for Microstructure Physics in Halle and the Institute of Applied Mechanics at the University of Erlangen-Nuremberg, respectively, he joined the Loctite Global Engineering Center at Garching near Munich in 1999 as Senior Engineer. Since 2000 he has been working for SKF in Schweinfurt, from 2005 as manager of the Material Physics laboratory. He defended his postdoctoral degree in Materials Science (venia legendi, “Dr. rer. nat. habil.”) with a habilitation thesis on solid state diffusion and a lecture on adhesive bonding at the University of Siegen in 2005, where he was promoted to Adjunct Professor in 2012. 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\r\n\tThe field of pediatric oral health management is ever-evolving; with humble beginnings in providing basic requirements of oral health, the all-encompassing field is directed towards comprehensive skill sets, including preventive and corrective dentistry.
\r\n\tThe emphasis is on developing or modifying the available oral health diagnosis and preventive and corrective methods for children starting from newborn to pre-schoolers to school going and up to adolescence.
\r\n\tProfessionals involved in providing oral health care to children must keep themselves updated with the available and newer behaviour management and dental procedures and techniques that may begin with the first dental visit of the child write up to providing preventive and comprehensive treatment to the child and develop long-lasting good oral health habits.
\r\n\tThis book will provide an opportunity for various health professionals to share their expertise which may vary from providing various forms of oral health procedures to children at an individual and community level.
Pathological classification of brain tumors is the corner stone upon which the management plan and treatment strategy depends. It is the pathologist who defines the “target” at which the rest of the clinical team members aim their “weapons”. Despite of the great advancement of the ancillary studies, the simple H&E stained slide remains an invaluable mean in the diagnosis, classification and stratification of primary brain tumors. Slides should be interpreted in correlation with patient’s age and clinical presentation. Radiological findings substitute the macroscopic/gross description in other organs and assessment of the location (supratentorial, infratentorial, intra-ventricular), growth pattern (circumscribed versus infiltrative, solid versus cystic), enhancement pattern (non-enhancing versus enhancing), and the presence or absence of edema, necrosis, calcification should all be consolidated with the microscopic findings in formulating the final diagnosis. The need for an expert neuropathologist is becoming crucial in reviewing the cases before commencing on treatment [1-3]. The importance of multidisciplinary clinics/teams cannot be overemphasized and neuropathologist plays a central role in these clinics [4, 5]. In less developed countries, telemedicine and twinning programs as well as affiliation with recognized international experts may offer an accessible and relatively affordable tool which can help narrowing the knowledge and practice gaps, thus providing patients in these countries with better standards of care [6, 7].
This chapter aims at providing a concise yet comprehensive description of the histology of the most common neuroepithelial primary central nervous system tumors, based on the most recent pathological classification of tumors of the CNS; 2007 WHO Classification of Tumours of the CNS [8]. The morphological features as well as the most useful immunohistochemical stains that can be used to support the diagnosis will be provided. In primary brain tumor there is a considerable overlap in diagnostic features and morphological criteria that are used to grade the tumor, which although is not the primary intention of this chapter, will be alluded to briefly for sake of completeness.
Primary brain tumors are divided into 2 major groups, neuroepithelial and non-neuroepithelial tumors. Table-1.
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tGanglioglioma and gangliocytoma | \n\t\t\t\n\t\t\t\t | \n\t\t
Pilocytic astrocytoma | \n\t\t\tDesmoplastic infantile ganglioglioma/astrocytoma | \n\t\t\tBenign Meningioma variants | \n\t\t
Pilomyxoid astrocytoma | \n\t\t\tDysembryoplastic neuroectodermal tumor | \n\t\t\tAtypical | \n\t\t
Pleomorphic astrocytoma | \n\t\t\tCentral neurocytoma | \n\t\t\tClear cell | \n\t\t
Sub-ependymal giant cell astrocytoma | \n\t\t\tExtra-ventricular neurocytoma | \n\t\t\tChordoid | \n\t\t
Fibrillary astrocytoma | \n\t\t\tCerebellar liponeurocytoma | \n\t\t\tAnaplastic | \n\t\t
Anaplastic astrocytoma | \n\t\t\tPapillary glio-neuronal tumor | \n\t\t\tPapillary | \n\t\t
Glioblastoma | \n\t\t\tRosette forming tumor of the 4th ventricle | \n\t\t\tRhabdoid | \n\t\t
Gliomatosis Cerebri | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tChoroid plexus papilloma | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tAtypical choroid plexus papilloma | \n\t\t\tHemangioblastoma | \n\t\t
\n\t\t\t\t | \n\t\t\tChoroid plexus carcinoma | \n\t\t\t\n\t\t\t\t | \n\t\t
Myxo-papillary ependymoma | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Sub-ependymoma | \n\t\t\tPineocytoma | \n\t\t\t\n\t\t\t\t | \n\t\t
Cellular ependymoma | \n\t\t\tPineal parenchymal tumor of intermediate differentiation | \n\t\t\t\n\t\t\t\t | \n\t\t
Clear cell ependymoma | \n\t\t\tPineoblastoma | \n\t\t\t\n\t\t |
Tanycytic ependymoma | \n\t\t\tPapillary tumor of the pineal region | \n\t\t\t\n\t\t |
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t |
Medulloblastoma | \n\t\t\tAngiocentric glioma | \n\t\t\t\n\t\t |
CNS- primitive neuroectodermal tumor | \n\t\t\tChordoid glioma of the 3rd ventricle | \n\t\t\t\n\t\t |
Atypical teratoid rhabdoid tumor | \n\t\t\tAstroblastoma | \n\t\t\t\n\t\t |
WHO classification of tumors of the nervous system (2007) [8]
Cribriform Neuroepithelial Tumor (CRINET); This tumor is a recently described neuroepithail tumor and is not part of the WHO classification of primary brain tumors.
This is by far the most common group of central nervous system tumors, both in adults and pediatrics. They are thought to originate from the brain framework cells; the glial cells. This group is divided into several tumor families which are further divided into entities, patterns and variants based on the presumed cell of origin and the growth pattern.
Pilocytic astrocytoma (PA)/pilomyxoid astrocytoma(PMA)
Pilocytic astrocytoma (PA) is assumed to arise from reactive astrocytes [9], this tumor predominates in children in the first decade of life and is the prototype of circumscribed tumors. It typically involves midline structures most commonly the cerebellum followed by optic pathway, hypothalamus, basal ganglion and thalamus but can occasionally arise elsewhere. The morphological features are at large similar regardless of the site of origin with one exception; the optic pathway glioma. Typically this is a biphasic tumor with compact and microcystic areas, the proportion of which may vary from one tumor to the other. Proliferation of bipolar spindle “piloid” cells with long fibrillary processes is seen mostly within the compact areas “Figure 1”.
There is proliferation of piloid cells with elongated cytoplasmic processes. Rosenthal fibers are acidophilic processes seen in these areas (arrow).
The microcystic areas, on the other hand show protoplasmic-like astrocytes with multi-polar short cytoplasmic processes and small cell body with round to oval bland nuclei “Figure 2”.
The microsystic areas are composed of proliferation of protoplasmic astrocytes. Eosinophilic granular bodies are seen in these areas (red arrow). Multinucleated giant cells are somtimes seen in pilocytic astrocytoma (black arrow).
Areas with oligodendroglial like proliferation can be encountered, especially in the posterior fossa tumors. Various forms of vascular proliferation can be seen including reactive vascular proliferation, vessels with hyalinized walls and granulation tissue like vessels, none of which carries a prognostic significance. Conspicuous pleomorphic cells, some of which appear multinucleated can be seen focally within tumor and are not associated with unfavorable outcome. Rosenthal fibers which correspond to thick, tortuous bright acidophilic cytoplasmic processes of variable length are seen mostly in the compact areas, while eosinophilic granular bodies predominate in the microcystic foci, both of which representing products of degeneration [9]. Calcifications with psammoma like spherules, perivascular inflammatory infiltrate and hemosiderin-laden macrophages are detected in few tumors. Scattered mitotic figures and foci of infarction-type necrosis can be identified in anotherwise typical pilocytic astrocytoma. However; unlike fibrillary astrocytoma neither of these features warrant a higher grade diagnosis [10]. Areas with diffusely infiltrative growth pattern with entrapment of normal ganglion producing the “trapped neuron” appearance, can be seen in some tumors. In addition; infiltration into the overlying leptomeninges can sometimes be encountered [9].
Cases that exhibited anaplastic features and persued a more malignant behavior are reported in the literature, especially but not exclusively following radiotherapy [11]. The presence of increased mitotic activity per high power field, hypercellularity, endothelial proliferation and/or palisading necrosis should alert the pathologist to such a possibility. The diagnosis of “anaplastic pilocytic astrocytoma” is the term proposed by the WHO book for such tumors [8, 9]. Atypical pilocytic astrocytoma is, on the other hand assigned to few tumors that display few mitotic figures in conjunction with hypercellularity and marked nuclear atypia [8, 11].
Tumor cells are typically reactive with glial fibrillary acidic protein (GFAP) and vimentin. Reactivity for synaptphysin but not other neuronal markers is seen in some cases [10]. Neurofilament protein (NFP) highlights occasional axons in the background or can be totally negative thus is helpful in confirming the circumscribed nature of the tumor. Rosenthal fibers are reactive for GFAP but not NFP in support of their origin from astrocytic processes. This typically takes the form of positivity at the periphery of the fiber, with negative central core. In Masson Trichrome special stain they appear bright red. Eosinophilic granular bodies (EGBs) on the other hand are positive for PAS diastase, which highlights their variably-sized granular appearance. Pilocytic astrocytomas are typically negative for P53 and EGFR, an important differentiating point from low and high grade diffuse astrocytoma; respectively [10, 12]. MIB-1 labeling index is variable and can range from 1-8% [10, 13], and this does not seem to be associated with prognosis [14]. BRAF immunostain has been recently described in some cases. However; this is not helpful in determining BRAF duplication [10], the genetic signature of pilocytic astrocytoma.
Pilomyxoid astrocytoma (PMA) is a distinctive tumor that occurs mostly in infants in the hypothalamic/ supra-sellar region. As the name implies this tumor manifests prominent myxoid stroma that can be highlighted with alcian blue stain and a monomorphic piloid astrocytes that arrange themselves in a distinct perivascular growth pattern with sun-ray like orientation “Figure 3”.
Distinct perivascular pseudorosette is seen in this case of pilomyxoid astrocytoma.
Few mitotic figures can be detected. Unlike pilocytic astrocytoma, there is no biphasic growth pattern, Rosenthal fibers or eosinophilic granular bodies and infiltration into adjacent brain parenchyma is more prominent [15]. Interestingly; some PMA cases have matured into pilocytic astrocytoma following several recurrences [16], suggesting a close relation between both tumors. The tumor cells demonstrate strong and diffuse positivity for GFAP and vimentin and focal positivity for synaptophysin. Neurofilament protein highlights the limited infiltration into adjacent parenchyma [17]. MIB-1 labeling index is around 5%, although higher figures would still be compatible with the diagnosis.
Pleomorphic xantho-astrocytoma (PXA)
PXA is a superficially located tumor with close relation to the meninges that predominates in the temporal lobe. It occurs in children and young adults with history of epilepsy [18]. Morphologically it is a composite tumor with a variegated appearance in which spindle cells closely intermingle with small and large mononuclear and multinucleated bizarre tumor giant cells with acidophilic cytoplasm “Figure 4”. Intra-nuclear cytoplasmic pseudo-inclusions are frequently seen in the giant cells. Cytoplasmic lipidization in the form of intra-cytoplasmic droplets that occupy much of the cytoplasm and displace the organelles and glial filaments to the periphery is seen in tumor cells scattered through the tumor, hence the “xantho” prefix.
Multinucleated tumor giant cells are seen (right lower) admixed with cells with intracytplasmic fine lipid droplets (arrow).
These lipidized cells can be prominent or alternatively can only be scattered through out the tumor substance. Oil-red O confirms the intra-cytoplasmic lipid content on fresh material. An infiltrating astrocytoma pattern is seen at the deeper aspect of the tumor and this does not affect the outcome [19]. Invasion of the overlying meninges can be encountered in some tumors, creating resemblance with meningioma. Striking positivity for reticulin stain with fibers surrounding groups of cells or individual cells is seen in many tumors; probably representing a reaction to infiltration of the meninges. The blood vessels show peri-vascular lymphoplasmacytic infiltration. Eosinophilic granular bodies, but not Rosenthal fibers can be seen scattered within the tumor substance. Despite of this alarming appearance mitotic figures are not seen and necrosis is at best focal; important discriminating features from giant cell glioblastoma [20]. GFAP labels the tumor cells including the giant cells, and is displaced to the periphery in lipidized cells. Positivity for synaptophysin, NFP and CD34 in tumor cells has been noted in some cases, rendering separation from ganglioglioma difficult [18, 20]. PXA with anaplasia is reserved for tumors showing no or rare degeneration, increased mitoses ≥5 MF/10HPFs and atypical mitoses [14]. MIB-1 and P53 are not helpful in predicting more aggressive tumors, i.e. PXA with anaplasia [21].
Sub-ependymal giant cell astrocytoma (SEGA)
This intra-ventricular tumor is typically associated with tuberous sclerosis complex. It exhibits proliferation of three cell types; large gemistocytes -like cells with perivascular pseudorosette pattern, long spindle fibrillary astrocytes arranged in broad fascicles and giant cells, some with ganglioid appearance “Figure 5”.
Calcification is noted in some cases and can be prominent in long standing ones [22]. Various combinations of glial and neuronal markers are reported in different cell population. Co-expression of GFAP, neuron-specific enolase (NSE) and synaptophysin is noted in tumor cells, including the spindle cells, while NFP is usually positive in ganglioid cells only. Mitosis, vascular proliferation and necrosis do not seem to affect the prognosis [23, 24].
This intraventricular tumor shows admixture of large gemistocytic-like cells, ganglioid cells and spindle cells in a fibrillary background.
This group of tumors is composed of proliferation of astrocytes that diffusely infiltrate pre-existing brain parenchyma, thus precluding successful attempts at complete excision and cure. In addition; there is a natural tendency for progression and transformation from lower into high grades. On a rising scale of malignacy these tumors are divided into the following entities:
Fibrillary astrocytoma (FA,
FA is at the lower end of the malignancy scale, and can raise diagnostic difficulties with reactive gliosis on one hand and circumscribed low grade astrocytoma on the other. Morphologically there is proliferation of “well-differentiated“ fibrillary astrocytes with elongated, irregular and hyperchromatic nuclei exhbiting angulated contours with many coma-shaped forms that lack nucleoli “Figure 6”.
Fibrillary astrocytoma with mild increase in cellularity with scattered dark, elongated and minimally irregular nuclei (arrow).
Thin cytoplasmic process originate from the cytoplasm and form the mesh-like fibrillary background. Morphological variation include the proliferation of gemistocytic and protoplasmic astrocytes. Gemistocytes contain a globular acidophilic cytoplasm with distinct membranous accentuation, eccentric irregular nuclei and thick cytoplasmic processes. Protoplasmic astrocytes on the other hand show multi-polar cytoplasmic processes and grow in a myxoid background, forming microcysts [25]. Features of anaplasia are lacking and mitoses are generally not detected [25, 26]. GFAP positivity is seen both as haphazardly crossing processes in which “naked” tumor nuclei are enmeshed, and as dense cytoplasmic rim positivity surrouding the nuclei. Gemistocytes demonstrate diffuse cytoplasmic GFAP positivity with membranous accentuation; an important discriminating point from mini-gemistocytes seen in oligodendroglioma (see below). To support the infiltrating astrocytoma diagnosis NFP, P53 and IDH1 can be used. Neurofilament protein is useful to highlight the the infiltrative growth pattern “Figure 7”.
Neurofilament protein immunostain highlights the neuronal processes, with negative tumor cells in between confirming the infiltrative nature of the tumor.
P53 may be strongly positive in tumor cell nuclei versus the negative/ minimal staining in gliosis. [27]. Recently; IDH1 antibody is reported to be positive in all infiltrating gliomas (astrocytoma, oligodendroglioma and mixed oligo-astrocytoma) with granular cytoplasmic reactivity pattern [20, 28].MIB-1 labeling index is low, although the cut-off value is not exactly determined (see below) [29].
A recently described morphological pattern is the “glioneuronal tumor with neuropil-like islands”, in which nodules of well differentiated neurocytic cells are embedded within and surround acellular synaptophysin-positive neuropil islands. These are seen focally in what is an otherwise typical infiltrating astrocytoma of either fibrillary or anaplastic types [15]. There is a relative abrupt transition between both components [30]. In these islands the cells are positive for synaptophysin and NeuN, while the neuropil in the background displays granular positivity for synaptophysin [17].
Anaplastic astrocytoma (AA)
AA occupies an intermediate position between fibrillary astrocytoma and glioblastoma. Features of anaplasia include higher cellularity, greater degree of pleomorphism and increased proliferation. The exact number of mitotic figures needed to separate this from FA is still debatable and this feature should be evaluated in relation to the amount of tissue sample examined. While the presence of a single mitotic figure in a small stereotactic biopsy justifies assigning grade III to a tumor, the presence of a single mitotic figure in an ample biopsy after careful searching and deeper sections might not be as relevant. In one study; >3MF/10HPFs was the cut-off value proposed [27]. Ancillary studies might help in defining the proliferative activity of a tumor and can be used to support the diagnosis of AA. Although cut-off values are variable an elevated MIB-1 labeling index (>9%) and proliferative activity as measured by PHH3 mitotic index (>4per 1000 cells) were found to be supportive of AA diagnosis over FA, in which MIB-1 and PHH3 labeling indices were low (≤ 9% and ≤4 per 1000 cells) [27]. In addition; MIB-1 labeling index prognostic value independent from histologic grade was reported [14], which might be indicative of an early anaplastic transformation [31], even in the absence of detectable mitoses.
Glioblastoma (GBM)
This is the most malignant and unfortunately the single most common primary brain tumor. The essential features for the diagnosis of GBM are microvascular proliferation (MVP) and/or necrosis whether palisading or not. Microvascular proliferation is loosely defined to include endothelial hypertrophy, endothelial hyperplasia and glomeruloid vessels, in which multilayered tufts of proliferating endothelium are accompanied by smooth muscles and pericytes“Figure 8” [32].
Microvascular proliferation with glomeruloid growth pattern.
As the original name implies glioblastoma “multiforme” is characterized by heterogeneous cell population with proliferation of fibrillary, gemistocytic and scattered tumor giant cells “Figure 9”.
A case of GBM with large cells with abundant acidophilic cytoplasm at the upper left corner, and with intra-nuclear inclusion seen in a single giant tumor cell. The lower right filed is composed of smaller cells. Note multiple mitoses (arrows).
On the basis of their origin GBM is divided into primary (type II) and secondary (type I) types. Primary GBM is a tumor of elderly patients, is characterized by short presenting history and it arises de-novo with no detectable pre-existing lower grade tumor. Secondary GBM on the other hand affects younger patients with prolonged history and is typically preceded by a lower grade astrocytoma. Prognosis seems to be better for the secondary tumors. Whether a tumor is primary or secondary GBM cannot be predicted on basis of morphologic features. However; the presence of large vessel thrombosis with large areas of infarction-like necrosis seems to be more prevalent in primary GBM. Immunohistochemically; reactivity for P53, MGMT and IDH1 is more frequent in secondary GBM, while positivity for EGFR is more common in primary GBM [32].
Several GBM variants and patterns are described some of which might be prognostically relevant, Table-2.
Giant cell glioblastoma (GCG)
GCG accounts approximately for 1.5- 5% of GMB cases [32]. This is characterized by the predominance of bizarre markedly enlarged, often multinucleated tumor giant cells that tend to grow in cohesive pattern with rich reticulin-positive stroma, accounting for the deceptively circumscribed nature of the tumor seen radiologically. GFAP tends to be strongly positive in many of the tumor cells. Up to 90% of these tumors are positive for P53 [20]. Recently; it was shown that CD34 can be positive in giant cell glioblastoma, thus losing its discriminating power from pleomorphic xanthoastrocytoma; its main differential diagnosis [33]. Giant cell glioblastoma is claimed to carry a slightly better prognosis than classical GBM [20].
Gliosarcoma (GS)
This is a well-circumscribed, biphasic tumor that brings morphological remembrance to “carcinosarcoma” in other sites. There is a near mutually exclusive staining for GFAP and reticulin in the glial and mesenchymal components; respectively [34]. In the glial component a clear GFAP-positive, reticulin-free usually fibrillary and sometimes gemistocytic astrocytes proliferation is seen with necrosis and vascular proliferation. The sarcoma component, on the other hand is typically GFAP-negative, and reticulin-rich. This component may be fibroblastic with proliferation of long bundles of malignant spindle cells, or can show heterologous component including smooth muscle, adipose tissue, cartilage and osteoid formation [32].
Glioblastoma with oligodendroglial component (GMB-O)
This is thought to represent a variant of glioblastoma with a probable better prognosis [35]. Its relation to the mixed oligo-astrocytic tumors is discussed below. The essential component for establishing this diagnosis is the presence of an oligodendroglial component in addition to the astrocytic component in association with necrosis [15]. In 15-20% of tumors 1p/19q co-deletion is detected.
Small cell glioblastoma (SCG)
This is characterized by proliferation of deceptively bland, uniform, small, round to slightly elongated cells with minimal atypia, but with brisk mitoses. Of note is the rarity of micro-vascular proliferation and necrosis in most cases [20]. GFAP is at best focally positive in thin cytoplasmic processes. Resemblance to anaplastic oligodendroglioma is further accentuated by the presence of tumor cell satellitosis, chicken-wire vascular proliferation and microcalcifications [15, 20]. The disconnection between the bland cytology and the brisk mitosis should act as a clue in this differential diagnosis. Furthermore; immunreactivity for EGFRvIII supports the diagnosis of small cell GBM [20].
Glioblastoma with primitive neuroectodermal tumor (PNET)-like component
In this variant proliferation of a clone of primitive cells reminiscent of PNET/medulloblastoma is seen, sometimes forming discrete nodule. The cells have high nuclear cytoplasmic ratio and exhibit frequent neuroblastic and Homer-Wright rosettes. Features of anaplasia with cell-cell wrapping, increased cell size with prominent nucleoli are seen in a subset of cases; thus bringing resemblance to anaplastic/large cell medulloblastoma (see below). Mitotic activity is brisk. Immunohistochemistry shows diffuse staining for neural markers including synaptophysin and NeuN and in many cases P53. GFAP is positive only in occasional cells. MIB-1 labeling index shows a nearly diffuse positivity (almost 100%) [31, 36].
Adenoid glioblastoma
This is an extremely rare variant that brings metastatic carcinoma into the differential diagnosis. There is glandular-metaplastic component that intermingles with the better defined glial component. Reactivity for a variety of cytokeratins including CK7 can add further to the confusion [32, 37].
Granular cell glioblastoma (GCA)
This is a deceptively bland tumor with proliferation of astrocytes showing abundant granular PAS-positive cytoplasm and regular nuclei, so they can be confused with macrophages. Reactivity with GFAP is the rule with few cases displaying EMA but not cytokeratin positivity. P53 can be positive in few cases [32].
Table 2 summarizes the clinicopathological features of GBM variants ( From Miller et al with modification) [32]
\n\t\t\t\t | \n\t\t|||||||||
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t6-7 | \n\t\t\t5-6 | \n\t\t\t6-7 | \n\t\t\t6-7 | \n\t\t\t6-7 | \n\t\t\t5-6 | \n\t\t\t6-7 | \n\t\t\t6-7 | \n\t\t\t5-6 | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t- | \n\t\t\t- | \n\t\t\t+/- | \n\t\t\t+ | \n\t\t\t+ | \n\t\t\t- | \n\t\t\t- | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t++ | \n\t\t\t+ | \n\t\t\t+/- | \n\t\t\t+++ | \n\t\t\t++ | \n\t\t\t+/- | \n\t\t\t+ | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t++ | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t- | \n\t\t\t- | \n\t\t\t+ | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t\t+++ | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t- | \n\t\t\t- | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t\t+++ | \n\t\t\t- | \n\t\t\t- | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t+/- | \n\t\t\t++ | \n\t\t\t+/- | \n\t\t\t+ | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t\t+/- | \n\t\t
\n\t\t\t\t | \n\t\t\t… | \n\t\t\t… | \n\t\t\t+/- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t- | \n\t\t\t+++ | \n\t\t
1ry, primary; 2ry, secondary; Fib, fibrillary; Gem, gemistocytic; GCA, granular cell astrocytoma; GC, giant cell; GS, gliosarcoma; SCA, small cell astrocytoma; GBM-O, GBM with oligodendroglial features; …, no data available; -, absent; +/-, infrequent; + to +++, increasing frequency; PVI, peri-vascular inflammation.
Gliomatosis cerebri
This entity has been shifted to join astrocytic tumors in 2007 classification. By definition; it is an infiltrative tumor involving at least 2 lobes but lacking mass effect. When crossing from one side to the other it causes widening of the corpus callosum. Microscopically; there is an infiltrative glioma, usually corresponding to grade III anaplastic astrocytoma and occasionally to oligodendroglioma. Rarely grade II fibrillary astrocytoma or grade IV glioblastoma can be encountered. Characteristically; the infiltrating malignant cells preserve the underlying structures intact without destruction. P53 can highlight the tumor cells and MIB-1 labeling index is variable reflecting the grade of the tumor [38, 39].
This is characterized by proliferation of monotonous cells with regular round, uniform nuclei with delicate chromatin, sharply defined nuclear membrane and inconspicuous nucleoli, brining a “highly-uniform” appearance on low power examination. In formalin-fixed tissue there is clearing artifact creating “haloes” around tumor cell nuclei due to shrinkage of the cytoplasm; a useful diagnostic clue, although not an absolute criteria for diagnosis “Figure 10” [31].
A case of oligodendroglioma with monotonous fried-egg appearance, chicken-wire vascularity and scattered calcification (arrow).
However; a small eccentric acidophilic cytoplasm can sometimes be appreciated. Hypertrophy of the cortical vessels leads to the development of the characteristic chicken-wire vascular proliferation [35].Micro-calcification, extensive infiltration of the cortical structures with perineural satellitosis and microcysts with basophilic mucinous contents are additional diagnostic features [20]. In the anaplastic variant; the vascularity becomes more prominent leading to the development of a nodular growth pattern at low power magnification. The cells become larger and exhibit more abundant cytoplasm with vesicular nuclei and prominent nucleoli; yet they retain their uniform appearance. There is increased cellularity with increased mitosis (≥6 MF/10HPFs), microvascular proliferation and necrosis. Important companions are the glio-fibrillary oligodendrocytes and the mini-gemistocytes “Figure 11”.
Minigemistocytes with whorling GFAP positive filaments. The tumor cells can be positive for GFAP. This is especially seen in the perinuclear staining in glio-fibrillary oligodendrocytes and the diffuse cytoplasmic staining in the mini-gemistocytes, thus potentiating confusion with infiltrating astrocytoma, or mixed oligo-astrocytoma [
Mixed oligo-astrocytoma is one of the most common tumors associated with considerable diagnostic difficulty and inter-observer variability [31]. A mixture of oligodendroglioma and infiltrative diffuse astrocytoma is seen. Both components can be spatially separated (compact variant) or they can be intermixed (diffuse variant). The minimum percentage of each component needed to establish the diagnosis is debatable, although a minimum of 10% astrocytic component of either fibrillary or gemistocytic morphology was used in some studies [43]. In the anaplastic variant; the tumors are highly cellular with pleomorphism and nuclear atypia, mitosis (≥6 MF/10HPFs) and/or microvascular proliferation [31] which could be identified in either or both components. Recent literature supports the up-grading into glioblastoma in the presence of necrosis (see above) [17, 35].
Myxo-papillary ependymoma
This is a slowly growing tumor that is almost exclusively seen in the cauda equina and filum terminale of young adults. It is composed of hypo- and hypercellular areas. The hypocellular areas show abundant mucicarmine-positive mucinous matrix with scattered epithelioid-appearing cells. The hypercellular areas are formed of tumor cells arranged in papillary structures. Cystic spaces filled with alcian-blue, PAS positive mucin separate the tumor cells from the blood vessels “Figure 12”.
In myxo-papillary ependymoma, alcian-blue positive cores surround vessels and cells grow in between forming sheets and sometimes perivascular psuedorosettes.
The cells are bland with processes radiating to the walls of the vessels and are arranged in single or multiple layers. Cribriform areas, sheets of cells and cells with clear cytoplasm can occasionally be encountered, creating resemblance to metastatic carcinoma. Pleomorphic cellular features, proliferation of vascular spaces, mitosis or necrosis are not seen, even in more aggressive tumors [44].Tumor cells are reactive for GFAP and S-100 and MIB-1 labeling index is low. A potential pitfall is positivity of the cells for pancytokeratin (AE1/AE3), cam 5.2 and cytokeratin 7 [45]. EMA can show cytoplasmic positivity in few tumor cells, similar to the pattern seen in other ependymoma (see below).
Sub-ependymoma
This mostly arises in the 4th followed by lateral ventricles [46]. Many cases are asymptomatic and discovered incidentally, although symptoms of increased intra-cranial pressure are the presenting features in others [47]. Morphologically; this is a well-delineated tumor that is characterized by nodules of clustered isomorphic cells arranged against a fibrillary background alternating with hypocellular fibrillary areas. Vague perivascular rosettes can be seen “Figure 13”.
Sub-ependymoma shows the typical microcysts formation, aggregated nuclei with nuclear-free zones made up of fine fibrillary background.
Focal cystic degeneration is noted [48], as well as vascular hyalinization, nuclear pleomorphism and calcification [46]. This distinctive pattern may frequently be admixed with classical ependymoma (See below). No mitotic figures, vascular proliferation or necrosis is detected in most tumors. GFAP is diffusely positive in these cases. MIB-1 labeling index is extremely low approaching zero [46].
Cellular ependymoma;
This is characterized by the presence uniform monomorphic cells extending their fine processes radially to the walls of blood vessels creating a fibrillary cellular free zone around the vessels and forming perivascular pseudorosettes. True rosettes and ependymal canals, where clusters of ependymal cells are arranged around a lumen resembling spinal canal, are less commonly encountered “Figure 14”.
Ependymal rosettes and canals can be seen in few cases. They are less common than perivascular pseudorosettes (arrow).
Feature of anaplasia include diffuse hypercellularity with diffuse nuclear pleomorphism, vascular endothelial proliferation, palisading necrosis, increased mitosis (usually ≥5MF/10HPFs) and elevated MIB-1 labeling index (≥20.5%) [27, 49]. Necrosis, in the absence of palisading, is a common feature in posterior fossa tumors, and is not a poor prognostic feature [31]. Interestingly; the identification of sub-ependymoma like areas in infratentorial ependymoma seems to be associated with adverse outcome [14]. Another important microscopic feature is the focal hypercellular nodules, in which focal increase in cellularity is associated with nuclear pleomorphism and an increase in mitosis. In the absence of diffuse changes, these nodules are not associated with an adverse prognosis and as such may not warrant assigning a higher grade to the tumor [49]. GFAP is variably positive in tumor cells, especially in perivascular processes. EMA [50] and CD99 show charactersitic dot-like perinuclear cytoplasmic positivity [51]. Other positive stains include other intermediate filaments like vimentin and desmin [27].
Clear cell ependymoma
This is a tumor that predominates supratentorially and displays an enhancing cystic component in the majority of cases. It is characterized by proliferation of sheets of cells with round nuclei and prominent, clear haloes. Focal ependymal perivascular pseudorosettes may be seen but true rosettes and canals are not typical. Features of anaplasia including increased cellularity, mitosis and microvascular proliferation, and at least focal necrosis are frequent. Reactivity for GFAP with perivascular accentuation, dot-like cytoplasmic EMA and CD99 staining should all help in reaching the appropriate diagnosis. MIB-1 labeling index is increased especially in areas of increased mitosis. [52]. Clear cell ependymoma should be differentiated from oligodendroglioma [20, 52].
Tanycytic ependymoma
This is primarily a tumor of the spinal cord, but occasional cases may arise from the third ventricle or the hypothalamus. Tanycytic ependymoma posses an “astrocytoma-look”, with solid proliferation of spindle cells with elongated processes and with at best focal ill-defined ependymal psuedorosettes. The nuclei are uniform, round to oval with salt and pepper chromatin, similar to other ependymoma “Figure 15“.
Tanycytic ependymoma is composed of “piloid” like tanycytes with only vague perivascular pseudorosettes noted.
Strong GFAP positivity is seen in the elongated processes. Other positive markers include S-100, vimentin and CD99 [20].
They all share proliferation of small round blue cells with increased mitosis and apoptosis. This group includes
Medulloblastoma
This is a primitive neuroectodermal tumor that arises from the cerebellum. It is the most common malignant brain tumor in children and the most common embryonal tumor. Medulloblastoma is thought to originate from a primitive cell type in the cerebellum. The multi-potent progenitor cells of ventricular zone that forms the innermost boundary of the cerebellum is the postulated origin of the classical medulloblastoma, while the external germinal layer that lines the outside of the cerebellum; the external granular layer, is the postulated origin of the desmoplastic medulloblastoma [53].
Several morphologic sub-types are recongized, some of which are prognostically relevant:
Classic medulloblastoma; is the most common variant, and represents 66% of cases [54]. It is composed of densely-packed cells with hyperchromatic, round, oval or carrot-shaped nuclei with minimal cytoplasm “Figure 16”.
Sheets of tumor cells with Homer-Wright rosettes (right side) and neurocytic nodules (left) can be encountered in typical medulloblastoma.
The cells are usually arranged in diffuse sheets, but trabeculae, spongioblastic pattern, Homer-Wright rosettes and nodules can be identified. Necrosis, sometimes palisading, may be seen in some tumors, and has been identified as an adverse prognostic feature [55].
Desmoplastic/nodular medulloblastoma(DNM) and medulloblastoma with extensive nodularity (MEN); both of these variants share the presence of reticulin-rich desmoplastic component and a reticulin-free, nodular component showing comparatively extensive neurocytic differentiation, fibrillary background, less mitoses and frequent apoptosis “Figure 17”.
Desmoplastic medulloblastoma with pale islands and internodular area giving a reactive lymph node like appearance.
Both variants are claimed to be associated with better prognosis [54]. DNM can be seen in children and adults and represents 25% of cases of medulloblastoma. MEN, on the other hand, is characteristically seen in infants, where is accounts for 57% of medulloblastoma in this age group and is associated with excellent outcome. Whereas the reticulin-rich component predominates in DNM, and the presence of any percentage of nodularity and desmoplasia qualifies the tumor for DNM subtype [56], the reticulin-free differentiating component predominates in MEN, representing 96-100% of the tumor [57]. Thus MEN might be perceived as an exaggerated form of DNM [15]. Importantly; the borders between the nodules and the surrounding desmoplasia is usually sharp [54]. The presence of desmoplasia due to infiltration of the meninges in the absence of nodules does not qualify the tumor as DNM [57] and vice versa; the identification of less-delineated neurocytic nodules in the absence of desmoplasia i.e.biphasic medulloblastoma is considered a variation of classical or sometimes anaplastic/large cell medulloblastoma morphological patterns that is not assocaited with improved outcome in some [54], but not all studies [55]. Immunohistochemistry helps further confirming both growth patterns. The pale islands are synaptophysin positive with low MIB-1 labeling index, while the inter-nodular areas are at best focally positive for synaptophysin with high MIB-1 labeling index, in keeping with presence or absence of neuronal differentiation; respectively.
Anaplastic/large cell medulloblastoma; these are closely related variants that frequently co-exist and account for17- 24 % of cases of medulloblastoma [54, 57]. In anaplastic medulloblastoma there is marked nuclear pleomorphism with angular, crowded pleomorphic cells with nuclear molding, cell-cell wrapping and numerous mitotic and apoptotic figures“Figure 18”.
Anaplastic medulloblastoma with frequent cell wrapping (lower right), apoptosis and abnormal mitosis.
The nuclei are twice to three times the size of an RBC in moderate to severe anaplasia, thus varying in size from 18-21 micrometers; respectively [57, 58]. Hyperchromasia per se is not a defining feature of anaplasia. The large cell variant on the other hand is characterized by large spherical cells possessing round vesicular nuclei and prominent central nucleoli“Figure 19” [57, 58].
In large cell medulloblastoma; the cells have abudant cytoplasm, vesicular nuclei and prominent nucleoli.
Anaplasia is considered diffuse when seen involving every low power field, otherwise it is considered focal. It is the diffuse, moderate to severe anaplasia that is associated with poor prognosis. Anaplastic/large cell features can be detected in what appears to be DNM or in recurrent classical medulloblastoma. The presence of features of DNM, Homer-Wright rosettes or previously classical medulloblastoma is not incompatible with the diagnosis of anaplasia [31, 57, 58].
“Medulloblastoma with myogenic differentiation” and “medulloblastoma with melanotic differentiation” are considered morphological patterns with divergent differentiation that can be seen in any of the medulloblastoma variants, but with no effect on prognosis. Respectively; desmin and myogenin positive rhabdomyoblasts and S-100 positive melanotic tumor cells are seen in both patterns, hence the nomenclature [15].
In medulloblastoma, the tumor cells are positive for synaptophysin in up to 80% of cases, while microtubule-associated protein 2 antibody (MAP2) is seen in cases with weak synaptophysin reactivity [27]. CD99 is usually negative in contrast to peripheral PNET [59]. GFAP reactivity can be seen in medulloblastoma cells in a perinuclear pattern and this might carry adverse prognosis [27]. Diffuse positivity for P53 (strong nuclear stain in > 50%), ErbB2 (strong membranous staining in ≥ 50% of tumor cells) and survivin (nuclear stain) is associated with poor prognosis [56, 60-62]. TrK-C (strong cytoplasmic staining in >50% of tumor cells) and beta-catenin (either diffuse, strong cytoplasmic and nuclear or nuclear staining in cell clusters of at least 10% of nuclei among others with negligible or weak staining) are associated with improved outcome [60, 63, 64]. MIB-1 labeling index is variable but with a mean that ranges between 46.5-59.03%. The prognostic importance of elevated MIB-1 labeling index varies from one study to another [56, 60], with higher figures reported among anaplastic/large cell variant, and correlating with poor outcome [65].
CNS-primitive neuroectodermal tumor (CNS-PNET)
This is a heterogeneous group of poorly-differentiated primitive small round blue cells that can be seen supratentorially, in the brainstem or in the spinal cord. Divergent differentiation along neuronal/ ganglio-neuronal, epithelial or ependymal lines can be seen occasionally, hence the neuroblastoma/ CNS ganglioneuroblastoma, medulloepithelioma and ependymoblastoma variants; respectively [15]. The presence of necrosis adversely affects the outcome [14]. Embryonal tumor with abundant neuropil and ependymoblastic rosettes (ETANTR) is a newly described variant that is considered a hybrid tumor where both neuroblastic and ependymoblastic differentiation co-exist. Characteristically; ETANTR has been reported to have extra-copies of chromosome 2 [66] and 19q amplification [67].
CNS-PNET can show positivity for synaptophysin, GFAP and occasionally dot-like cytoplasmic EMA, according to differentiation [68]. Of note is the total negativity for CD99 in contrast to the peripheral type PNET tumors [69].
Atypical teratoid/rhabdoid tumor (AT/RT)
This tumor predominates in infants and can be seen in supratentorial and infratentorial compartments. Growth pattern are predominantly diffuse in most cases with reticular and papillary patterns noticed in few [70]. The typical cell, “rhabdoid cell” is seen in most but not all tumors and is not an absolute prerequisite for establishing the diagnosis. It is a large cell with eccentric acidophilic cytoplasm, vesicular nucleus with prominent nucleolus, reminiscent of “rhabdomyoblasts” hence the name. Intra-cytoplasmic spherical filamentous inclusions are identified in a proportion of rhabdoid cells“Figure 20”.
Typical case of AT/RT composed of cells with eccentric acidophilic cytoplasm and vesicular nuclei with prominent nucleoli. Note the myxoid background in the lower left corner.
Other common cellular components included large pale cells and primitive small round blue cells. Pale cells are characterized by vesicular nuclei, prominent nucleoli, and granular vacuolated wispy or water clear cytoplasm lacking intra-cytoplasmic inclusions, while small cells are cells with high nuclear: cytoplasmic ratio reminiscent of medulloblastoma/PNET [42, 71]. Admixture of all three cell components is noted in most cases. However; cases composed entirely of one cell type are not uncommon. Variable mesenchymal structures including myxoid changes, chondroid, lipoblastic and spindle cells elements can be seen. Occasional cases may contain glandular or papillary structures as an evidence of epithelial differentiation. Dystrophic calcifications and necrosis can be identified in some tumors.
Nowadays; the diagnosis of AT/RT can be confirmed by loss of INI1/BAF47 immunostain in tumor cells nuclei with appropriate positive normal endothelial and mononuclear cell control in the background [42]. In the rare instances of retained INI1/BAF47 nuclear stain, which is seen in 2% of cases, positivity for a panel of other markers can help in suggesting the diagnosis. A panel of EMA, synaptophysin, GFAP, vimentin, smooth muscle actin and pan-cytokeratin can show various combination of positive staining and thus can be of help in suggesting the diagnosis [27]. Confirmation by cytogenetics for monosomy 22 may be warranted in such cases. Notably is the absence of desmin [72]. MIB-1 labeling index ranges between 30-50%.
This is the most heterogeneous and rapidly expanding group of tumors with many newly recognized and added entities. As the name implies, many tumors are composed of a mixture of glial and neuronal components.
Ganglioglioma (GG) and gangliocytoma
Frequently presenting as long standing chronic seizure, this biphasic tumor is most commonly located in the temporal lobe and is seen mostly in children and young adults. This is a variably circumscribed tumor with intimate mixture of disfigured and dysplastic neurons and neoplastic glial cells of varying proportions. The ganglion cells are characterized by cyto-architectural disorientation with sub-cortical localization, abnormal aggregations and clustering. Morphologically; the neurons show abnormal forms with frequent cytomegaly, bi- and multinucleation, prominent nucleoli, and peri-membranous condensed Nissl substance [73]. The glial component can vary as well from pilocytic to diffuse astrocytoma to oligodendroglioma like component ”Figure 21” [73, 74]. This is the proliferative component that ultimately determines the biological behavioral of GG. Tumors composed predominantly of ganglion cells, which are devoid of a glial component are termed gangliocytomas [73, 74]. Dysplastic calcification (globules or incrustation), eosinophilic granular bodies and increased reticulin meshwork can be seen in the background. Perivascular lymphocytes and scattered parenchymal plasma cells are common supportive features. An atypical or anaplastic ganglioglioma is rarely encountered and can arise either de novo or at recurrences of a previously diagnosed GG [74]. The presence of cellular atypia and pleomorphism, microvascular proliferation, necrosis and elevated MIB-1 labeling index supports the diagnosis of anaplastic ganglioglioma [17, 73]. It was suggested to lable tumors exhibiting features of anaplasia without necrosis as atypical GG [74]. Gemistocytes identified in some tumors might represent an additional feature of anaplasia [74].
Ganglioglioma with dysplastic ganglion cells that are haphazardely oriented with abnormal aggregation of Nissl substance in the cytoplasm. Perivascular lymphocytic infiltrate is seen.
Immunohistochemically; the dysplastic ganglion cells are positive for synaptophysin, with peri-somatic synaptophysin reactivity, chromogranin A, neurofilament protein and MAP2 [74-76], while the glial component is positive for GFAP. Dysplastic ganglions frequently fail to react with NeuN, a potentially useful marker to differentiate dysplastic from normal neurons [42]. CD34 is reported to be positive in up to 80% of tumors; labeling the dysplastic neurons, being less frequently positive in atypical and anaplastic tumors [74]. MIB-1 labeling index is seen in the glial component and is usually <1% [77] and labeling index >5% is associated with a more aggressive behavior (see above). P53 is reported in only atypical/anaplastic tumors [74, 77].
Desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA)
DIG is a massive, supratentorial tumor that primarily affects infants, usually younger than 6 months of age. It is characterized by superficial leptomeningeal attachment, multiple conspicuous cysts, firm consistency and focal infiltration into adjacent brain parenchyma without clear plane of resection [78].Microscopically; there is admixture of fibroblasts, neuroastroglial cells and primitive cells, all enmeshed within a desmoplastic stoma, that can be highlighted by reticulin and Massons\'s trichrome stains [79]. The proportion of the different cellular components varies from one tumor to the other. The astroglial cells are the most abundant cell component, especially in regions of desmoplasia, are characterized by strap-like to polygonal, GFAP positivity. The neuronal cells; on the other hand are more frequently seen in the less desmoplastic areas, with proliferation of small abortive neurons to occasional polygonal ganglioid cells with prominent nucleoli and Nissl substance that are reactive with synaptophysin and NFP. The proportion of the small primitive cells can vary from scattered to a considerable amount in some tumors. It is within these areas that rare mitosis and foci of micro-necrosis, but not endothelial proliferation can be detected [78, 79]. However; regardless of their amount; this tumor continues to carry a favorable prognosis in most cases. MIB-proliferative index is low with a mean of 6.5% [79]. There has been reported cases in the literature in which the prognosis was not as favorable and resulted occasionally in patient’s death [80]. DIA shares with DIG the desmoplasia and the astrocytic components, but not the neuronal or the primitive cells [78].
Dys-embryoplastic neuroectodermal tumor (DNET)
The essential diagnostic features of this peculiar epilepsy-associated tumor are the combination of cortical localization, multi-nodular architectures with nodules composed of glial cells of either astrocytic or oligodendroglial or a mixture of both, foci of dysplasia in the adjacent cortex and the “specific glioneuronal elements” [81]. These are composed of bundles of axons lined by small S-100 positive, GFAP-negative oligodendrocytes with normal appearing neurons floating within pale eosinophilic interstitial fluid i.e.“floating neurons”, all arranged in columns perpendicular to the overlying cortex, and is strikingly similar from one case to another. Thin capillaries run within the columns. When sectioned perpendicular to the columns; the capillaries are seen to be rosetted by the oligodendroglial cells with the “floating neurons” in between. Calcification can sometimes be seen. Two morphological forms exist; the simple and complex forms [81]. In the simple form; only the “specific glioneuronal elements” are seen within the cortex. The complex form, on the other hand; features the glial nodules and/or cortical dysplasia in addition to the “specific glioneuronal elements”. The nuclei of the oligodendrocytes within the nodules are frequently voluminous and multilobated “fleurettes-like”, while the astrocytic component is usually in the form of pilocytic astrocytoma, sometimes accompanied by the “vascular arcade” proliferation typically seen in cerebellar pilocytic astrocytoma. Fibrillary astrocytoma, of both grades II and III like features can also be seen. The presence of morphological features of anaplasia in the form of rare mitosis and necrosis can occasionally be seen. MIB-1 labeling index is mostly negative in the simple form with rare reactive cells in the complex form, although higher labeling index can be seen in some cases according to the type and grade of the glioma seen within the nodules [81]. Cases can still be diagnosed as DNET even in the absence of histological appearances previously described, if all of the following clinical and radiological features are fulfilled including 1)partial seizure with or without secondary generalization beginning before the age of 20 years, 2)no neurological deficit or stable congenital deficits, 3)cortical topography of the lesion as demonstrated by MRI and 4) absence of mass effect on imaging. The underlying spectrum of histopathologic entities that can be seen include mostly pilocytic and fibrillary astrocytoma [82].
Central neurocytoma
This tumor typically occupies the lateral ventricles or less commonly the third ventricle in young adults without significant invasion into the adjacent brain tissue [83]. It is characterized by proliferation of uniform round cells, embedded within and focally separated by a fibrillary background, the “neuropil” giving an overall monotonous appearance ”Figure 22”.
Typical neurocytoma with monotonous tumor cells with vesicular chromatin and delicate capillary-sized vessels. The background is fibrillary.
The tumor cells grow in sheets, clusters, “Indian filing” but rarely rosettes. The fibrillary areas can be seen to form acellular aggregates, bringing resemblance to pineocytomatous rosettes (see below). The nuclei are round to oval with finely speckled chromatin and occasional prominent nucleoli. The cytoplasm is scanty and can be acidophilic or rarely clear. Calcification, which is seen throughout the tumor, and delicate-branching capillaries bring resemblance to oligodendroglioma. Occasional cases show ganglion cells [17]. Mitosis is scarce and there is usually no necrosis [15]. When present such features warrant the diagnosis of atypical neurocytoma. Synaptophysin is strongly and diffusely positive in both the neurocytes and neuropil. NeuN shows strong nuclear stain in tumor cells [42]. Other positive neural markers include neurofilament protein and MAP2. Leu-7 can be positive but it is not specific as is staining for neuron-specific enolase (NSE). Chromogranin is typically negative in both the neurocytoma cells and neuropil [84]. Occasional positivity for GFAP can be seen in some tumors [83]. MIB-1 labeling index is < 2% in typical cases [83]. An elevated MIB-1 labeling index >3% correlates with poorer outcome [14].
Extra-ventricular neurocytoma (EVN)
EVN shares morphologic and immunophenotypic features with central neurocytoma. It arises, however from the parenchyma, mostly in the cerebral hemispheres in adults [15, 84]. In addition, Ganglion cell differentiation is a more frequent occurrence, being described in more than half of the cases and can be either focal or diffuse [17, 84]. Frequent reactivity for GFAP is seen in nearly half of cases [84].
Cerebellar liponeurocytoma
This is another biphasic tumor that occurs in adults. Originally described in the posterior fossa mostly in the cerebellar hemispheres, cases with identical morphological features are also being reported supratentorially, arising from the lateral ventricle [85]. Morphologically a well differentiated neurocytic component composed of uniform round nuclei and minimal cytoplasm is admixed with mature lipomatous component. Thin and occasionally hyalinized vessels can be detected in the tumor as well as dispersed foci of neuropil. The tumor is diffusely reactive for synaptophysin, NSE and NeuN. Other neuronal markers including chromogranin and NFP can be focally positive. The lipomatous component shows cytoplasmic reactivity for NFP, chromogranin, occasionally for GFAP and S-100 rimming the vacuoles. MIB-1 labeling index is low (<1%) in the majority of cases [17].
Papillary glio-neuronal tumor (PGNT)
This tumor is characterized by pseudopapillae and less frequently by papillae, with hyalinized cores lined by a single or multiple layers of hyperchromatic GFAP positive, S-100 positive astrocytes that exhibit acidophilic cytoplasm. These are separated by sheets of synaptophysin positive, Neu-N positive mature neuronal cells in the inter-papillary areas. The neurocytic component includes neurocytes with vesicular nuclei and clear cytoplasm, ganglionoid cells and ganglion cells [15]. A fibrillary or mucoid matrix is seen in the background and can form nodules outside the papillary regions [30]. Sharp demarcation from the adjacent brain is seen. Mitoses is rare or absent and microvascular proliferation and necrosis are not seen. MIB-1 labeling index is low usually in the range of 1-2%.
Rosette forming tumor of the 4th ventricle (RGNT)
This is another example of hybrid glial/neuronal tumor, that arises in midline structures, mostly but not exclusively the 4th ventricle. It often shows involvement of the surrounding periventricular tissue [30]. The neural component shows neuropil-rich rosettes and perivascular pseudorosettes that are lined by synaptophysin-positive neurocytes with clear cytoplasm. A microcystic component with blue mucinous extracellular matrix is sometimes described [17]. The glial component is in the form of pilocytic astrocytoma with Rosenthal fibers and eosinophilic granular bodies [15]. No nuclear atypia or mitosis is seen. However; vascular proliferation of the type seen in pilocytic astrocytoma can be encountered and should not lead to the suggestion of anaplasia [30]. Reactivity for NSE and MAP2 can be seen in the neural component, while GFAP and S-100 are positive in glial component. MIB-1 labeling index is low.
These tumors originate within the ventricular system, and are composed of “epithelial-like” cells reminiscent of choroid plexus [86].
Choroid plexus papilloma (CPP)
This is the most frequent entity in this group of tumors and is characterized by papillae lined by a single layer of bland looking cuboidal to columnar epithelial-like cells with abundant acidophilic cytoplasm, bland basal, round to oval nuclei [15]. Tubular or solid growths may occasionally be encountered [86]. Rare mitotic figures, microscopic infiltration into adjacent brain but not necrosis can be seen [14, 17]. Oncocytic changes, melanin deposition, calcification, ossification, and xanthogranulomatous changes may occasionally be encountered [86].
Atypical choroid plexus papilloma (atypical CPP)
This recent addition is characterized by preservation of the papillary architecture similar to papilloma, but with increased mitotic activity of ≥ 2 mitoses per 10 high power fields “Figure 23” [15, 87].
Atypical Choroid plexus tumor with typical papillary arrangement but several mitotic figures per high power field (arrows).
The additional presence of at least 2 of the following features might warrant the diagnosis of atypical CPP including increased cellularity, nuclear pleomorphism, solid growth and necrosis [17]. However; these are not necessary for the diagnosis.
Choroid plexus carcinoma
This is the most aggressive entity in this group of tumors and is characterized microscopically by blurring of the papillae with increased cellularity and pleomorphism in addition to features of frank malignancy including brisk mitosis of >5 MF/10HPFs, and necrosis [15]. Diffuse invasion into brain parenchyma is often seen [17]. PAS positive, diastase resistant variably-sized hyaline globules can be seen that are positive for alpha-1-antitrypsin [14].
The choroid plexus tumors are positive for cytokeratins, especially Cam 5.2, vimentin, S-100, transthyretin, and GFAP, with stains being more positive in papilloma versus carcinoma. Two recently described markers, stanniocalcin 1 and Kir 7.1 are claimed to be specific for choroid plexus tumors. EMA is typically negative in choroid plexus tumors [17], while CK7/CK20 show variable patterns and should be interpreted with caution [86]. MIB-1 proliferative index ranges between 1.9% in CPP to 13.8% in CPC, with higher indices correlating with poor outcome [14].
Pineocytoma
This is a histologically bland tumor composed of mature-looking pinealocytes [17]. The cells are bland looking with amphophilic cytoplasm and round nuclei. Large fibrillary pineocytomatous rosettes and pseudorosettes can be seen. A pleomorphic variant is described with giant cells and abnormally-shaped hyperchromatic nuclei and gangliocytic cells [88]. No mitosis is seen in both variants. Immunostains are typically positive for NSE, synaptophysin, chromogranin A and neurofilaments [89]. MIB labeling index is usually zero [90].
Pineal parenchymal tumor of intermediate differentiation (PPTID)
This group accounts for at least 20% of tumors of the pineal gland and shows intermediate differentiation between pineocytoma and pineoblastoma [17]. They grow in sheets or lobules and are composed of uniform cells with moderate nuclear atypia. Although occasional Homer –Wright rosettes can be seen, pineocytoma-like rosettes are not reported. On the other hand; this tumor lacks the primitive cell appearance and necrosis typically seen in pineoblastoma [35]. According to the number of mitosis, proliferative index labeling and neurofilament immunostains, these tumors are divided into two prognostically different groups [17, 89]. MIB labeling index ranges between 5.2-11.2% [90].
Pineoblastoma
This is a small primitive tumor similar to CNS-PNET. It is hypercellular with proliferation of primitive cells with scant cytoplasm, hyperchromatic nuclei, nuclear pleomorphism and occasional prominent nucleoli. Frequent mitoses, necrosis and calcification can all be encountered [91]. Immunostains for NSE, synaptophysin, chromogranin A and neurofilaments are typically weak or negative [89]. MIB labeling index is around 36.4%-50% [90, 91].
Papillary tumor of the pineal region (PTPR)
This is the most recent addition to this group of tumors. It is seen both in children and adults. It grows in papillae with hyalinized cores that are lined by epithelial-like cells. The cells are large columnar to cuboidal, with pale to acidophilic cytoplasm and vesicular round nuclei, thus being different from pineal parenchymal tumors. These tumors are positive for cytokeratin, S-100 and vimentin with only focal positivity for GFAP [15]. EMA is usually negative or at best focally positive; an important feature in the differential diagnosis with ependymoma [17].
Angiocentric glioma
This is probably a benign tumor that occurs in young adults with history of epilepsy. It is cortically based and is characterized by monomorphous bipolar cells with an angiocentric growth pattern, hence the name [15]. In most cases the cells tend to arrange themselves radially around blood vessels. Additionally 2 important distinct growth patterns can be seen in a subset of cases; the arrangement of the elongated tumor cells parallel to blood vessels causing sometimes expansion of the perivascular spaces and the tendency of the tumor cells to accumulate perpendicularly beneath the pia [17]. Immunostains are positive for EMA, GFAP, S-100 and vimentin. Neuronal markers are negative.
Chordoid glioma of the third ventricle
This tumor usually arises from the anterior third ventricle and is characterized by cohesive clusters and cords of epithelial-like cells growing in a myxoid background [92], hence the close resemblance to chordoma and chordoid meningioma [93], from which it should be differentiated. The presence of lympho-plasmacytic infiltrate which can sometimes be heavy with abundant Russell bodies is seen at the periphery and is helpful in supporting the diagnosis. Chondroid metaplasia can occasionally be encountered [94]. Reactivity for GFAP and vimentin is the rule but with variable reactivity for S-100. EMA is positive in the infiltrating plasma cells [20, 92].
Astroblastoma
A well circumscribed tumor that involves mostly the cerebral hemispheres, astroblastoma is characterized by perivascular pseudorosettes with sclerosed fibrovascular cores, on which broad cytoplasmic processes of astroblasts rest “Figure 24”.
In astroblastoma hyalinized blood vessels are surrounded by cells with broad-based cytoplasmic processes.
This is in contrast to the fine tapering processes of classical ependymoma [20, 95]. A high grade “malignant” variant is diagnosed when hypercellularity, increased mitoses, vascular proliferation and palisading necrosis are seen, otherwise the tumor is considered a low grade or “benign” [14]. The tumor cell processes are strongly positive for vimentin and S-100, but focally for GFAP with focal membranous EMA reactivity.
Cribriform Neuroepithelial Tumor (CRINET)
This recently described tumor is composed of proliferation of a relatively small undifferentiated cells, arranged in cribriform, trabeculae, strands and focal compact areas exhibiting rosette formation [96]. Well defined surfaces characterize the cellular strands, which exhibit elongated nuclei but with no stratification. The cytoplasm is ill-defined and slightly acidophilic and the nuclei posses dense chromatin and lack prominent nucleoli. Mitoses and necrosis are seen. The tumor cells are immunoreactive for EMA highlights the surface as well as for vimentin, and synaptophysin with focal expression of cytokeratin and S-100. Other markers including GFAP, neurofilament, NeuN, chromogranin are negative. MIB-1 labeling index is elevated. Characteristically this tumor lack INI-1/Baf47 nuclear immunoreactivity, despite of lacking the typical features of AT/RT including eccentric acidophilic cytoplasm, cytoplasmic inclusions and vesicular nuclei with prominent nucleoli [96, 97]. CRINET seems to be associated with a better prognosis than AT/RT.
This chapter will introduce the single port robotic system. Topics include an introduction to the robotic single site port, the trocars, and the single site instruments. Step-by-step instruction is provided on how to create the umbilical incision and properly insert the single site port and trocars. The advantages and disadvantages of single port robotic surgery compared to multiple port robotic surgery and laparoscopic single site surgery are reviewed. Surgical tips and tricks are provided throughout each section to maximize efficiency, minimize complications, and overcome the inherent limitations of the robotic single site system. The utility of the robotic single site platform for performing minor gynecologic surgery is discussed in detail. Finally, a simple method for umbilical closure is described.
Single site surgery, whether laparoscopic or robotic, offers several advantages over traditional multiple port surgery. The anatomy of the umbilicus is unique. It is the only part of the anterior abdominal wall where the skin and peritoneum are located directly adjacent to each other, without intervening fat and muscle. As a result, the umbilicus provides easy access to the abdomen, even in morbidly obese patients. Furthermore, the stalk of the umbilicus is composed primarily of fibrotic scar tissue with minimal vascularity. Consequently, most umbilical incisions are relatively bloodless [1]. In addition, single site surgery obviously eliminates the risks associated with the placement of accessory trocars, including bleeding, flank hematomas, incisional hernias, and visceral injury. The lack of additional trocars also contributes to less post-operative pain [2, 3].
The most obvious advantage of single site surgery, however, is cosmesis. Even a 2-3 cm incision can be hidden in the umbilicus, and it often becomes virtually invisible as it heals [4]. The poor vascularity of the umbilicus also minimizes the risk for a postoperative hematoma and virtually eliminates the risk for keloid formation [5].
The most functional advantage of single site surgery is using the umbilical incision for specimen retrieval. The lack of intervening muscle and fat provides easy access to the surgical specimen. Specimen retrieval is easy, and any morcellation required is readily accomplished by bringing the specimen bag up through the umbilical incision [6].
Robotic single site surgery offers advantages over traditional laparoscopic single site surgery. The 3-D binocular vision provided by the robotic platform allows for better depth perception and facilitates more precise surgical movements. Although the only wristed instrument is the robotic needle driver, this is also a significant advantage over all “straight stick” laparoscopic instruments. The binocular vision and wristed needle driver greatly facilitate intracorporeal suturing and knot tying. The needle driver can also be employed as a grasper and its dexterity can improve exposure for adhesiolysis or facilitate the excision of an ovarian cyst. Finally, the robotic single site platform is more ergonomic and intuitive. Intra-abdominally, the surgeon’s right hand controls the right sided instrument and the left hand controls the left-sided instrument, even though, externally, these instruments and trocars are located on the opposite side (Figure 1).
Surgeon’s right hand controls the right instrument intra abdominally and vice versa.
Compared to traditional multiple port robotic surgery, there are some disadvantages to the single site robotic system. The robotic single site instruments are relatively primitive. There are no advanced energy instruments such as the harmonic scalpel or bipolar transection tools built into the robotic single site system. The only unipolar tool available is the hook; the scissors do not have any unipolar power capability. In addition, the required semi-rigid flexibility of the robotic single site instruments leads to a relatively weak grasping force. This is most readily apparent when attempting to suture with the needle driver or when trying to hold tissue on tension. Furthermore, even though the needle driver is wristed, it has less range of motion than traditional robotic instruments.
Finally, the “working space” of the robotic single site system is limited compared to traditional robotic surgery. The trocar length is fixed, and the instruments cannot be retracted back any further than the tip of the trocars. This can make surgery more difficult in the setting of big pathology such as a large fibroid uterus or large ovarian cyst. In addition, in patients of short stature, the distance from the umbilicus to the pelvis is often smaller, and this can further compromise the functional workspace.
Access by the assistant surgeon can be compromised with the robotic single site system. Lateral movements can lead to repeated collisions (often coined “sword fighting”) between the instruments and camera both inside the abdomen and outside. The most unencumbered instrument movements by the assistant are those performed in an anterior to posterior direction — parallel to the camera. Despite these disadvantages, the robotic single site system can readily handle most gynecologic surgery. Various techniques for overcoming these disadvantages are discussed in the “Tips and Tricks” section of this chapter.
The initial step in any single site operation, whether robotic or laparoscopic, is the umbilical incision. Various incisions have been proposed, but the simplest, easiest, and most cosmetic approach is a midline vertical incision right through the center of the umbilicus. Local anesthesia (with or without epinephrine) is injected into the base of the umbilicus. Toothed forceps placed at the superior and inferior edges of the umbilicus are used to elevate the skin and an incision is made vertically through the center of the umbilicus. Allis clamps are then placed laterally and used to elevate the skin edges. With the edges elevated, the stalk of the umbilicus is palpated as a horizontal band of fascia in the center of the incision. Kocher clamps are then placed laterally on this fascia band, and the Allis clamps are removed. While elevating with the Kocher clamps, an incision is then made vertically in the fascia. The fascial incision is then sharply enlarged to allow the surgeon to bluntly enter the abdomen digitally. The skin and fascial incisions are then enlarged as needed. For robotic single site surgery, a 2-3 cm incision is required. This is slightly larger than what may be required for laparoscopic single site surgery, depending on the intended operation. The fascial incision should be extended vertically in both directions until it is slightly larger than the skin incision (Figures 2–5).
Vertical umbilical skin incision.
Allis clamps placed bilaterally on the skin edges and gently elevated.
Kocher clamps placed bilaterally on the umbilical stalk which appears as a horizontal fascial band in the incision.
Vertical fascial skin incision followed by blunt digital abdominal entry.
Aggressive incisions in the skin and fascia facilitate entry, and hesitant incisions complicate entry. The base and stalk of the umbilicus is composed of thick fibrotic scar tissue, thicker than any other part of the anterior abdominal wall. A number 15 scalpel is used, as bigger blades may not reach the base of the umbilicus, especially if it is anatomically smaller. Generally, the entire length of the number 15 blade is needed to achieve proper incision depth in both the skin and fascia.
Not infrequently a hernia is encountered in the umbilicus during initial entry. Virtually all of these are fat containing. Excision of any excess fat with unipolar cautery easily restores normal anatomy, and the operation then continues as planned. When an umbilical hernia is encountered upon entry, closure of the umbilicus at the end of surgery is done with either a permanent suture such as 0-Prolene or a significantly delayed absorbable suture such as 0-PDS.
Patients with a previous umbilical hernia repair require special attention. If mesh present, entry is accomplished by making an incision through the mesh just as it is performed for the fascial incision. During closure, the mesh is re-approximated with a permanent suture such as 0-Prolene
Periumbilical adhesions can also complicate surgical entry. When these are encountered, the fascia is elevated with Kocher clamps and the adhesions are lysed sharply under direct visualization as far as possible. Insertion of a laparoscopic single site port with a small intra-abdominal footprint (such as the Covidien SILS port or the Gel-Point Mini) then allows for further adhesiolysis laparoscopically under direct visualization. Once the adhesions are taken down, the robotic single site port can then be inserted without difficulty in the usual manner
The single site robotic system consists of three main components — the port, the individual instruments, and the various trocars.
The robotic port is a flexible hourglass shaped device designed to sit in the umbilicus. It has a lip on each end. The inner lip is designed to sit in the peritoneal cavity and the outer lip above the skin. The port itself has four lumens for the various single site trocars and an insufflation channel with a plastic trocar embedded in it. An arrow is present on the exposed lip and the port should be oriented so that this arrow points towards the intended operative field. The two channels closest to the operative field are for the camera trocar and the assistant trocar (Figures 6 and 7). The two port channels furthest away for the operative field (or more cephalad in the case of gynecologic surgery) are for the single site trocars.
Robotic port.
Robotic port with the camera trocar and assistant trocar in place.
In preparation for port insertion, place a Kocher clamp laterally on each side of the incision, holding both the peritoneum and the fascia together. Lifting these clamps provides counter traction to facilitate port insertion and holding both the peritoneum and the fascia together prevents pre-peritoneal insertion of the port. Some surgeons alternatively prefer to use “S” shaped retractors to elevate the anterior abdominal wall instead of Kocher clamps; however, I have found this method less effective. Two long Kelly clamps are then placed on the port as shown (Figure 7). With the surgeon’s non-dominant hand steadying the port, the dominant hand holds the inferiorly placed Kelly clamp and inserts the port into the abdomen with a “C” shaped motion. It is important to assure that the leading edge of the port is in the abdominal cavity at this time. While applying constant pressure to hold the port in place with the surgeon’s non-dominant hand, the dominant hand then removes the inferior Kelly clamp and grabs the superior one. Final insertion of the port is then accomplished by pushing the second clamp in a vertical direction, essentially dragging the port into the umbilicus (Figure 8A and B). During insertion of the port, the assistant provides constant counter traction by elevating the anterior abdominal wall with the Kocher clamps. Once the port is in the umbilicus, the second clamp is then removed. Before the Kocher clamps are removed, digital pressure is applied to the center of the port to push the port as deeply into the umbilicus as possible. When properly placed, the inner lip of the port should be located in the abdominal cavity and the outer lip above the level of the skin. The port is then adjusted so that the arrow is pointed towards the operative field. This assures that, when the single site trocars are placed, they will be properly oriented to the surgical field. At this point the abdomen is inflated and the patient is placed in the Trendelenburg position.
Kocher clamps placed on robotic port to facilitate placement.
Initial placement of the robotic port can be a challenge when the umbilicus is relatively deep, as it can be difficult to place the inner lip of the port past the peritoneum. To overcome this, it helps to place an extra small Alexis retractor in the umbilicus. Once the Alexis retractor is folded down, the depth of the umbilicus is reduced, and the peritoneum is pulled upward towards the skin. Using two Kocher clamps to elevate the fascia bilaterally, the robotic port can then be placed in the umbilicus inside the Alexis retractor. Some surgeons routinely use this technique to place the robotic single incision port (Figures 9 and 10).
The robotic single site port is relatively fragile. Excessive force will cause it to tear which can lead to difficulty maintaining an adequate pneumoperitoneum during surgery. If difficulty is encountered with insertion, enlarge the skin and fascial incisions by a millimeter or two and re-attempt port placement.
The key to easy port placement is to make sure that the tip of the second Kelly clamp is intra-peritoneal once the first Kelly clamp is removed. This allows the second Kelly clamp to pull the port into the abdomen rather than to push it in. Pushing it in often leads to tearing of the port. To maintain the proper location of the second Kelly clamp while removing the first one, the operator’s non-dominant hand needs to maintain firm and constant pressure holding the port in place. If the port slips out even slightly, the tip of the second Kelly will not be intraperitoneal.
Initial Kocher clamp slides the robotic port into the abdomen in a “C” shaped motion.
Second Kocher clamp drags the port completely into the umbilicus after removing the first clamp.
The camera trocar is straight and 8 mm in diameter. It is placed through the vertical middle channel between the plastic insufflation tube and the assistant trocar channel. The assistant trocars are also straight and either 5 mm or 10 mm in diameter. Either one can be placed through the vertical assistant channel adjacent to the camera trocar. The 5 mm single site trocars are curved and come in two sizes — one shorter and one longer. They are placed through the remaining channels on the robotic port. These channels traverse the port diagonally, so that the right trocar emerges one the left side intra-abdominally, and vice versa. Once placed, the trocars criss cross each other in the port (Figure 11). All trocars are inserted until the thin black line on the trocars reaches the external edge of the port. All of the trocars have a blunt obturator to assist with insertion through the robotic port.
With the Alexis retractor secured to the umbilicus, and Kocher clamps attached to the fascia, the robotic port is inserted in the usual manner.
The trocars are inserted after the robotic port has been placed in the umbilicus, the abdomen insufflated, and the patient placed in Trendelenburg position. The camera trocar is introduced first. With the surgeon and assistant stabilizing the robotic port in the umbilicus, the trocar is placed through the appropriate channel in a direction parallel to the long axis of the port. Unlike multi-port robotic surgery, the robot is docked at this point, the camera trocar is attached to the appropriate robotic arm, and targeting is performed. Docking at this stage facilitates placement of the additional trocars.
To place the 5 mm curved single site trocars, the laparoscope is placed in the 30 degree up position and oriented 90 degrees from the pelvis towards the right lower quadrant of the abdomen. The intra-abdominal right sided trocar is placed first (from the left side of the patient). Using one hand to stabilize the port, the surgeon’s other hand inserts the trocar through the port in a direction perpendicular to the long axis of the patient, from left to right. Once through the port and within the abdomen, the laparoscope can then visualize the tip of the trocar with the obturator in it. Under continuous laparoscopic visualization, the 5 mm trocar is then turned and advanced towards the pelvis until the thin black line on the trocar shaft reaches the robotic port. After placing the left-sided trocar into the right intra-abdominal space, the laparoscope is turned 180 degrees and oriented to visualize the left lower quadrant of the abdomen. The right-sided trocar is then placed into the left lower abdominal region using the same technique. The robotic arms are then docked to the curved trocars. Keeping the laparoscope in the 30 degree up position the assistant trocar is then placed parallel to the camera trocar.
Lubricating the trocars makes insertion easier. Surgilube lubricating jelly helps. However, in my experience, coating the trocars and obturator tip with a little blood and grease from the umbilical incision works best and makes trocar insertion very smooth.
When attaching the robotic arms to the trocars, it helps to visualize the operative field with both trocars visible on the monitor. This orients the trocars for easy docking.
The robotic single site instruments are all 5 mm, semi-rigid, and flexible. The semi-rigid nature of the instruments allows them to effectively manipulate tissue. The flexibility allows them to be inserted through the curved single site trocars. However, that flexibility comes at a price — the grasping power of the instruments is significantly weaker than standard robotic instruments. This makes it harder to hold tissue on tension, and it makes needles in the needle driver more likely to pivot with any lateral tension. Another drawback is that the only instruments with electrical energy are the unipolar hook and the bipolar forceps. The scissors have no electrical power. The robotic single site instruments currently available are
5 mm Maryland Dissector
5 mm Hem-o-Lok ML Clip Applier
5 mm Suction Irrigator
5 mm Cadiere Grasper
5 mm Curved Scissors
5 mm Fundus Grasper
5 mm Crocodile Grasper
5 mm Maryland Bipolar Forceps
5 mm Curved Needle Driver
5 mm Permanent Cautery Hook
5 mm Fenestrated Bipolar Forceps
5 mm Wristed Needle Driver
While this appears to be a wide array of instruments, in reality, most single site surgery is performed primarily with the bipolar forceps, unipolar hook, and wristed needle driver. The bipolar forceps functions as a grasper. As a result, unless extra tension is needed for traction, most of the other graspers will be used infrequently. Without unipolar power, the scissors become less valuable. The scissors are probably most useful only when operating near bowel or other situations where unipolar energy may pose an unnecessary risk.
The unipolar hook is an instrument relatively unfamiliar to gynecologic surgeons. As a result, there is a learning curve associated with its use. However, most experienced surgeons readily adapt to it without much difficulty.
When transecting tissue with the hook, constant tension is required. Otherwise, the hook will tend to over-cauterize the tissue and stick to it. This not only makes the surgery look awkward but tends to cause bleeding from the tissue when the hook is pulled free.
As discussed previously, there are some inherent disadvantages in the robotic single site system. The purpose of this section is to offer some practical advice to help overcome these limitations
Performing surgery with the robotic laparoscope in the 30 degree up position (as opposed not 30 degree down) dramatically increases the ability of the surgical assistant to aid in the operation. Thirty degree up places the robotic laparoscope in a more vertical position. This provides easy access to the abdominal cavity via the assistant trocar. In this position, when the assistant places an instrument, it presents to the surgeon right between the single site trocars in the middle of the operative field. The major advantage of this positioning is that it allows introduction of advanced energy into the operative field in a functional manner (Figure 12).
For instance, when performing a single site hysterectomy, I routinely utilize the 30 degree up positioning for most of the surgery. After isolating the uterine vessels, I grasp them with the single site instruments distally and proximally. My assistant can then easily secure the pedicle with a Ligasure device brought through the assistant trocar. The 30 degree up positioning also allows more freedom of movement for the assistant to manipulate tissue laterally and assist the surgeon.
The most obvious tip for facilitating the performance of single site robotic surgery is to add an 8 mm accessory robotic trocar laterally to the umbilicus. The colloquial term for this would be “single site plus one.” A right-handed surgeon would likely place this on the patient’s right side; the opposite placement is preferred for left-handed surgeons. All regular wristed robotic instruments are then potentially available to be placed through this port, including the Vessel Sealer, unipolar scissors, single tooth tenaculum, or needle drivers with (more wristing capability and more grasping power). Adding an 8 mm plus one port is a great way to get started with single site surgery.
Despite the fact that most single-site robotic gynecologic surgery is performed with the shorter curved trocars, one of the biggest difficulties to contend with is that the workspace is still limited. The trocars are fixed in length, and the instruments cannot be retracted back past the trocar tips. However, this limitation can be overcome with several strategies. First, it helps to pull the tissue to be operated on into the pelvis. This is somewhat counter-intuitive to the normal pelvic surgeon. In general, we tend to elevate tissue or push the pelvic organs cephalad with a vaginal manipulator. Retracting the tissue inferiorly pulls it into the workspace of the single site instruments. Second, a small advantage can be gained by pulling the single site trocars back slightly so that the black line on the trocar is 1-2 cm above the robotic port. This technique can be helpful with larger pathology or if access is needed to the pelvic brim or sacral promontory.
Passing sutures and needles can only be done through the 10 mm assistant trocar. 10 mm needles tend to easily pass into the abdomen through the port. However, retrieval can be difficult and frustrating. Often the needle can get caught in the trocar tip, become dislodged from the grasper holding it, and fall back into the abdominal cavity. One solution is to anchor the used needles into the peritoneum in the midline of the anterior abdominal wall. Multiple needles can be stored in this manner, When the procedure is completed, the needles can be placed in a laparoscopic bag. Once the robotic port is removed, the bag can be retrieved through the umbilicus with the needles in it.
Make the umbilical incision as small as possible to allow placement of the robotic port. Too large an incision increases the risk for air leakage around the port and can lead to difficulty maintaining an adequate pneumoperitoneum during surgery. When creating the incision, keep in mind that it can always be made bigger, but it cannot be made smaller. If a 10 mm assistant trocar is not needed during the surgery, an 8 mm AirSeal trocar with a 5 mm channel (specifically made for robotic single site surgery) can be inserted through the robotic port. The AirSeal trocar will maintain the pneumoperitoneum even with significant leakage of gas.
When operating laterally the workspace can also be limited. Angling the camera way from the horizontal axis towards the lateral pelvis can overcome the obstacle. When the camera is angled, it allows for greater lateral movement of the single site instruments. Such a strategy helps access areas such as the pelvic brim or the base of the infundibulopelvic ligament.
Cauterizing a vascular pedicle such as the infundibulopelvic ligament can take longer due to the weaker grasping power of the bipolar forceps. When bipolar cautery is engaged, bubbling can be seen around the forceps. The pedicle is adequately cauterized when the bubbling recedes. Cautery should continue until this is seen, and only then should the pedicle be cut.
Most gynecologic surgery is performed using the shorter 5 mm curved trocars. However, the longer trocars can assist with suturing deep in the pelvis, particularly the vaginal cuff. The semi-rigid nature of the single site instruments can make it difficult to drive a needle through relatively tough tissue. The instruments tend to bend when tension is applied, and this weakens the force that can be applied to the needle in order to drive it through tissue. Exchanging the shorter 5 mm trocar for the longer one minimizes the bending of the needle driver when force is applied. This increases the driving force that can be applied to the needle to drive it through tissue.
Single site trocars cross within the robotic port.
Once the port is removed, the fascia and peritoneum are closed with a single running non-locking 0 Vicryl suture. With the fascia closed, flaps are created bilaterally by undermining the skin on either side of the incision until all tension is released. This assures that the umbilicus will appear symmetric when finally closed. Several millimeters of skin are then trimmed on either side along the entire length of the vertical incision. More skin is trimmed from the center of the incision and less inferiorly or superiorly. Trimming of the skin improves blood flow to the edges. Given the generally poor blood flow to the umbilicus, freshening the edges improves healing. Additionally, trimming the skin makes the size of the incision smaller when it is ultimately closed; it tends to pull the incision into the umbilicus.
The base of the umbilicus is then recreated. One or two 2–0 Vicryl sutures on a non-cutting needle are then used to tack the middle of each half of the incision to the fascia. A non-cutting needle is used to avoid inadvertently cutting the fascial stitch. A deep bite is taken in the fascia to assure that the skin is securely attached. Interrupted inverted 3–0 Vicryl sutures on a cutting needle are then placed in the inferior and superior poles of the incision to reapproximate the skin. Care is taken to include a significant amount of subcutaneous fat with these sutures in order to bulk up the tissue at both poles of the incision (Figures 13–17).
With the laparoscope in the 30 degree up position, the surgeon’s assistant has easy access to the operative field. When the assistant places an instrument, it presents directly between both single site trocars.
Skin flaps are created bilaterally by sharply detaching the skin from the fascia until no tension remains.
Redundant skin.
Redundant skin is trimmed.
The skin of both sides of the incision is secured to the fascia with one or two absorbable sutures.
A small amount of packing is placed in the umbilicus, and an eye patch trimmed to a 2–3 cm circle is placed over the packing. A medium Tegaderm patch is then placed over the trimmed eye patch. Using a small needle and a 10 ml syringe with reverse suction, the air under the Tegaderm is removed creating a negative pressure dressing. The needle should be placed through the Tegaderm and skin adjacent to the dressing not through the center over the eye patch, otherwise the negative pressure will not be maintained.
Minor gynecologic surgery generally encompasses surgery on the adnexa and excision of pelvic endometriosis. The single site robotic approach for minor gynecologic surgery offers advantages over both traditional multi-port laparoscopic and robotic surgery. Compared to traditional multi-port surgery, the single site approach is more cosmetic, decreases postoperative pain, and removes the risk of trocar related complications.
In addition, with traditional multi-port laparoscopic or robotic surgery, specimen removal from the abdomen can be challenging. Often one of the incisions needs to be enlarged in order to extract the tissue, resulting in the potential for increased post-operative pain and other wound complications. By contrast, single site robotic surgery provides easy access through the umbilicus for specimen retrieval and morcellation if necessary.
Compared to laparoscopic surgery, both single site and multi-port, the 3D binocular vision and the intuitive ergonomics of the robotic single site platform offer significant advantages. The 3D vision improves dexterity and makes complex ergonomic tasks easier. In addition, the manipulation of tissue is more intuitive with the single site system. This results in more fluid surgical movements and less sword fighting. Finally, although only the single site needle driver is wristed, this compares favorably to laparoscopic instruments that are all uniformly non-wristed.
When contemplating whether to employ the single site robotic approach, consider several factors. First, how difficult is the expected operation. Depending on the surgeon’s experience and familiarity with single site surgery, more complex operations may necessitate a multi-port approach. Second, how skilled is the individual surgeon in performing laparoscopic single site surgery. Single site surgery, whether robotic or laparoscopic, virtually always benefits the patient. If a particular surgeon is skilled in laparoscopic single site surgery, this may be a more appropriate technique to use. For an experienced single site surgeon, the laparoscopic approach can be more efficient and can be performed with a slightly smaller umbilical incision.
Ovarian cystectomy is arguably the operation uniquely suited to the robotic single site system. Stripping of an ovarian cyst and suturing the ovary are ergonomically difficult with the laparoscopic single site approach. Multi-port approaches, whether laparoscopic or robotic, may facilitate performing the cystectomy, but they increase the risk for postoperative complications. With the robotic single site approach, the cyst can be easily opened and decompressed. The cyst lining is easily stripped using a grasper and wristed needle driver. Specimen retrieval is easily accomplished through the umbilicus.
For the same reasons, excision of pelvic endometriosis is an operation often well suited to the robotic single site approach. To excise endometriotic implants or explore the pelvic sidewall, significant dexterity is often required. The surgical site is often in a tight space with minimal mobility to the tissue. This creates difficulties even for the experienced laparoscopic single site surgeon.
When first starting to perform robotic single site surgery, the option of adding an additional 8 mm accessory trocar can increase the comfort level of the surgeon. The additional trocar makes all wristed robotic instruments potentially available to assist in the surgery. Eventually, with experience, the extra trocar will become less necessary. Adding the additional trocar mitigates but does not cancel out the benefits of the single site approach. One extra trocar is still better for the patient than 2 or 3 additional ones.
The robotic single site system provides a unique surgical approach that can be easily adopted and utilized for gynecologic surgery. It expands the opportunities to perform single surgery beyond just the laparoscopic approach. The single site approach, whether laparoscopic or robotic, virtually always benefits the patient. For the individual surgeon, especially one not particularly comfortable with laparoscopic single site surgery, the robotic single site system can facilitate the transition to single incision surgery as the primary approach to many gynecologic operations. However, even the experienced single site laparoscopic surgeon will find instances where the robotic single site approach is more advantageous.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
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\\n\\nLicense
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\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
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\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
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\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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The researchers all over the world have been studying fundamental and advanced processes to better understand and thereby predict the genesis and evolution of TCs. This review chapter provides a brief overview on TC climatology, their basic characteristics, movement and intensification, research on structure analysis and prediction of these fascinating storms, with primary emphasis to North Indian Ocean (NIO). The role of ocean and atmosphere in determining the genesis and intensification of TCs is discussed. This chapter reviews the past and current research activities including inter-annual and intra-seasonal changes in TCs, current status of TC research using numerical weather prediction, gaps identified and relevant measures taken by the meteorological and government agencies in this direction, along with future directions in order to improve the understanding and predictability over the NIO region.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Kasturi Singh, Jagabandhu Panda, Krishna K. Osuri and Naresh\nKrishna Vissa",authors:[{id:"178828",title:"Dr.",name:"Naresh",middleName:null,surname:"Vissa",slug:"naresh-vissa",fullName:"Naresh Vissa"},{id:"178872",title:"Dr.",name:"Jagabandhu",middleName:null,surname:"Panda",slug:"jagabandhu-panda",fullName:"Jagabandhu Panda"},{id:"180613",title:"Ms.",name:"Kasturi",middleName:null,surname:"Singh",slug:"kasturi-singh",fullName:"Kasturi Singh"},{id:"180614",title:"Dr.",name:"Krishna K.",middleName:null,surname:"Osuri",slug:"krishna-k.-osuri",fullName:"Krishna K. Osuri"}]},{id:"51981",doi:"10.5772/64859",title:"An Operational Statistical Scheme for Tropical Cyclone-Induced Rainfall Forecast",slug:"an-operational-statistical-scheme-for-tropical-cyclone-induced-rainfall-forecast",totalDownloads:1675,totalCrossrefCites:1,totalDimensionsCites:9,abstract:"Nonparametric methods are used in this study to analyze and predict short-term rainfall due to tropical cyclones (TCs) in a coastal meteorological station. All 427 TCs during 1953–2011, which made landfall along the Southeast China coast with a distance less than 700 km to a certain meteorological station, Shenzhen, are analyzed and grouped according to their landfalling direction, distance, and intensity. The corresponding daily rainfall records at Shenzhen Meteorological Station (SMS) during TCs landfalling period (a couple of days before and after TC landfall) are collected. The maximum daily rainfall (R24) and maximum 3-day accumulative rainfall (R72) records at SMS for each TC category are analyzed by a nonparametric statistical method, percentile estimation. The results are plotted by statistical boxplot, expressing in the probability of precipitation. The performance of the statistical boxplots was evaluated to forecast the short-term rainfall at SMS during the TC seasons in 2012 and 2013. The results show that the boxplot scheme can be used as a valuable reference to predict the short-term rainfall at SMS due to TCs landfalling along the Southeast China coast.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Qinglan Li, Hongping Lan, Johnny C.L. Chan, Chunyan Cao, Cheng Li\nand Xingbao Wang",authors:[{id:"179370",title:"Dr.",name:"Qinglan",middleName:null,surname:"Li",slug:"qinglan-li",fullName:"Qinglan Li"},{id:"185562",title:"Prof.",name:"Hongping",middleName:null,surname:"Lan",slug:"hongping-lan",fullName:"Hongping Lan"},{id:"185563",title:"Prof.",name:"Johnny C.L.",middleName:null,surname:"Chan",slug:"johnny-c.l.-chan",fullName:"Johnny C.L. Chan"},{id:"185564",title:"Ms.",name:"Chunyan",middleName:null,surname:"Cao",slug:"chunyan-cao",fullName:"Chunyan Cao"},{id:"185565",title:"Mr.",name:"Cheng",middleName:null,surname:"Li",slug:"cheng-li",fullName:"Cheng Li"},{id:"185566",title:"Dr.",name:"Xingbao",middleName:null,surname:"Wang",slug:"xingbao-wang",fullName:"Xingbao Wang"}]},{id:"50973",doi:"10.5772/64009",title:"Influence of Tropical Cyclones in the Western North Pacific",slug:"influence-of-tropical-cyclones-in-the-western-north-pacific",totalDownloads:2275,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"The Western North Pacific (WNP) is the most favorable area in the world for the generation of tropical cyclones (TCs). As the most intense weather system, TCs play an important role in the change of ocean environment in the WNP. Based on many investigations published in the literature, we obtained a collective and systematic understanding of the influence of TCs on ocean components in the WNP, including sea temperature, ocean currents, mesoscale eddies, storm surges, phytoplankton (indicated by chlorophyll a). Some ocean responses to TCs are unique in the WNP because of the existence of the Kuroshio and special geographical configurations such as the South China Sea.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Wen-Zhou Zhang, Sheng Lin and Xue-Min Jiang",authors:[{id:"179513",title:"Dr.",name:"Wen-Zhou",middleName:null,surname:"Zhang",slug:"wen-zhou-zhang",fullName:"Wen-Zhou Zhang"},{id:"180488",title:"BSc.",name:"Sheng",middleName:null,surname:"Lin",slug:"sheng-lin",fullName:"Sheng Lin"},{id:"180491",title:"BSc.",name:"Xue-Min",middleName:null,surname:"Jiang",slug:"xue-min-jiang",fullName:"Xue-Min Jiang"}]},{id:"51916",doi:"10.5772/64114",title:"Satellite Remote Sensing of Tropical Cyclones",slug:"satellite-remote-sensing-of-tropical-cyclones",totalDownloads:2520,totalCrossrefCites:4,totalDimensionsCites:3,abstract:"This chapter provides a review on satellite remote sensing of tropical cyclones (TCs). Applications of satellite remote sensing from geostationary (GEO) and low earth orbital (LEO) platforms, especially from passive microwave (PMW) sensors, are focused on TC detection, structure, and intensity analysis as well as precipitation patterns. The impacts of satellite remote sensing on TC forecasts are discussed with respect to helping reduce the TC's track and intensity forecast errors. Finally, the multi‐satellite‐sensor data fusion technique is explained as the best way to automatically monitor and track the global TC's position, structure, and intensity.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Song Yang and Joshua Cossuth",authors:[{id:"178744",title:"Dr.",name:"Song",middleName:null,surname:"Yang",slug:"song-yang",fullName:"Song Yang"},{id:"179320",title:"Dr.",name:"Joshua",middleName:null,surname:"Cossuth",slug:"joshua-cossuth",fullName:"Joshua Cossuth"}]},{id:"51288",doi:"10.5772/64099",title:"Upper Ocean Physical and Biological Response to Typhoon Cimaron (2006) in the South China Sea",slug:"upper-ocean-physical-and-biological-response-to-typhoon-cimaron-2006-in-the-south-china-sea",totalDownloads:1602,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The physical dynamic and biological response processes to Typhoon Cimaron (2006) in the South China Sea are investigated through the three‐dimensional Regional Ocean Modeling System (ROMS). For sea surface temperatures, ROMS achieves a correlation of more than 0.84, with respect to satellite observations, indicating a generally high level of skill for simulating the sea surface temperature variations during Typhoon Cimaron (2006). However, detailed analysis shows that ROMS underestimates the sea surface temperature cooling and mixed layer deepening because of insufficient mixing in the model simulations. We show that the simulation accuracy can be enhanced by adding a wave‐induced mixing term (BV) to the nonlocal K‐profile parameterization (KPP) scheme. Simulation accuracy is needed to investigate nutrients, which are deeply entrained to the oligotrophic sea surface layer by upwelling induced by Typhoon Cimaron, and which plays a remarkable role in the subsequent phytoplankton bloom. Simulations show that the phytoplankton bloom was triggered 5 days after the passage of the storm. The surface ocean was restored to its equilibrium ocean state by about 10–20 days after the typhoon's passage. However, on this time‐scale, the resulting concentrations of nitrate and chlorophyll a remained higher than those in the pre-typhoon equilibrium.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Yujuan Sun, Jiayi Pan and William Perrie",authors:[{id:"179303",title:"Prof.",name:"Jiayi",middleName:null,surname:"Pan",slug:"jiayi-pan",fullName:"Jiayi Pan"},{id:"180358",title:"Dr.",name:"Yujuan",middleName:null,surname:"Sun",slug:"yujuan-sun",fullName:"Yujuan Sun"},{id:"180359",title:"Prof.",name:"William",middleName:null,surname:"Perrie",slug:"william-perrie",fullName:"William Perrie"}]}],mostDownloadedChaptersLast30Days:[{id:"51652",title:"Satellite Climatology of Tropical Cyclone with Concentric Eyewalls",slug:"satellite-climatology-of-tropical-cyclone-with-concentric-eyewalls",totalDownloads:1495,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"An objective method is developed to identify concentric eyewalls (CEs) for tropical cyclones (TCs) using passive microwave satellite imagery from 1997 to 2014 in the western North Pacific (WNP) and Atlantic (ATL) basin. There are 91 (33) TCs and 113 (50) cases with CE identified in the WNP (ATL). Three CE structural change types are classified as follows: a CE with the inner eyewall dissipated in an eyewall replacement cycle (ERC, 51 and 56% in the WNP and ATL), a CE with the outer eyewall dissipated first and the no eyewall replacement cycle (NRC, 27 and 29% in the WNP and ATL), and a CE structure that is maintained for an extended period (CEM, 23 and 15% in the WNP and ATL). The moat size and outer eyewall width in the WNP (ATL) basin are approximately 20–50% (15–25%) larger in the CEM cases than that in the ERC and NRC cases. Our analysis suggests that the ERC cases are more likely dominated by the internal dynamics, whereas the NRC cases are heavily influenced by the environment condition, and both the internal and environmental conditions are important in the CEM cases. A good correlation of the annual CE TC number and the Oceanic Niño index is found (0.77) in WNP basin, with most of the CE TCs occurring in the warm episodes. In contrast, the El Niño/Southern Oscillation (ENSO) may not influence on the CE formation in the ATL basin. After the CE formation, however, the unfavorable environment that is created by ENSO may reduce the TC intensity quickly during warm episode. The variabilities of structural changes in the WNP basin are larger than that in the ATL basin.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Yi-Ting Yang, Hung-Chi Kuo, Eric A. Hendricks and Melinda S. Peng",authors:[{id:"24152",title:"Dr.",name:"Melinda",middleName:null,surname:"Peng",slug:"melinda-peng",fullName:"Melinda Peng"},{id:"24153",title:"Prof.",name:"Hung-Chi",middleName:null,surname:"Kuo",slug:"hung-chi-kuo",fullName:"Hung-Chi Kuo"},{id:"179607",title:"Dr.",name:"Yi-Ting",middleName:null,surname:"Yang",slug:"yi-ting-yang",fullName:"Yi-Ting Yang"},{id:"180632",title:"Prof.",name:"Eric",middleName:null,surname:"Hendricks",slug:"eric-hendricks",fullName:"Eric Hendricks"}]},{id:"51981",title:"An Operational Statistical Scheme for Tropical Cyclone-Induced Rainfall Forecast",slug:"an-operational-statistical-scheme-for-tropical-cyclone-induced-rainfall-forecast",totalDownloads:1675,totalCrossrefCites:1,totalDimensionsCites:9,abstract:"Nonparametric methods are used in this study to analyze and predict short-term rainfall due to tropical cyclones (TCs) in a coastal meteorological station. All 427 TCs during 1953–2011, which made landfall along the Southeast China coast with a distance less than 700 km to a certain meteorological station, Shenzhen, are analyzed and grouped according to their landfalling direction, distance, and intensity. The corresponding daily rainfall records at Shenzhen Meteorological Station (SMS) during TCs landfalling period (a couple of days before and after TC landfall) are collected. The maximum daily rainfall (R24) and maximum 3-day accumulative rainfall (R72) records at SMS for each TC category are analyzed by a nonparametric statistical method, percentile estimation. The results are plotted by statistical boxplot, expressing in the probability of precipitation. The performance of the statistical boxplots was evaluated to forecast the short-term rainfall at SMS during the TC seasons in 2012 and 2013. The results show that the boxplot scheme can be used as a valuable reference to predict the short-term rainfall at SMS due to TCs landfalling along the Southeast China coast.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Qinglan Li, Hongping Lan, Johnny C.L. Chan, Chunyan Cao, Cheng Li\nand Xingbao Wang",authors:[{id:"179370",title:"Dr.",name:"Qinglan",middleName:null,surname:"Li",slug:"qinglan-li",fullName:"Qinglan Li"},{id:"185562",title:"Prof.",name:"Hongping",middleName:null,surname:"Lan",slug:"hongping-lan",fullName:"Hongping Lan"},{id:"185563",title:"Prof.",name:"Johnny C.L.",middleName:null,surname:"Chan",slug:"johnny-c.l.-chan",fullName:"Johnny C.L. Chan"},{id:"185564",title:"Ms.",name:"Chunyan",middleName:null,surname:"Cao",slug:"chunyan-cao",fullName:"Chunyan Cao"},{id:"185565",title:"Mr.",name:"Cheng",middleName:null,surname:"Li",slug:"cheng-li",fullName:"Cheng Li"},{id:"185566",title:"Dr.",name:"Xingbao",middleName:null,surname:"Wang",slug:"xingbao-wang",fullName:"Xingbao Wang"}]},{id:"51916",title:"Satellite Remote Sensing of Tropical Cyclones",slug:"satellite-remote-sensing-of-tropical-cyclones",totalDownloads:2520,totalCrossrefCites:4,totalDimensionsCites:3,abstract:"This chapter provides a review on satellite remote sensing of tropical cyclones (TCs). Applications of satellite remote sensing from geostationary (GEO) and low earth orbital (LEO) platforms, especially from passive microwave (PMW) sensors, are focused on TC detection, structure, and intensity analysis as well as precipitation patterns. The impacts of satellite remote sensing on TC forecasts are discussed with respect to helping reduce the TC's track and intensity forecast errors. Finally, the multi‐satellite‐sensor data fusion technique is explained as the best way to automatically monitor and track the global TC's position, structure, and intensity.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Song Yang and Joshua Cossuth",authors:[{id:"178744",title:"Dr.",name:"Song",middleName:null,surname:"Yang",slug:"song-yang",fullName:"Song Yang"},{id:"179320",title:"Dr.",name:"Joshua",middleName:null,surname:"Cossuth",slug:"joshua-cossuth",fullName:"Joshua Cossuth"}]},{id:"51496",title:"Progress in Tropical Cyclone Predictability and Present Status in the North Indian Ocean Region",slug:"progress-in-tropical-cyclone-predictability-and-present-status-in-the-north-indian-ocean-region",totalDownloads:3306,totalCrossrefCites:8,totalDimensionsCites:14,abstract:"Tropical cyclone (TC) is an important research area since it has a significant impact on human life, properties and environment. The researchers all over the world have been studying fundamental and advanced processes to better understand and thereby predict the genesis and evolution of TCs. This review chapter provides a brief overview on TC climatology, their basic characteristics, movement and intensification, research on structure analysis and prediction of these fascinating storms, with primary emphasis to North Indian Ocean (NIO). The role of ocean and atmosphere in determining the genesis and intensification of TCs is discussed. This chapter reviews the past and current research activities including inter-annual and intra-seasonal changes in TCs, current status of TC research using numerical weather prediction, gaps identified and relevant measures taken by the meteorological and government agencies in this direction, along with future directions in order to improve the understanding and predictability over the NIO region.",book:{id:"5180",slug:"recent-developments-in-tropical-cyclone-dynamics-prediction-and-detection",title:"Tropical Cyclone Dynamics, Prediction, and Detection",fullTitle:"Recent Developments in Tropical Cyclone Dynamics, Prediction, and Detection"},signatures:"Kasturi Singh, Jagabandhu Panda, Krishna K. Osuri and Naresh\nKrishna Vissa",authors:[{id:"178828",title:"Dr.",name:"Naresh",middleName:null,surname:"Vissa",slug:"naresh-vissa",fullName:"Naresh Vissa"},{id:"178872",title:"Dr.",name:"Jagabandhu",middleName:null,surname:"Panda",slug:"jagabandhu-panda",fullName:"Jagabandhu Panda"},{id:"180613",title:"Ms.",name:"Kasturi",middleName:null,surname:"Singh",slug:"kasturi-singh",fullName:"Kasturi Singh"},{id:"180614",title:"Dr.",name:"Krishna K.",middleName:null,surname:"Osuri",slug:"krishna-k.-osuri",fullName:"Krishna K. Osuri"}]},{id:"50973",title:"Influence of Tropical Cyclones in the Western North Pacific",slug:"influence-of-tropical-cyclones-in-the-western-north-pacific",totalDownloads:2275,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"The Western North Pacific (WNP) is the most favorable area in the world for the generation of tropical cyclones (TCs). As the most intense weather system, TCs play an important role in the change of ocean environment in the WNP. Based on many investigations published in the literature, we obtained a collective and systematic understanding of the influence of TCs on ocean components in the WNP, including sea temperature, ocean currents, mesoscale eddies, storm surges, phytoplankton (indicated by chlorophyll a). 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Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. 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Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. 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