A general Bernoulli distribution in
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These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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Their aim is to walk and fly in search of food or to propagate their species. Thus, changing positions is important for creatures’ survival and maintaining the environment. As such, this book examines movement with a focus on force and propulsion. Chapters cover topics including rocket engines, electric propulsion, mechanisms of force, and more.",isbn:"978-1-83968-835-5",printIsbn:"978-1-83968-834-8",pdfIsbn:"978-1-83968-836-2",doi:"10.5772/intechopen.87830",price:119,priceEur:129,priceUsd:155,slug:"propulsion-new-perspectives-and-applications",numberOfPages:102,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"042ab0c0a8270b1bacf6a8e385601863",bookSignature:"Kazuo Matsuuchi and Hiroaki Hasegawa",publishedDate:"December 15th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10007.jpg",numberOfDownloads:1345,numberOfWosCitations:0,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:4,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:6,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 16th 2020",dateEndSecondStepPublish:"October 14th 2020",dateEndThirdStepPublish:"December 13th 2020",dateEndFourthStepPublish:"March 3rd 2021",dateEndFifthStepPublish:"May 2nd 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"42387",title:"Prof.",name:"Kazuo",middleName:null,surname:"Matsuuchi",slug:"kazuo-matsuuchi",fullName:"Kazuo Matsuuchi",profilePictureURL:"https://mts.intechopen.com/storage/users/42387/images/system/42387.jpg",biography:"Dr. Kazuo Matsuuchi obtained his Ph.D. in Engineering from Osaka University, Japan, in 1976. In 1977, he served as a research assistant at the Institute of Structural Engineering, University of Tsukuba, Japan. He became a full professor at the same university in 1995. In 2012 he earned the title of Professor Emeritus and he is still active at the University of Tsukuba. Dr. Matsuuchi was a visiting professor at Khon Kaen University, Thailand, and a specially appointed professor at the Oguz Khan Engineering and Technology University of Turkmenistan.",institutionString:"University of Tsukuba",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Tsukuba",institutionURL:null,country:{name:"Japan"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"321873",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Hasegawa",slug:"hiroaki-hasegawa",fullName:"Hiroaki Hasegawa",profilePictureURL:"https://mts.intechopen.com/storage/users/321873/images/system/321873.png",biography:"In 1989, Dr. Hiroaki Hasegawa started as a research engineer working on research and development of ramjet and jet engines at the Japan Defense Agency. In 1998, he earned the title of senior research engineer at the same agency. He obtained a Ph.D. in Engineering from the University of Tsukuba, Japan, in 1999. Dr. Hasegawa was appointed a lecturer in the Department of Mechanical Engineering, Akita University, Japan, in 2002. He is currently a professor in the Department of Mechanical and Intelligent Engineering, Utsunomiya University, Japan.",institutionString:"Utsunomiya University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Utsunomiya University",institutionURL:null,country:{name:"Japan"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"124",title:"Vehicle Engineering",slug:"vehicle-engineering"}],chapters:[{id:"79180",title:"Introductory Chapter: Propulsion and Movement",doi:"10.5772/intechopen.101071",slug:"introductory-chapter-propulsion-and-movement",totalDownloads:95,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Kazuo Matsuuchi",downloadPdfUrl:"/chapter/pdf-download/79180",previewPdfUrl:"/chapter/pdf-preview/79180",authors:[{id:"42387",title:"Prof.",name:"Kazuo",surname:"Matsuuchi",slug:"kazuo-matsuuchi",fullName:"Kazuo Matsuuchi"}],corrections:null},{id:"76789",title:"Hybrid Propulsion System: Novel Propellant Design for Mars Ascent Vehicles",doi:"10.5772/intechopen.96686",slug:"hybrid-propulsion-system-novel-propellant-design-for-mars-ascent-vehicles",totalDownloads:240,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"This chapter briefly introduces hybrid rocket propulsion for general audience. Advantageous of hybrid rockets over solids and liquids are presented. This chapter also explains how to design a test setup for hybrid motor firings. Hybrid propulsion provides sustainable, safe and low cost systems for space missions. Therefore, this chapter proposes hybrid propulsion system for Mars Ascent Vehicles. Paraffin wax is the fuel of the rocket. Propulsion system uses CO2/N2O mixture as the oxidizer. The goal is to understand the ignition capability of the CO2 as an in-situ oxidizer on Mars. CO2 is known as major combustion product in the nature. However, it can only burn with metallic powders. Thus, metallic additives are added in the fuel grain. Results show that CO2 increase slows down the chemical kinetics thus reduces the adiabatic flame temperature. Maximum flammability limit is achieved at 75% CO2 by mass in the oxidizer mixture. Flame temperature is 1700 K at 75% CO2. Ignition quenches below the 1700 K.",signatures:"Ozan Kara and Arif Karabeyoglu",downloadPdfUrl:"/chapter/pdf-download/76789",previewPdfUrl:"/chapter/pdf-preview/76789",authors:[{id:"332637",title:"Dr.",name:"Ozan",surname:"Kara",slug:"ozan-kara",fullName:"Ozan Kara"}],corrections:null},{id:"74791",title:"Keeping the Dream Alive: Is Propellant-less Propulsion Possible?",doi:"10.5772/intechopen.95603",slug:"keeping-the-dream-alive-is-propellant-less-propulsion-possible-",totalDownloads:418,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"“Breakthrough” advanced propulsion can only take place with a correct understanding of the role of inertia in general relativity. Einstein was convinced that inertia and gravitation were the obverse and reverse of the coin. The most general statement of the principle of relativity, captured in his Equivalence Principle and the gravitational induction of inertia. His ideas and how they have fared are reprised. A rest mass fluctuation that is expected when inertia is gravitationally induced is then mentioned that can be used for propulsion. Recent work supported by National Innovative Advanced Concepts Phase 1 and 2 NASA grants to determine whether thrusters based on gravitationally induced inertia can actually be made to work is presented. A recent design innovation has dramatically increased the thrust produced by these Mach Effect Gravity Assist (MEGA) impulse engines.",signatures:"James F. Woodward",downloadPdfUrl:"/chapter/pdf-download/74791",previewPdfUrl:"/chapter/pdf-preview/74791",authors:[{id:"335130",title:"Emeritus Prof.",name:"James F.",surname:"Woodward",slug:"james-f.-woodward",fullName:"James F. Woodward"}],corrections:null},{id:"75849",title:"Introduction to Plasma Based Propulsion System: Hall Thrusters",doi:"10.5772/intechopen.96916",slug:"introduction-to-plasma-based-propulsion-system-hall-thrusters",totalDownloads:322,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Technically, there are two types of propulsion systems namely chemical and electric depending on the sources of the fuel. Electrostatic thrusters are used for launching small satellites in low earth orbit which are capable to provide thrust for long time intervals. These thrusters consume less fuel compared to chemical propulsion systems. Therefore for the cost reduction interests, space scientists are interested to develop thrusters based on electric propulsion technology. This chapter is intended to serve as a general overview of the technology of electric propulsion (EP) and its applications. Plasma based electric propulsion technology used for space missions with regard to the spacecraft station keeping, rephrasing and orbit topping applications. Typical thrusters have a lifespan of 10,000 h and produce thrust of 0.1–1 N. These devices have E→×B→ configurations which is used to confine electrons, increasing the electron residence time and allowing more ionization in the channel. Almost 2500 satellites have been launched into orbit till 2020. For example, the ESA SMART-1 mission (Small Mission for Advanced Research in Technology) used a Hall thruster to escape Earth orbit and reach the moon with a small satellite that weighed 367 kg. These satellites carrying small Hall thrusters for orbital corrections in space as thrust is needed to compensate for various ambient forces including atmospheric drag and radiation pressure. The chapter outlines the electric propulsion thruster systems and technologies and their shortcomings. Moreover, the current status of potential research to improve the electric propulsion systems for small satellite has been discussed.",signatures:"Sukhmander Singh, Sanjeev Kumar, Shravan Kumar Meena and Sujit Kumar Saini",downloadPdfUrl:"/chapter/pdf-download/75849",previewPdfUrl:"/chapter/pdf-preview/75849",authors:[{id:"282807",title:"Dr.",name:"Sukhmander",surname:"Singh",slug:"sukhmander-singh",fullName:"Sukhmander Singh"}],corrections:null},{id:"76364",title:"Estimation of Cumulative Noise Reduction at Certification Points for Supersonic Civil Aeroplane Using the Programmed Thrust Management at Take-off and Approach",doi:"10.5772/intechopen.97465",slug:"estimation-of-cumulative-noise-reduction-at-certification-points-for-supersonic-civil-aeroplane-usin",totalDownloads:155,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The reduction of the cumulative noise level at certification points applying to the supersonic civil aeroplane is estimated in the paper. The reduction is obtained by using an programmed thrust management with Programmed Lapse Rate based on the variation of engine power setting at take-off and approach. The use of proposed programmed reduced noise thrust management requires a change of the conventional noise certification procedures as well as further implementation as fully automated system (Variable Noise Reduction System) into aircraft/engine control system. The main engine noise sources such as the fan and exhaust jet are taken into account in the estimation. It is shown that the cumulative noise level using proposed programmed thrust management is lower by 10.7–12.2 EPNdB than using the conventional engine thrust control as currently applied to subsonic jet aeroplanes at take-off and approach.",signatures:"Artur Mirzoyan and Iurii Khaletskii",downloadPdfUrl:"/chapter/pdf-download/76364",previewPdfUrl:"/chapter/pdf-preview/76364",authors:[{id:"335693",title:"Dr.",name:"Artur",surname:"Mirzoyan",slug:"artur-mirzoyan",fullName:"Artur Mirzoyan"},{id:"345912",title:"Dr.",name:"Iurii",surname:"Khaletskii",slug:"iurii-khaletskii",fullName:"Iurii Khaletskii"}],corrections:null},{id:"79119",title:"Thrust Force Generated by Heaving Motion of a Plate: The Role of Vortex-Induced Force",doi:"10.5772/intechopen.100435",slug:"thrust-force-generated-by-heaving-motion-of-a-plate-the-role-of-vortex-induced-force",totalDownloads:115,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"To understand the force acting on birds, insects, and fish, we take heaving motion as a simple example. This motion might deviate from the real one. However, since the mechanism of force generation is the vortex shedding due to the motion of an object, the heaving motion is important for understanding the force generated by unsteady motion. The vortices released from the object are closely related to the motion characteristics. To understand the force acting on an object, information about momentum change is necessary. However, in vortex systems, it is impossible to estimate the usual momentum. Instead of the momentum, the “virtual momentum,” or the impulse, is needed to generate the force. For calculating the virtual momentum, we traced all vortices over a whole period, which was carried out by using the vortex-element method. The force was then calculated based on the information on the vortices. We derived the thrust coefficient as a function of the ratio of the heaving to travelling velocity.",signatures:"Kazuo Matsuuchi",downloadPdfUrl:"/chapter/pdf-download/79119",previewPdfUrl:"/chapter/pdf-preview/79119",authors:[{id:"42387",title:"Prof.",name:"Kazuo",surname:"Matsuuchi",slug:"kazuo-matsuuchi",fullName:"Kazuo Matsuuchi"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7198",title:"Propulsion Systems",subtitle:null,isOpenForSubmission:!1,hash:"fd56f1620b0b201a3de0cd3f7e04d15c",slug:"propulsion-systems",bookSignature:"Alessandro Serpi and Mario Porru",coverURL:"https://cdn.intechopen.com/books/images_new/7198.jpg",editedByType:"Edited by",editors:[{id:"217145",title:"Dr.",name:"Alessandro",surname:"Serpi",slug:"alessandro-serpi",fullName:"Alessandro Serpi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10810",title:"Modern Ship Engineering, Design and Operations",subtitle:null,isOpenForSubmission:!1,hash:"579a9da63aca2172c0f0584328ae91c1",slug:"modern-ship-engineering-design-and-operations",bookSignature:"Carlos Reusser",coverURL:"https://cdn.intechopen.com/books/images_new/10810.jpg",editedByType:"Edited by",editors:[{id:"209816",title:"Dr.",name:"Carlos",surname:"Reusser",slug:"carlos-reusser",fullName:"Carlos Reusser"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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\r\n\tDemand for crude oil plummeted and prices fell during the coronavirus lockdown. Now, the world economy is recovering and the fuel demand is increasing. Crude oil has been one of the major energy sources globally and crude oil-derived products always play a crucial role as fuel and feedstock for the petrochemical industry, which is irreplaceable pro tem.
\r\n\tWith the discovery of more unconventional heavier crude and alternative hydrocarbon sources, primary upgrading or cracking of the oil into lighter liquid fuel is critical. With increasing concern for environmental sustainability, the regulations on fuel specifications are becoming more stringent. Processing and treating crude oil into a cleaner oil with better quality is equally important. Hence, there has been a relentless and continuous effort to develop new crude upgrading and treating technologies, such as various catalytic systems for more economical and better system performance, as well as cleaner and higher-quality oil.
\r\n\tThis edited book aims to provide the reader with an overview of the state-of-the-art technologies of crude oil downstream processing which include the primary and secondary upgrading or treating processes covering desulfurization, denitrogenation, demetallation, and evidence-based developments in this area.
",isbn:"978-1-80356-681-8",printIsbn:"978-1-80356-680-1",pdfIsbn:"978-1-80356-682-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"808b0ddfb3b92e0636ae44a83ef7dbd9",bookSignature:"Dr. Ching Thian Tye",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11542.jpg",keywords:"Crude Oil Properties, Hydrocracking, Catalytic Cracking, Coking, Visbreaking, Thermal Cracking, Hydroprocessing, Hydrodesulfurization, Desulfurization, Denitrogenation, Demetallation, Dearomatization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"April 19th 2022",dateEndThirdStepPublish:"June 18th 2022",dateEndFourthStepPublish:"September 6th 2022",dateEndFifthStepPublish:"November 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Associate professor at the School of Chemical Engineering in Universiti Sains Malaysia and dedicated researcher in fuel-related catalytic process and chemical reaction engineering. Dr. Tye serves on a review panel for international and national refereed journals, scientific proceedings as well as international grants.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"304947",title:"Dr.",name:"Ching Thian",middleName:null,surname:"Tye",slug:"ching-thian-tye",fullName:"Ching Thian Tye",profilePictureURL:"https://mts.intechopen.com/storage/users/304947/images/system/304947.jpg",biography:"Dr. Tye is an associate professor at the School of Chemical Engineering in Universiti Sains Malaysia. She received her doctoral degree at The University of British Columbia, Canada. She is working in the area of chemical reaction engineering and catalysis. She has been involved in projects to improve catalysis activities, system efficiency, as well as products quality via different upgrading and treating paths that are related to petroleum and unconventional oil such as heavy oil, used motor oil, spent tire pyrolysis oils as well as renewable resources like palm oil. She serves as a review panel for international & national refereed journals, scientific proceedings as well as international grants.",institutionString:"Universiti Sains Malaysia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Universiti Sains Malaysia",institutionURL:null,country:{name:"Malaysia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453623",firstName:"Silvia",lastName:"Sabo",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/453623/images/20396_n.jpg",email:"silvia@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"10198",title:"Response Surface Methodology in Engineering Science",subtitle:null,isOpenForSubmission:!1,hash:"1942bec30d40572f519327ca7a6d7aae",slug:"response-surface-methodology-in-engineering-science",bookSignature:"Palanikumar Kayaroganam",coverURL:"https://cdn.intechopen.com/books/images_new/10198.jpg",editedByType:"Edited by",editors:[{id:"321730",title:"Prof.",name:"Palanikumar",surname:"Kayaroganam",slug:"palanikumar-kayaroganam",fullName:"Palanikumar Kayaroganam"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"79602",title:"Primary Gastrointestinal Lymphoma",doi:"10.5772/intechopen.101424",slug:"primary-gastrointestinal-lymphoma",body:'The incidence of lymphoma, especially extranodal lymphoma, such as non-Hodgkin lymphoma (NHL) of the central nervous system (CNS), GI and cutaneous lymphomas has been increasing over the last decades [1, 2, 3].
The definition of PGIL has differed among different authors but typically refers to a lymphoma that develops in any part of the gastrointestinal tract (GIT) from the oropharynx to the anal canal. PGIL is the most common type of extranodal lymphoma comprising 25–40% of the latter depending on geographic regions [4, 5]. PGIL, however, is a rare malignancy, accounting for 1% to 4% of the malignant lesions in GIT [3, 6]. GIT several times more frequently is involved secondarily from nodal lymphoma [4].
Dawson’s criteria that were suggested 6 decades ago are used for the definition of PGIL, that include (1) absence of peripheral lymphadenopathy at the time of presentation; (2) lack of enlarged mediastinal lymph nodes (LNs); (3) normal total and differential white blood cell count; (4) predominance of bowel lesion at the time of laparotomy with only LNs affected in the immediate vicinity (LNs which are confined to the drainage area of the primary tumor site); and (5) no involvement of liver and spleen [7].
Histopathologically, almost 90% of the PGILs are of B-cell lineage, and T-cell lymphomas (TCLs) and Hodgkin lymphoma (HL) are rarely encountered in GIT [4, 8, 9]. Some histological subtypes of lymphoma have a relative propensity to develop in specific sites as mucosa-associated lymphoid tissue (MALT) lymphoma in the stomach, follicular lymphoma (FL) in the duodenum, enteropathy-associated T-cell lymphoma (EATL) in the jejunum, mantle cell lymphoma (MCL) in the terminal ileum and colon [10].
Due to the rarity of PGIL, opinions upon some aspects of this neoplasm are still controversial. The increasing incidence of this malignancy, makes it necessary for clinicians to understand the characteristic clinical manifestation, diagnostic properties, treatment and prognosis of PGIL more comprehensively [11].
In the last decades, a great achievement has been reached in the diagnosis, staging and management of PGIL attributed to a better understanding of its etiology and molecular aspect including signaling pathways [4]. The therapeutic approach to the cure of PGIL has completely changed over the last decade, including innovative conservative options to reduce the complication rate following treatment [11]. Nevertheless, the prognostic and diagnostic significance of mutational analysis in daily practice and its role in novel targeted therapy remains and requires to be determined [12].
PGIL, as mentioned above, is a rare malignancy, constituting 1% to 4% of the GIT cancer [4, 6]. Although theoretically lymphoma can arise from any region of the GIT stomach is the most frequently involved site (60–75%) followed by the small intestine [20–30%], ileocecal region (7%) and colon (6–12%). More than one gastrointestinal (GI) site is involved in 6–13% of the cases [4, 6, 13, 14, 15].
Primary esophageal lymphoma (PEL) is extremely rare comprising <1% of all PGILs. Less than 30 cases of PEL have been reported in the literature [4]. Primary gastric lymphoma (PGL) accounts for up to 5% of all malignancies of the stomach [16]. Primary small intestinal lymphoma (PSIL) constitutes 15–20% of all small bowel neoplasms [4]. Primary colorectal lymphoma (PCRL) comprises only 0.2% of all malignancies arising from the colorectum with caecum, ascending colon and rectum more frequently involved in decreasing order [14].
PGIL approximately 2–3 times more frequently is seen in men compared to women [4, 8, 11]. This ratio can be varied depending on the sites of PGIL and pathological subtypes. For example, DLBCL is seen in males 1.2–2 times more [17, 18], and FL affects males and females equally [19] or demonstrates a clear female predominance [20].
The age of the patients with PGIL can range from 19 to >90 years with a median age of 55 years [4, 8, 21]. The age range (and median age) depends on involved sites and pathological subtypes of PGIL. The median age of patients with TCL is usually by 10–14 years younger compared to B-cell lymphoma (BCL) [8, 22].
Different entities of the PGILs of B-cell lineage can demonstrate different peak ages. MALT lymphoma and MCL are most commonly detected between the age of 50 and 60 years [23]. On the contrary immunoproliferative small intestine disease (IPSID) is mainly seen in adolescents and younger adults [24, 25] and endemic Burkitt’s lymphoma (BL) is mainly detected in children [26].
Some forms of PGIL have a tendency to increase in its incidence in younger age group of people, the other ones tend to be encountered among some ethnics or have different geographical distribution. It has been observed that the incidence of MALT lymphoma has increased significantly in people older than 40 years [27]. Monomorphic epitheliotropic intestinal TCL (MEITL) is more common in people of Hispanic descent and is the most frequent primary intestinal TCL being detected in Asia [28]. PGL is the most common extranodal site of lymphoma in the USA. The predominant part of this neoplasm is either extranodal marginal zone lymphoma (MZL) of MALT or DLBCL. PSIL, while uncommon in Western countries, comprises up to 75% of PGIL in the Middle East, North and South Africa, and Mediterranean basin, because of that is commonly called “Mediterranean type lymphoma”. Endemic BL, the most common type of BL, has a geographical distribution identical to that of
Certain risk factors and disorders can be involved in the pathogenesis of PGIL including
Chronic gastritis related to
MALT lymphoma can be divided into
The role of
IPSID, also recognized as an alpha-chain disease, is considered as a variant of MALT lymphoma related to
Pathogenesis of primary PGIL can also be associated with other infectious agents like EBV, HIV, HBV and HTLV-1 [11]. The role of EBV-infection in the pathogenesis of B-cell NHL has been established [38]. Hui et al. reported 11 cases of PGL that harbor the EBV encoded small messenger RNA, EBER-1, detected by fluorescence in situ hybridization (FISH). The cases comprised 18% of 61 consecutive PGL. Nine of the 11 (81.8%) EBER-1-positive PGL cases were DLBCL-type without LG components. None of the EBER-1-positive gastric BCLs showed histological features characteristic of LG lymphoma of MALT-type being common in Western countries. Of the two patients with TCL, one had a pleomorphic TCL and the other had an angiocentric lymphoma. They concluded that a significant proportion of PGL in Hong Kong Chinese are EBV-related and that they show histological features more similar to conventional nodal lymphomas than to MALT-type lymphomas [39].
BL has three recognized clinical variants: endemic form, sporadic variant and immunodeficiency-associated BL. There is clear evidence regarding the role of EBV and
EBV infection is also associated with the EBV-positive DLBCL, recently recognized as a definite entity. The term “elderly” in the 2008 WHO classification has been substituted by NOS (not otherwise specified) because this lymphoma can be encountered in younger patients as well [12].
A recently recognized entity, EBV-positive mucocutaneous ulcer (MCU) is characteristically associated with iatrogenic immunosuppression (for autoimmune or inflammatory conditions and solid organ transplantation), HIV-infection and age-related immunosenescence that leads to inadequate immune surveillance for EBV. It is characterized by the propagation of EBV-positive atypical large B-cells affecting the skin or mucous sites, presumably related to local trauma or inflammation [41, 42]. Most cases of EBV-positive MCU are detected in the elderly (due to predisposing age-associated immunosenescence in half of the patients), but the patients with iatrogenic immunosuppression usually have a younger age. Patients treated by immunosuppressive therapy for IBD may be all the more vulnerable due to the presence of local tissue injury related to the mentioned disease [19].
NK/T cell neoplasms are invariably associated with EBV infection and are mostly aggressive; thus, differentiation from a benign NK-cell enteropathy is paramount [15]. BL is associated with EBV and HIV/AIDS, and most commonly affects children [26].
GI lesions as the most frequent extranodal manifestation of HIV-associated NHL lymphoma (occurs in 5–10% of individuals with HIV-infection), are late events of HIV-infection with severe immunosuppression and are mostly diagnosed in advanced stages of the disease. They are characterized by HG B-cell histology, frequently multifocal location in the GIT, high rates of life-threatening complications (bleeding, perforation or obstruction) [43, 44]. NHL is the second most common type of malignancy in HIV-patients following Kaposi sarcoma [45]. The high incidence of GI NHL prompted Powitz et al. to commence a prospective survey on 93 of 341 HIV-infected patients with GI symptoms who were examined by endoscopy, some selected patients by endoscopic ultrasound (EUS). NHL of the GIT was detected in seven of 93 endoscopically examined patients (7.5%) [44].
Nearly 70–90% of AIDS-related lymphomas are highly aggressive and are almost exclusively BL and an immunoblastic variant of DLBCL. Compared to the general population, the relative risk for highly aggressive lymphomas is higher >400-fold overall [46], and 260-fold and 650-fold for BL and DLBCL, respectively among HIV-infected people [47]. BL can be one of the diseases associated with the initial manifestation of AIDS [48]. The indolent lymphomas are less common, comprising <10% of AIDS-related lymphomas. Compared to the general population, the relative risk is increased nearly 15-fold for indolent lymphomas and TCLs in the HIV-positive population [46, 47, 49]. However, TCLs are less common in HIV-infected people as well despite the increased relative risk. Of note, 40–50% of cases of HIV-associated BL are positive for EBV [48].
The epidemiologic association between HBV-infection and NHL, notably DLBCL is well established. Most studies concerning this association have been conducted in endemic areas. Some researchers report up to 2.5 times higher risk of NHL in HBV-infected people. Deng et al. studied HBV-infection status and clinicopathologic features of 587 patients with DLBCL in HBV-endemic China. Eighty-one (13.8%) patients were HBsAg-positive, 20 of which (25%) had DLBCL in GIT. Compared to HBsAg-negative DLBCL, HBsAg-positive DLBCL demonstrated a younger median onset age by 10 years, more advanced stages of the disease and significantly worse outcome [50].
PGL with a T-cell phenotype is very rare, comprising only 7% of PGLs in endemic areas of HTLV-1 infection. Primary gastric TCL without HTLV-1 infection is extremely rare, and sporadic cases have been occasionally reported [51].
PGIL is one of the major and serious complications of different diseases and conditions presenting with immunodepression, both congenital (Wiskott-Aldrich syndrome, ataxia-telangiectasia, X-linked agammaglobulinemia) and acquired immunodeficiency (HIV-infection, iatrogenic immunosuppression). Lymphomas developed in the setting of the diseases associated with immunodepression are pathologically and clinically heterogeneous, but share some hallmarks such as frequent involvement of extranodal sites, association with EBV-infection, B-cell lineage genesis, and aggressive behavior. Although PGIL associated with congenital immunodeficient conditions seems to be an infrequent occasion despite the higher prevalence of post-transplantation lymphoproliferative disorders GIT is one of the most involved sites of lymphoma [43]. It should be noted that PEL in an immunocompetent patient is very rare [52].
The three most common systemic autoimmune diseases—rheumatoid arthritis, primary Sjögren’s syndrome (PSS) and systemic lupus erythematosus, are characterized by an increased risk of lymphoma. Of these diseases, the highest risk of lymphoma is associated with PSS [53]. The development of the NHL is the most serious complication of PSS. Up to 25% of NHL associated with PSS is PGL that predominantly demonstrates MALT lymphoma. NHLs complicated PSS are not associated with viral agents known to be present in other types of lymphoma [54].
TCL of the small bowel comprises 10–25% of all primary intestinal lymphomas (PIL) primarily occurring as EATL, and most of them are often associated with Crohn’s disease [55, 56]. Intestinal EATL, type I in particular, usually occurs in the setting of celiac disease [15]. T-cell gene rearrangement confirms clonality [57]. MEITL was formerly known as type II EATL. Even in this older classification, it had been recognized that the “type II” form of the disease had rarely demonstrated (if demonstrated) association with underlying gluten-sensitive enteropathy [19].
Although the stomach is devoid of lymphoid tissue, it is the organ most commonly involved of MALT lymphoma, especially the antrum and distal body. Lymphoid cells are attracted and transformed into gastric MALT tissue by a chronic
The association of gastric MALT lymphoma with
In normal B and T-cells signals produced by the interaction of antigen with antigen receptors on the cell surface cause the protein bcl-10 (B-cell leukemia/lymphoma 10) to bind to the protein MALT1 (lymphoma-associated translocation protein 1) [60]. During
The t(14;18)(q32;q21) fuses the
In
In specific subtypes of non-Hodgkin’s BCL particular oncogene rearrangements related to chromosomal translocations have been determined. The t(11;14)(q13;q32) translocation is one of such fusions specific for MCL, which involves the
Nakamura et al. (2000) believe that gastric MALT lymphoma can be rationally subdivided into 3 subtypes, MALT-A, MALT-B, and MALT-C. They suppose that MALT-A may represent a dysplasia or incipient neoplasm, MALT-B a neoplasm promoted by antigenic stimulation of
Data of Wang et al. show that identification of a t(11;18)(q21;q21) by reverse transcription real-time PCR is highly specific for extranodal MZL of MALT and helps in the diagnosis of this type of lymphoma. This translocation correlates with morphological features of gastric extranodal MZL of MALT and frequently shows monocytoid morphology, less often small lymphocytic morphology and not purely plasmacytoid morphology [76].
Proto-oncogene
MCL as a rule has been known to be an aggressive and incurable small BCL that is derived from naïve B-cells of the pregerminal center. Two types of clinically indolent variants are now identified reflecting that MCL might develop along 2 very different pathways [12]. Classical MCL is consisting of
Genetics plays an essential role in the development of PGL. Patients with MALT lymphomas have a high prevalence of HLA-DQA1*0103, HLA-DQB1*0601 and R702W mutation in the
It should be noted that the list of genetic aberrations that are present in NHL and that are useful either for diagnosis or for understanding the pathogenesis of different diseases has been growing continuously [12].
Although lymphoma can involve any part of the GIT, the most frequent sites in order of its occurrence are the stomach followed by the small intestine and the ileocaecal region as mentioned earlier. Visually PGIL appears as a polyp, mass, ulcer or infiltration depending on the pathological subtypes of lymphoma and the involved sites. Sometimes PGIL can be multifocal. Multifocality has been reported particularly in MALT lymphoma and FL [4]. Multiple lymphomatous polyposis (MLP) is a rare and particular clinical type of GI lymphoma characterized by the development of multiple polyps. Polypoid lesions of MLP are commonly encountered in several sites of the GIT including the esophagus, stomach, duodenum, and bowel. This is classified as B-cell centrocytic NHL; most of the cases of MLP pathohistologically tend to be classified as MCL, rarely as MALT lymphoma [23] and a few cases of FL or TCL have been reported [88, 89].
According to 2016 revised WHO classification there are around 40 different subtypes of NHL, each with characteristics and peculiar clinical behavior. Although the goals of the WHO classification are to identify well-defined entities and to facilitate the recognition of uncommon subtypes that require further clarification, as they move forward some challenges in the classification continue. The borders between some of the disease entities remain ill-defined for example nodular lymphocyte predominant HL with diffuse growth pattern versus T-cell/histiocyte rich large BCL [12].
Some discoveries have been rapidly incorporated into daily diagnostic practice such as IHC for SOX11 or BRAF used to help in the diagnosis of MCL or hairy cell leukemia (HCL), respectively. Molecular detection of the recurrent
Theoretically, with the possible exception of a few subtypes, any lymphoma entities listed in the last WHO classification of lymphoid malignancies may arise in the GIT. There are various inflammatory and reactive conditions in the GIT that can give rise to, mimic, or mask lymphomas. As mentioned earlier, the GIT is home to various lymphoid neoplasms, most of which are of B-cell lineage, including the most common DLBCL subtype. Not frequently TCLs also are encountered in GIT, however, some of them are related to underlying GI disorders or treatment. Some subtypes of GI lymphoma are characterized by aggressive clinical behavior, but others are indolent and may not require treatment. Identifying these entities can provide adequate treatment and, equally importantly, avoiding of overtreatment when aggressive therapy is not needed. The 2016 revised WHO classification has introduced some important changes to the schema used to categorize lymphomas that affect the GIT, and several TCL and NK-cell lymphomas have been reclassified and/or introduced [90].
DLBCL is the most common pathological type of lymphomas in essentially all sites of the GIT, although recently the frequency of other forms has also increased in certain regions of the world. Histopathologically, almost 90% of the PGIL are of B-cell lineage with very few TCLs and HL [4, 8].
The majority of PELs are the DLBCL type of NHL. Only a few cases of MALT lymphoma, MCL, TCL involving the esophagus have been reported [91, 92, 93]. HL of the esophagus is extremely rare. FL affecting the esophagus is a part of the multifocal presentation in the GIT [4].
PGL is the most common extranodal NHL and represents a wide spectrum of diseases, ranging from indolent extranodal MZL of MALT to aggressive DLBCL [11]. Although all histological types of nodal lymphoma can arise from the stomach, the majority of them are of B-cell origin, and MALT lymphoma and DLBCL account for over 90%. Gastric DLBCL occurs in 59% while the extranodal MZL of the MALT occurs in 38% of the PGL cases. Approximately one-fourth of the cases of DLBCL is encountered with the MALT component. MCL is seen in 1% of the cases, FL in 0.5%. Peripheral TCL accounts for 1.5% of PGL [94]. It should be noted that small BCLs are composed mainly of small lymphocytes and are often referred to as “LG” BCLs. The WHO classification intentionally does not divide lymphomas by grade, and because they (“LG” BCLs) are not surely indolent, the preferred name used is “small BCLs”. They include MALT lymphoma, FL, MCL, etc. In the literature, most of the authors use the terms “HG MALT lymphoma” and “LG MALT lymphoma” without reference to the official name in the classification. The use of such terminology is confusing, because, this leads to some tangles. So, the “MALT” descriptor implies that there is only one type of lymphoma with various grades that develops in organs with mucosa. In terms of biological behavior, however, there are two common subtypes of lymphoma that arise in mucosal locations, one indolent and the other aggressive. Therefore, the term “MALT” would comprise both subtypes and blur the border between them. This was the main ground why WHO classification chose the term “extranodal MZL” for the indolent entity—to distinguish it from DLBCL, the aggressive entity. The acronym “MALT” is fine for shorthand but should not be used without reference to the official name for the indolent neoplasm “extranodal MZL” [83] as it is specified in the 2008 WHO classification and 2016 revised WHO classification [95, 96].
PSIL that are more heterogeneous than those in the stomach includes MALT lymphoma, DLBCL, MCL, EATL, FL, IPSID [97], a variant of extranodal MZL of MALT, and BL. IPSID and EATL are the main histological subtypes of PSIL. TCL of the small intestine accounts for approximately 10–25% of all PILs primarily occurring as EATL [55, 56]. Lymphocytic lymphoma (chronic lymphocytic leukemia) rarely arises primarily from GIT [4].
PCRL is mostly (>90%) of the B-cell lineage as other sites of the GIT [37, 97]. The most common histological subtype of PCRL is DLBCL. Other histological subtypes include FL, BL, MALT lymphoma, MCL [60, 98] and TCL. MALT lymphoma is less common in the large bowel than in the small intestine (0.5–1% vs. 1–2% of total cases, respectively). MCL in the colorectum presents commonly in the setting of diffuse systemic diseases. Peripheral TCL is rare in Western countries but has an increasing incidence in many Asian countries, and is more aggressive than the other types of lymphoma. Perforation is a common feature of TCL, and its prognosis is poor [22, 98].
As mentioned earlier DLBCL is the most common histological subtype (up to 58%) of all PGILs [99] and is encountered in all sites of GIT more than 50% being seen in the stomach followed by the small intestine [18]. It originates from GC B-cells or post-germinal B-cells [100]. DLBCL is characterized by large lymphoid cells, with nuclei greater than twice the size of a small lymphocyte, and frequently larger than nuclei of tissue macrophage. The tumor cells contain round, oval, or slightly irregular nuclei with vesicular nuclear chromatin, prominent nucleoli, and ample amount of basophilic cytoplasm and have a diffuse growth pattern [15, 100, 101]. In most cases, the predominant cells resemble either large centroblasts or immunoblasts; nonetheless, a mixture of these two cell types is also commonly encountered. So cytologically, DLBCL is diverse and can be divided into the following morphologic variants: centroblastic, immunoblastic, T-cell/histiocyte rich and anaplastic. Histologically, there is an intense cellular infiltration of the lamina propria [15]. The tumor cells are CD45 positive and express the pan-B antigens (CD19, CD20, CD22 and CD79a) [4, 100, 101]. Variability has been observed in CD5 and CD10 expression [102]. CD10 is expressed in 30 to 60% of cases though CD5 is generally negative and only seen in
2008 WHO classification recognized GC B-cell-like (GCB) and activated B-cell-like (ABC) molecular “subgroups” of DLBCL based on gene expression profiling (GEP). The GCB and ABC subgroups are distinct biologic entities and differed in their chromosomal alterations, activation of signaling pathways, and clinical outcome. The identification of the molecular characteristics of these 2 subgroups, however, has led to the investigation of more adequate treatment strategies to improve the worse outcome of the cases with ABC/non-GCB type DLBCL [83].
MALT lymphoma mainly involves the stomach and also can rarely be encountered in the small intestine and colorectum [103]. Gastric MALT lymphoma can involve any part of the organ, but more frequently it affects the antrum [32]. It is typically an LG neoplasm, characterized by a dense lymphoid infiltration that invades and destroys gastric glands and results in the so-called “lymphoepithelial lesion” which is pathognomonic for lymphoma [103]. It has been postulated that MALT lymphoma arises from post-germinal center memory B-cells with the capacity to differentiate into marginal zone cells and plasma cells [104]. MALT lymphomas do not have a specific antigenic profile, the B-cells share the immunophenotype with marginal zone B-cells present in the spleen, Peyer’s patches and LNs [4, 33]. So, the tumor B-cells can express the surface immunoglobulins (often IgM, not frequently IgA and IgG, rarely IgD) and pan-B antigens (CD19, CD20, CD22 and CD79a), the marginal zone-associated antigens (CD35 and CD21, and lack CD5, CD10, CD23) [4]. Therefore, gastric MALT lymphoma is CD20+, rarely CD5+; CD10-, CD23- and cyclin D1- [15, 32, 33].
B lymphocytes of the extranodal marginal zone are the lineage of MALT lymphoma and are characterized by the heterogeneous cellular population which is prevalently composed of small (monocytoid) lymphocytes and large cells (immunoblasts and centroblasts) [106]. The increase in the proportion of large cells in MALT lymphoma can lead pathologists to confusion, suggesting a conversion into DLBCL which is characterized by the presence of solid aggregates or sheet-like proliferation of large cells [107].
The question about whether all cases of primary gastric DLBCL are derived from previous LG MALT lymphomas or they develop
IPSID or alpha heavy chain disease (αHCD) is an extranodal BCL and represents a variant of MALT lymphoma, which involves mainly the proximal small intestine [24, 25]. This disorder is morphologically characterized by small bowel infiltration by a uniform population of lymphoplasmacytic cells associating with atypical lymphoid propagation to DLBCL. The centrocyte-like lymphocytes express CD20, and both atypical lymphocytic and plasmacytic populations will strongly stain with IgA heavy chain, with lack of light chain staining [25]. IPSID lymphomas reveal excessive plasma cell differentiation and produce truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. Cytogenetic studies demonstrated clonal rearrangements involving predominantly the heavy and light chain genes, including t(9;14)(p13;q32) translocation with the involvement of the
BL, a type of non-Hodgkin BCL, displays a diffuse, monotonous infiltrate of medium-sized neoplastic lymphoid cells with round nuclei and little cytoplasm showing finely clumped and dispersed, with multiple basophilic nucleoli, presenting pathologically with a “starry sky” pattern [15, 29, 109]. It is most often found in the abdomen and the jaw, however, localization in the abdomen other than the ileocecal area is very rare [15, 109]. Mutations in the transcription factor 3 gene,
The morphological distinction between BL and DLBCL has been problematic for pathologists [12, 109]. Distinguishing between these two lymphomas, however, is critical, especially in adults (BL is rare in adults and rarely found in the stomach and colon), as the two diseases are treated differently [109]. GEP studies have demonstrated that BL has a specific signature but that there are cases that resemble DLBCL and aggressive BCLs, and have a molecular signature similar to BL, hence fall into an intermediate category. 2008 WHO classification recognized this issue and added a provisional entity of BCL, unclassifiable, with characteristics intermediate between DLBCL and BL (BCLU) [12, 29].
MCL originates from small to medium-sized lymphocytes located in the mantle zone (inner layer) of follicular tissue. Extra nodal involvement is present in the majority of cases, with a peculiar tendency to invade the GIT in the form of MLP. MLP is one of the most common primary GI presentations of MCL and accounts for approximately about 9% of PGIL [110]. MLP most commonly occurs in the ascending colon and the small bowel (particularly in the ileum and ileocecal region) and gastric involvement are next common [110, 111]. Occasionally, however, numerous polyps are present throughout the entire GIT. Polyps may be sessile, polypoid or both. They range in size from 0.1 to 4–5 cm and present with ulceration [110]. MCL is now recognized as an aggressive BCL with various growth patterns (mantle zone, nodular, or diffuse) and a broad range of cytological features [112, 113]. The prototype MCL is positive for pan B-cell antigens, although few cases of CD5-negative MCL have been reported [24]. Most cases of MCL exhibit a characteristic phenotype (CD20+, CD5+, CD43+, CD3-, CD10-, CD23-) and have the t(11;14)(q13;q32) translocation with overexpression of the
Duodenal-type FL, formerly known as primary intestinal FL, is a variant of FL sharing many morphological and immunohistochemical characteristics with nodal FL [19] but is a distinct entity from nodal FL in terms of clinicopathological and molecular standpoints [115] and demonstrates almost universally LG cytology. Morphologically, the mucosa and submucosa are infiltrated with well-circumscribed round neoplastic follicles which form small nodules and polyps corresponding to the endoscopic manifestation. The neoplastic follicles are similar to those seen in nodal FL and are composed of monotypic centrocytes and rare centroblasts. Although the disease is not graded in the same manner as nodal FL, it corresponds to LG (grades 1–2) lymphoma. The lymphoma cells often infiltrate into the surrounding lamina propria [19]. The immunoprofile of the lymphoma cells demonstrate similarity to that of nodal FL, with the expression of CD20, CD10, bcl-2, and bcl-6. The proliferation marker Ki-67 demonstrates a low rate. In contrast with systemic FL, duodenal-type FL is not characterized by the expression of activation-induced cytidine deaminase (AID) [116]. The indolent biological behavior of duodenal-type FL may bring its neoplastic nature into question. But it harbors the same t(14;18)(q32;q21) translocation with
MEITL differs from the “classic” form of EATL by characteristic morphologic and immunophenotypic features [19]. Recognizing these distinctions, 2016 revised WHO classification formally separated these 2 entities and now defines MEITL as a primary intestinal TCL not associated with celiac disease [118]. It is a rare and aggressive peripheral TCL deriving from intestinal intraepithelial T lymphocytes. The small intestine is affected most frequently, with rare cases involving the stomach and colon. The spreading pattern of MEITL is in contrast with EATL as well; the former often spreads diffusely within the intestinal mucosa with or without tumefactive lesions, since the latter is frequently associated with large and ulcerative tumors that may perforate the intestine. Ulceration may occur in cases of MEITL, and mesenteric LNs involvement is common [28]. No background villous atrophy in small intestinal mucosa associates the tumor. MEITL cells are positive for CD3, CD8, CD56, and MATK in most of the cases, but negative for CD4, CD5, CD30. Nearly 20% of the cases demonstrate aberrant expression of CD20, a feature that can potentially lead to diagnostic confusion with B-cell entities, such as DLBCL or BL. By contrast, classic EATL is usually negative for CD8, CD56, and MATK, with CD4 negativity and variable CD30 positivity [19].
Intestinal TCL, not otherwise specified, does not represent a specific disease entity; it is a term used to denote a heterogenous group of TCLs developing in the GIT with insufficient evidence to be diagnosed as EATL or MEITL, due to incomplete clinical information, scarce biopsy specimens, or insufficient immunophenotypic data. Furthermore, a part of the cases may be peripheral TCL, not otherwise specified, with GI involvement [19]. No reported cases of this TCL subset with a history of celiac disease at initial diagnosis [119]. The morphologic and immunohistochemical characteristics are heterogenous, because this term likely encompasses multiple disease entities [19]. This subset of lymphoma has an aggressive clinical course, with several reported cases demonstrating widespread disease at initial diagnosis [119].
The EBV-positive MCU has been added as a newly recognized entity and is characterized by limited growth despite the aggressive morphological features, and good outcome with a conservative approach [12]. In the involved mucosal surfaces of GIT is encountered superficial ulceration with underlying dense infiltrate of atypical lymphoid cells, necrotic debris, and a rim of reactive T-cells around B-cell areas. Plasma cells are present to a varying degree; they may be prominent and maybe light chain-restricted. The background inflammatory infiltrate can contain histiocytes, eosinophils as well. A significant number of large atypical lymphocytes are found within the necrosis, sometimes in dense sheets. The atypical lymphocytes are large and various in appearance and can resemble those seen in DLBCL or classic HL. They have large pleomorphic nuclei and prominent nucleoli with often Hodgkin and Reed-Sternberg (HRS) cytology. In the setting of iatrogenic immunosuppression for a solid organ transplant, this is a type of post-transplantation lymphoproliferative disorder [120]. The distinction between DLBCL and EBV-positive MCU is important in the post-transplantation setting because EBV-positive MCU has an indolent course. The lesions are typically well-circumscribed at the base and surrounded by a rim of reactive lymphocytes, which are mainly T-cells [115]. The large, atypical lymphocytes are positive for PAX-5, OCT2, MUM1, CD30, EBER and LMP1, and negative for CD10. BOB1 and bcl-6 are frequently positive, with variable expression of CD15, CD20, CD45 and CD79a [42]. T-cells in the inflammatory background are EBER-negative and express normal pan-T-cell markers, including CD3 and CD8. It is particularly important to distinguish these cases from classical HL, which is extremely rare in the GIT [19].
Indolent T-cell lymphoproliferative disorder (ITLPD) of the GIT is a provisional entity in the updated WHO classification and is a nonaggressive, largely nonepitheliotropic small, mature T-cell disorder of the GIT with evidence of clonality by T-cell receptor gene rearrangement studies [19, 121, 122]. This disease is encountered in adulthood (it occurs in children occasionally) and can involve any part of the GIT with the small intestine and colon being the most commonly involved sites. However, because many of the histologic features may overlap with IBD, it is uncertain whether these patients truly have to precede IBD, or whether the lymphoproliferative disorder itself has been initially misdiagnosed as IBD. No cases have been reported in association with celiac disease [121]. Moreover, GI ITLPD may be misdiagnosed as EATL or MEITL and lead to aggressive therapy since the latter lymphoma subtypes are rare but aggressive lymphomas of the GIT. Microscopically, the lamina propria is expanded by a dense and monotonous lymphoid infiltrate. The mucosal crypts or glands are displaced and often distorted, but not destroyed. Cryptitis and crypt abscesses are absent, but granulomas may be focally present, potentially mimicking those seen in Crohn’s disease. The lymphoid infiltrate is composed of small, mature lymphocytes with round nuclei and regular nuclear contours [19, 121, 122]. The lymphoma cells are mature T-cells that express CD2, CD3, CD4, CD5, or CD8, and variably CD7. The absence of CD56 expression is particularly important for diagnosis, distinguishing this entity from MEITL. All reported cases have demonstrated TCRβ expression, with no cases showing TCRγ expression. The proliferation marker Ki-67 rate is low (<10%) [121, 122]. Clonal rearrangements of TCR (either γ or β) have been observed in all cases, and all have been negative for EBV (EBER) by FISH, distinguishing this entity from extranodal NK/TCL of nasal type, which can involve the GIT [19].
Accurate diagnosis and staging of PGIL are essential for the stratification of treatment in this heterogeneous group of malignancies [4]. In other words, tumor stage is one of the most important guidelines in the choice of local (surgery, radiotherapy) and systemic (chemotherapy—ChTh) management modalities. There is a lack of consensus regarding the best staging system for PGIL. Different subtypes of PGIL have a different dissemination pattern from their nodal counterparts, which limits the use of the conventional Ann Arbor staging system [101]. The Ann Arbor staging system, developed for and routinely used in nodal NHL, is not optimal for documentation of the specific relevant features of primary extranodal lymphoma in the GIT [123]. Various modifications have been proposed to aid the staging of PGILs, including those of Musshoff, Blackledge and the Lugano Workshop [101, 123, 124].
TNM staging for tumors of epithelial origin has also been proposed as an alternative in PGIL to describe to what extent the disease is localized or spread. The “T” part of this system pertains to the anatomical structure of the organs and sufficiently fulfills the requirements for the staging of the local extent of the disease. The European Gastro-Intestinal Lymphoma Study (EGILS) Group proposed a modified TNM staging system, named after the first venue of the group in Paris. The modified staging system adjusted to the PGIL, considering histopathological characteristics of extranodal B and T-cell lymphomas, and accordingly enroll: (1) depth of tumor infiltration along with the thickness of GIT; (2) extent of nodal involvement; (3) lymphoma spreading [123]. Paris staging system is valid for lymphomas originating from the gastro-esophageal junction to the anus [123] and has increasingly gained its significance [4].
Paris staging system classifies PGIL as follows:
TX—lymphoma extent not specified
T0—no evidence of lymphoma
T1—lymphoma confined to the mucosa/submucosa
T1m—lymphoma confined to mucosa
T1sm—lymphoma confined to submucosa
T2—lymphoma infiltrates muscularis propria or subserosa
T3—lymphoma penetrates serosa (visceral peritoneum) without invasion of adjacent structures
T4—lymphoma invades adjacent structures or organs
NX—involvement of LNs not assessed
N0—no evidence of LN involvement
N1—involvement of regional LNs
N2—involvement of intra-abdominal LNs beyond the regional area
N3—spread to extra-abdominal LNs
MX—dissemination of lymphoma not assessed
M0—no evidence of extranodal dissemination
M1—non-continuous involvement of separate site in GIT (e.g., stomach and rectum)
M2—non-continuous involvement of other tissues (e.g., peritoneum, pleura) or organs (e.g., tonsils, ocular adnexa, lung, liver, spleen, breast, etc.)
BX—involvement of bone marrow not assessed
B0—no evidence of bone marrow involvement
B1—lymphomatous infiltration of bone marrow
TNM—clinical staging: status of tumor, node, metastasis, bone marrow
pTNMB—histopathological staging: status of the tumor, node metastasis, bone marrow
pN—the histological examination will ordinarily include six or more LNs
According to the site of the PGIL “regional” LNs implies: (a) stomach: perigastric LNs and those located along the branches of the coeliac artery (left gastric artery, common hepatic artery, and splenic artery); (b) duodenum: pancreatoduodenal, suprapyloric and infrapyloric, hepatic LNs, and those located along superior mesenteric artery; (c) small intestine: mesenteric LNs; the ileocolic as well as the posterior caecal LNs for the terminal ileum only; (d) colorectum: pericolic and perirectal LNs and those located along the ileocolic, right, middle, and left colic, inferior mesenteric, superior rectal, and internal iliac arteries [123].
PGIL is a relatively rare cancer that is easily misdiagnosed and indistinguishable from other benign and malignant conditions due to its unspecific symptoms attributable to the site of involvement [4, 11]. The clinical manifestation of PGIL is dependent on the involved site, pathological subtype and the stage of the tumor. The age of presentation varies with the histological subtypes of lymphoma [97].
Although PEL is often asymptomatic, the common symptoms of symptomatic patients include dysphagia, odynophagia, weight loss, chest pain or symptoms developed as a result of complications such as hemorrhage, obstruction or perforation [4, 125, 126]. Constitutional B symptoms (fever, night sweats) are not typically present and are seen rarely [4]. Some researchers suppose that the diagnosis of GI lymphoma, including PEL (despite its rare incidence) should be considered in any HIV-infected patient presenting with unexplained GI symptoms [44, 93].
Clinical manifestation of PGL is nonspecific and indistinguishable from other benign and malignant conditions. The most common complaints of patients with PGL are epigastric pain, nausea and vomiting (due to pyloric stenosis or reflex), iron-deficiency anemia due to chronic gastric bleeding, and weight loss. Occasionally, an abdominal mass is palpable. Severe complications such as perforation and life-threatening haemorrhage are seen rarely (4%) [127]. Lymphadenopathy is rare and such patients often have no physical signs [4]. Unlike nodal lymphoma, B constitutional symptoms are not common. Gastric MALT lymphoma is often an indolent, multifocal disease and in 10% of the cases, it can have synchronous involvement of intestinal and extraintestinal sites [128] with appropriate clinical signs.
The clinical presentation of PSIL is nonspecific and the patients have symptoms, such as colicky abdominal pain, nausea, vomiting, weight loss and rarely acute obstructive symptoms, intussusceptions, perforation or diarrhea [97]. However, the typical clinical features of IPSID, a subtype of MALT lymphoma, are different because the dominant region for IPSID is the duodenum and upper jejunum, and present diarrhea, malabsorption syndrome or protein-losing enteropathy [23, 24]. Intussusception is a common clinical finding in ileocecal lymphomas, occurring mainly in patients with the fungating type of the lesion [129]. In general, the most commonly affected region with PSIL is the ileum followed by the jejunum and duodenum (6–8%) [100].
PCRL presents with abdominal pain, altered bowel habit, palpable abdominal mass, lower GI bleeding and weight loss [22, 101, 130, 131]. Obstruction and perforation are relatively rare in patients with PCRL [131]. Primary colorectal TCLs are characterized by multifocal ulcerative lesions in relatively young patients and a high rate of hematochezia, fever or perforation, and aggressive clinical course even for cases of localized disease [22]. The caecum is the most common site of involvement because of the abundance of lymphatic tissue [101].
Some features of some PILs should be peculiarly noted. MCL, FL and MALT lymphoma of the small intestine rarely present with multiple polyps called MLP [20, 110, 132]. In one-third of the cases, MLP is due to MCL. MLP can present with symptoms such as abdominal pain, diarrhea, bleeding, and less frequently, protein-losing enteropathy, intestinal malabsorption, intestinal obstruction or chylous ascites. MLP polyps usually occur in the ileocecal region and one-third of cases present as a mass [110].
During diagnostics, the clinician verifies the lymphoma, determines its site and stage, and detects possible relationship of some lymphoma subtypes with some infections and disorders, and inherited conditions. Comprehensive history taking and physical examination may provide a very important clues for reaching the goal promptly. The first objective examination tool depends on the patient’s complaints and the result of the physical examination.
Endoscopy is the firstly used diagnostic modality for visualization of the lesion and for getting biopsy samples depending on the involved site. The histological examination of biopsy samples taken during endoscopy is the “gold standard” for the diagnosis of PGIL. The endoscopy by itself cannot identify lymphoma or differ it from the more common GI carcinomas [127]. The injury patterns of PGIL (ulceration, diffuse infiltration, polypoid mass, etc.) are characteristic also of GI carcinomas. However, the most common endoscopic appearances of PGIL are ulcerative and massive [8]. One of the main difficulties for accurate visual diagnosis of PGIL is the variation in endoscopic abnormalities, which varies from minimal mucosal irregularities to bigger ulcerations [18].
Endoscopic findings in PEL vary greatly and are nonspecific, which poses diagnostic challenges when it is differentiated from other benign and malignant lesions. The morphological features of PEL seen at endoscopy are nodular, polypoid, ulcerated or stenotic [92]. Multiple biopsies should be obtained from the stomach, gastroesophageal junction, duodenum, and from lesions in cases of PGL since gastroduodenal lymphomas (MALT lymphoma, duodenal-type FL, etc.) can occasionally present as a multifocal disease with involvement of tissue that appears to be unaffected on endoscopic visualization [133]. Endoscopic findings may vary from subtle mucosal changes (mucosal edema, friability, patchy redness, irregular patchy gray or whitish granularity, contact bleeding, superficial irregular erosions and ulcerations) to gross lesions (ulceration, diffuse infiltration, and a polypoid mass) [124] that are characteristic also for early gastric carcinoma and gastric carcinoma respectively and are not diagnostic (Figure 1A). The extension of a gastric lesion across the pylorus into the duodenum is highly suggestive of lymphoma, not of carcinoma, but is not pathognomonic. Endoscopy, however, is an indispensable tool for the initial diagnosis, for obtaining biopsy samples and as well as for follow-up of the cases. Conventional pinch biopsy results may be false-negative (up to 8%) owing to submucosal localization [127] without involving the mucosa. Repeated endoscopic biopsies are mandatory in case of clinical suspicion and negative or inconclusive histology [124] EUS-guided fine-needle aspiration biopsy can help to increase the yield in some cases. The presence of
Endoscopic (A) and CT (B) views of gastric DLBCL in H. pylori-positive 63-year-old man who complained of anorexia, epigastral discomphort and vomiting. The diagnosis of DLBCL was confirmed pathohistologically and immunohistochemically. The lesion involved the proximal third of the stomach. Perigastric, regional, paraaortic and mesenteric LNs were enlarged on CT.
The duodenum and the terminal ileum can be investigated by conventional endoscopy which is home to special subtypes of PGIL. Detection and assessment of PSIL have been revolutionized since the introduction of capsule endoscopy and double-balloon enteroscopy (push-and-pull enteroscopy) which is capable of providing biopsy samples, thereby limiting major surgical interventions. PSIL is presented as a polyp, bulky lesion, or ulcer on capsule endoscopy which cannot be visually differentiated from other lesions [134]. Unlike the other endoscopic approaches, capsule endoscopy does not permit tissue sampling. Primary ileocolonic lymphoma and PCRL can be classified endoscopically into fungating, ulcerative, infiltrative and mixed types. Among these, fungating and ulcerofungating are the most frequent [129]. Total colonoscopy with tissue sampling is crucial for accurate diagnosis in cases of suspicion of PCRL.
As mentioned earlier MCL, FL and MALT lymphoma of the small intestine rarely present with multiple polyps called MLP [20, 110, 132]. Upper GI endoscopy, enteroscopy and colonoscopy are important tools in diagnosing MLP to assess the locations of the polyps and obtain tissue biopsies. Differentiating MLP from adenomatous or hamartomatous polyposis by endoscopic or radiological evaluation alone is impossible and tissue diagnosis is required [110].
MALT lymphoma of the large intestine is manifested as multiple mucosal nodularities [22, 135]. IPSID tends to affect proximally with a disseminated nodular pattern leading to mucosal fold thickening, irregularity and speculation [136]. Extranodal BL is frequently seen but GIT involvement varies among the three clinical subtypes, with the sporadic variant usually presenting as a bulky mass, commonly in the terminal ileum and caecum [15, 29].
About 10% of all FL is of GI origin and the GIT is the most frequently involved site [115]. Primary FL of the GIT is very rare and constitute <7% of all GI NHL lymphomas [20]. Many cases (43–77%) of GI FL are asymptomatic and sometimes accidentally found by endoscopic examination [115]. Cases of GI FL often present as an incidental whitish polypoid lesion described as small polypoid nodules, multiple polypoid lesions, multiple small polyps, multiple nodules, or multiple granules in patients undergoing upper endoscopy for other unrelated reasons, such as dyspepsia or suspected gastroesophageal reflux [19, 137]. Other macroscopic features are infrequent, but they can present as erosions or ulcers [137]. The disease is usually found in the proximal part of the small intestine [19, 20, 115, 137, 138, 139] most often with duodenal involvement in the second portion [19, 115, 137]. Gastric and colorectal FL have been occasionally reported [137]. Multiple sites of small intestinal involvement are seen in 56–80% of cases [20, 139]. The most reliable way to distinguish primary GI FL from GI involvement of conventional FL, is to rule out intestinal involvement by mesenteric/retroperitoneal disease and/or systemic diseases by imaging and bone marrow biopsy [19].
PTCL preferentially involves the jejunum with an increased tendency to perforate [130]. EATL, usually proximal or diffuse, shows nodules, ulcers or strictures [136]. PTCL of the large intestine presents as a diffuse or focal segmental lesion with extensive mucosal ulceration similar to that observed in granulomatous conditions as Crohn’s disease or tuberculosis [22, 135]. The GIT EBV-positive MCU usually presents with sharply circumscribed ulcers in the oral mucosa, esophagus, colon, rectum, and/or perianal area. It is usually a localized (albeit potentially locally aggressive) process, and lymphadenopathy, bone marrow involvement, and disseminated disease are exceedingly rare [41, 42]. In cases of ITLPD, the affected GI mucosa (the disease most often localizes in the small intestine and colon; however, all sites in the GIT may be involved) is viewed thickened with prominent folds, nodularity, and/or polyps. The surface can be hyperemic with superficial erosions [121].
It is recommended that biopsy specimens should undergo histological, immunohistochemical and genotyping studies to make the diagnosis [124]. It should be noted that on histological examination Reed-Sternberg-like cells can be seen in LG BCLs [140] including extranodal MZL, FL, IPSID that can be confused with HL. Histological assessment is currently considered the “gold standard” also for the assessment of treatment response in gastric lymphoma [5].
The different procedures employed for the pre-treatment staging include computed tomography (CT), magnetic resonance imaging (MRI), EUS, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Contrast-enhanced techniques and functional imaging such as perfusion CT can also help the monitoring, assessment, and prediction of response [4, 11].
Radiographic patterns of PEL, described in the literature, are nonspecific and not diagnostic and include thickening of the wall mimicking other tumors, stricture, ulcerated mass, multiple submucosal nodules, varicoid pattern, achalasia-like pattern, progressive aneurysmal dilatation, and tracheoesophageal fistula formation, and none of them is specific and diagnostic [91, 141]. CT, however, is valuable for the evaluation of the mediastinal extension of PEL, fistula formation, and status of LNs, thus playing a role in staging disease, assisting in stratification of available treatment modalities, evaluating treatment responses, monitoring disease progression, and detecting relapses [141]. CT scan of the chest, abdomen and pelvis is should be employed to stage PGIL irrespective of the involved site.
Radiographic patterns of PGL observed in double-contrast upper GI studies include ulcers, thickened fold, polypoid mass, mucosal nodularities or infiltrating lesions, which are not conclusive, thus posing a diagnostic challenge while differentiating from other malignant and benign lesions, hence requiring pathological confirmation [142]. The radiological findings usually do not correlate to its pathological subtypes [4]. Conservation of pliability and distensibility of the gastric wall despite the substantial gastric fold thickening and extensive infiltration of the gastric wall is a finding very suggestive of lymphoma. Gastric wall thickening is much more severe in HG lymphoma compared to LG lymphoma on CT images, and abdominal lymphadenopathy is more common in cases of HG lymphoma (Figure 1B) [142]. The patterns of gastric involvement can be as localized polypoid mass or segmental/diffuse infiltrative lesion. Tumor infiltration is usually homogeneous, however, areas of low attenuation may be observed in larger tumors. Segmental infiltration and diffuse infiltration involving more than 50% of the stomach are the most common hallmarks of gastric NHL on CT images [143]. Preservation of the fat plane which is an indirect sign that there is no invasion into surrounding anatomical structures may be suggestive of lymphoma as well, however, it is nonspecific. Transpyloric extension of the PGL with involvement of the duodenal wall and presence of bulky LNs, notably below the renal hilum is more suggestive of lymphoma than carcinoma [142].
The radiologic appearances of PCRL are variable and significantly overlapped with other benign and malignant conditions of the colorectal region. The imaging findings during double-contrast barium enema can be divided into focal and diffuse lesions. The observed focal lesions include mucosal nodularity, mucosal fold thickening, polypoid mass, circumferential infiltration with smooth mucosal surface or extensive ulceration, cavitary mass. Diffuse lesions encompass diffuse ulcerative and nodular lesions [22, 135].
The MRI characteristics of PGIL include exophytic tumor mass, irregularly thickened mucosal folds with submucosal infiltration, a circular infiltrating lesion which narrows the lumen, mesenteric or/and retroperitoneal lymphadenopathy. The lymphomas are mostly homogeneous on T1-weighted images and have intermediate signal intensity. Heterogeneously increased signal intensities are observed on T2-weighted images. The enhancement is commonly mild-moderate after intravenous administration of gadolinium-based contrast agents [144].
In routine clinical practice, EUS is being employed widely for assessment of the primary lesion and clinical staging because it is able accurately to depict the neoplastic disease in the wall of the GIT organs, extent of the lesion and depth of invasion. EUS findings, however, are not pathognomonic, because PGILs can be presented as anechoic, hypoechoic or even rarely hyperechoic masses [5, 93, 127]. Infiltrative carcinoma tends to grow vertically along the gastric wall, while PGL demonstrates mostly horizontal growth. Moreover, the involvement of perigastric LNs is most common in PGL cases [5]. EUS is highly accurate in detecting the depth of infiltration of tumor and the presence of perigastric LNs, which are essential for adequate treatment planning. It should be noted that EUS can provide significant information to distinguish lymphoma from carcinoma regardless of the stage of the mentioned tumors [124].
EUS has become an integral tool in the diagnosis, locoregional staging, and monitoring response of PGIL to treatment. EUS is superior to CT scan for the T- and N-staging by providing vivid details for any invasion within and beyond the gastric wall. The significance of EUS and CT, however, is a matter of debate in the follow-up of patients, since it has been well studied that histological remission is confirmed earlier than the disappearance of the wall changes in cases of PGIL. It eliminates the necessity for endoscopic biopsy follow-up in the relevant patients. Gastric MALT lymphoma, often requires a more meticulous staging procedure despite its indolent clinical behavior since it is not infrequently multifocal, can be transformed into DLBCL, and is difficult to diagnose due to normal endoscopic appearance in many cases. Therefore, endoscopic biopsy samples should be taken from multiple sites of the stomach and duodenum encompassing the areas with normal and abnormal appearance [145]. Some authors suppose that EUS seems sufficient for the routine follow-up of patients with PGL without using gastroscopy with biopsy [5].
Recently, the incorporation of PET-CT has emerged as an indispensable tool in staging the disease and following up the patients with extranodal involvement of HL and NHL, with increased sensitivity and specificity. The intensity of FDG uptake in lymphoma is influenced by various intrinsic tumor factors such as histological features and grade, as well as various extrinsic factors [144]. Application of 18F-FDG PET-CT in the diagnosis of PGL is challenging due to the physiologic FDG activity in the stomach and variability in the degree of uptake in various histologic subtypes [146]. FDG-PET has a significant advantage in the staging of DLBCL independent of the affected anatomic site, and MCL, although it has no added benefit for MALT lymphomas due to their indolent behavior [11, 147]. PET-scanning has no sufficient sensitivity (<50%) and is not reliable to diagnose the intestinal FL [137]. Currently, for PGL, PET CT is a standard initial imaging study in DLBCL histology but not recommended in cases of gastric MALT lymphoma [11] and intestinal FL because aggressive PGILs have more intense uptake than LG MALT lymphoma and GI FL [137, 146]. GI DLBCL is manifested as circumferential thickening of the wall, with diffuse increased FDG uptake. FDG PET-CT can also detect indolent lesions that are undetectable on conventional cross-sectional imaging [147]. New promising techniques using recent PET tracers like 18F-fluoro-thymidine may significantly benefit the overall management of lymphomas [4].
In some cases, the diagnosis of PGIL cannot be made by traditional methods and novel diagnostic methods and surgery is needed. Chen et al. report that 48.4% (201/415) of their patients with PGIL were diagnosed by surgery. Reasons for that surgery became a method of diagnosis were as follows: (1) the lesions of PGIL mainly locate submucosally, which increase the difficulty of diagnosis through endoscopic biopsy; (2) when the diagnosis of a visualized malignant lesion after repeating endoscopic biopsy still cannot be confirmed, surgery can be the choice; (3) part of PGIL patients came to the hospital because of acute abdomen, especially patients of TCL and in those cases diagnosis could only be verified after an emergency operation. They report that in their study, 37 (18.4%) of the 201 patients diagnosed by surgery underwent emergency operations. It makes suggests that surgery is an essential way for diagnosis of PGIL, particularly in the cases of TCL because of their high frequency of acute abdomen [8].
The other laboratory analyses conducted encompass a complete haemogram, hepatic and renal function panels, measurement of blood glucose, serum lactate dehydrogenase, uric acid, potassium, calcium, and phosphorus levels. Bone marrow aspirate with a biopsy is fulfilled for assessment of lymphoma dissemination and monitoring of treatment response. In certain types of lymphoma serum protein electrophoresis and identification of paraproteins can be performed as well. For recognition of etiological factors, appropriate serological tests are frequently conducted in various types of lymphoma [145].
The optimal treatment of PGIL is a matter of debate. The treatment strategy of PGİL depends on multiple factors; involved site, pathological variants, stage of the tumor, the existence of bacterial or viral associations and chromosomal translocations. Accurate staging is necessary for the important therapeutic implications. If the disease affects beyond the organ and regional nodes, treatment strategies can no longer be focused on local control and systemic aggressive ChTh must be the mandatory option.
Surgery was the main treatment modality in the past, but now, in uncomplicated cases, it is replaced by the combination of anthracycline-containing ChTh and rituximab, a chimeric monoclonal antibody against the protein CD20 [13]. Treatment of PGIL is largely ChTh based, augmented with surgical and radiation therapy in many cases. The length and type of chemotherapeutic interventions depend on the extent of the disease but generally systemic therapy, as well as intrathecal delivery of agents, is required to prevent or treat involvement in the cerebrospinal fluid. Surgical resection is controversial and generally considered when complete resection is possible rather than debulking unless indicated by obstruction or perforation. Consolidation therapy with radiation is recommended in patients with localized disease [18]. So, the global therapeutic approach to the cure of primary GI NHL has completely changed over the last 10 years: innovative, conservative options to reduce treatment toxicity, therefore preventing systemic relapses, have made their appearance and are on the rise [16].
The discovery of a causative link between
No definite guidelines have been advocated for the treatment of advanced or
Surgery traditionally was the standard procedure or an indispensable component of combined treatment strategy in primary GI DLBCL. The arguments in favor of the surgery include removal of the primary tumor, availability of precise histological assessment and tumor staging, as well as avoidance of life-threatening complications (perforation, hemorrhage) that may emerge during radiotherapy and ChTh. In recent decades, opinions have increasingly shifted away toward conservative treatment even for patients with the resectable disease [152]. Gastric DLBCL is treated with aggressive poly-ChTh, which is usually combined with rituximab. Thus, gastric DLBCL should be treated with the front-line ChTh (CHOP) or chemoimmunotherapy with R-CHOP (CHOP with rituximab). Frontline chemoimmunotherapy with 3–4 cycles of standard R-CHOP followed by “involved-field” radiotherapy could be considered as a standard option for localized stages. Complete remission can be achieved in advanced gastric DLBCL patients after 6–8 cycles of R-CHOP as their nodal counterparts [4, 11, 16, 152]. In other words in the case of gastric DLBCL, either arising
If the patient has the progressive disease (according to PET CT), the consideration for second-line treatment (salvage ChTh) for DLBCL with a regimen, such as rituximab, ifosfamide, carboplatin, and etoposide or Gemcitabine, dexamethasone, cisplatin and rituximab, followed by autologous stem cell transplantation (SCT) should be considered [11].
Various recent studies have demonstrated a significant rate (50%) of complete regression (analogous to MALT lymphomas) in localized gastric DLBCL following anti-
Endoscopic (A) and CT (B) views of the patient with a history of gastric DLBCL (described in
Lymphomas originating from the duodenal bulbs might have similar characteristics with gastric MALT lymphomas. Unfortunately, the lesions observed over the descending portion might be less associated with
The treatment outcome of PIL is relatively poorer than that of PGL depending on their histological subtypes. Lymphoma primarily located in the small bowel usually warrants laparotomy with the affected segment removed both for its diagnosis and its treatment. LG BCL of the small intestine (stage IE) only requires surgical resection. A multi-agent chemotherapeutic strategy is warranted for advanced stage PIL with multifocal cases of lymphoma. Systemic treatment with anthracycline-based ChTh followed by radiotherapy is proposed for advanced PIL which cannot be removed [4]. No guidelines exist for the treatment of small intestinal DLBCL. Historically, in HIV patients ChTh combined with antiretroviral therapy remains the first step in the management of aggressive lymphomas [100].
IPSID in the early stage responds to antibiotics such as tetracycline or combined metronidazole and ampicillin, with remission occurring within 6–12 months. Patients without substantial regression following a 6-month course of antibiotic therapy or complete remission within 12 months should be administered ChTh with CHOP. ChTh is also recommended up-front combined with antibiotics for patients with intermediate or advanced stage of the disease at initial diagnosis. Surgery plays a limited role in the majority of cases due to diffuse involvement, although it may be required for accurate diagnosis [4, 24]. Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma invading the intestinal wall and mesenteric LNs, and may metastasize to a distant organ [24].
No optimized therapeutic guideline is available for BL which usually requires an aggressive approach. High-intensity chemotherapeutic agents for a short duration, such as cyclophosphamide, vincristine, doxorubicin, methotrexate and cytarabine, can significantly improve the treatment outcome [4]. The risks of emerging tumor lysis syndrome (TLS) and CNS dissemination of the disease are also important issues that should be taken into consideration at the first presentation of patients with BL. To reduce the risk of TLS, many regimens use relatively low doses of ChTh drugs (especially cyclophosphamide) and administration of prednisone. High-dose intravenous (as well as intrathecal) methotrexate and cytarabine, both of which have CNS penetration, are commonly administered to reduce CNS dissemination of the disease [155].
CODOX-M/IVAC, Magrath regimen (CODOX-M, cyclophosphamide, vincristine, doxorubicin, methotrexate; /IVAC, ifosfamide, cytarabine, and etoposide) is commonly used for the treatment of BL. Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with methotrexate and cytarabine is another effective strategy in BL. Most adults with BL can favor the Magrath or modified Magrath regimens (depending on risk group) with the addition of rituximab. The benefit of administering rituximab in front-line BL therapy has been demonstrated in both adults and children, and it is a standard treatment in both cases. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is an intermediate-intensity strategy, which was tested in BL because of its high efficacy in DLBCL and its hypothetical ability to overcome high tumor proliferation. Studies testing this strategy in patients with sporadic and immunodeficiency-associated BL demonstrated a progression-free rate > 90%, with low toxicity and low rates of TLS. A randomized trial comparing DA-EPOCH-R (dose-adjusted EPOCH-R) with R-CODOX-M/RIVAC (CODOX-M/IVAC with rituximab) is currently being conducted in several European countries for its comparative effect [155]. Rituximab exhibits sufficient promising results to recommend its adjunction to ChTh and it may even erase the prognostic difference between young and elderly patients. However, its administration is avoided during the debulking phase given the high risk of TLS [29].
Involved-field radiotherapy should not be considered in BL, except for patients with CNS involvement. In case of initial CNS invasion, the number of intrathecal ChTh administrations is increased. SCT should not be recommended for patients with complete responses. This approach must be employed for cases of partial response or patients with chemosensitive recurrence. Due to the high proliferative ability of BL, graft-versus-tumor effects that appeared following allogeneic SCT are too sluggish to be manifested. Therefore, this type of transplant should not be employed [29]. It should be noted that because modern ChTh may be curative for the majority of BL patients and up to 90% of adolescents and young adults, the interest in hematopoietic cell transplantation has now considerably diminished [156].
MCL is an aggressive and incurable type of B-cell NHL [110, 113]. Conventional therapeutic regimens are not effective in MCL cases and are associated with poor survival [4, 110]. Current combinations of multi-drug ChTh and monoclonal antibodies have conferred significant improvement in response rates of MCL. Overall response rates comprise 80–95% and complete response rates of 30–50% are not being achieved. Other ChTh regimens such as R-Hyper-CVAD (Rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) have demonstrated good results. However, it is a more aggressive regimen associated with increased toxicity. The R-CHOP regimen can be used in patients with poor performance status as a less toxic regimen [110]. Those who are eligible for grafting are previously induced with R-CHOP. ChTh regimen, consisting of rituximab alone or purine nucleoside analogs with rituximab, can be applied to those ineligibles for SCT [4, 157].
Compared with nodal FL, GI FL usually presents with localized disease [115] and shows indolent clinical course [4, 20, 117, 158, 159], with excellent long-term survival, even when the disease recurs in the intestine until they are symptomatic or show evidence of its progression [4, 117, 158, 159]. A small subset of patients (<10%) progress to nodal disease [158, 159]. Surgical resection might be curative for patients with GI FL who, after thorough evaluation, are considered to have disease confined to one segment of the bowel. However, given the multifocal nature of GI FL, the role of surgery is generally limited to establishing a diagnosis and treating actual or imminent complications [139]. Therefore, there is no consensus in the management strategy and some clinical problems are yet to be solved [115]. A variety of therapies have been used, but treatment is not likely to be necessary for most patients and a “watch-and-wait” approach is reasonable [4, 115] because unlike nodal FL, GI FL is known to be indolent [115]. Symptomatic cases, or advanced disease of FL necessitates surgery and ChTh (CHOP). Although rituximab is beneficial for FL, its true value has not been well ascertained [4].
No guidelines are available for the management of EATL although anthracyclin-based ChTh is a mainstay treatment modality. ChTh as the first-line therapy is more effective in GI BCL when compared with the T-cell subtype. In cases of serious comorbidities and complications attributed to ChTh, such as perforation, and profuse bleeding multimodal approaches including debulking or radical intent surgery should be performed to remove the gross EATL before ChTh, if the patients can tolerate it. It was reported that two-thirds of the patients with EATL undergone surgical resection followed by combination ChTh and autologous SCT can obtain a sustained complete response [4].
Most patients with EBV-positive MCU have a favorable clinical course, with nearly all reported cases showing resolution following a reduction of immunosuppressive therapy [41, 42]. Other interventions, such as local radiation or ChTh, may be necessary for those patients in whom the immunosuppression cannot be reversed, such as in the elderly [19].
GI ITLPD usually presents as an indolent neoplasm with no progression to aggressive TCLs. These cases are often misdiagnosed as TCL with little or no response to ChTh. Radiotherapy may be a more effective option compared with ChTh. But there are not enough clinical observations to confirm it [160].
Since the introduction of highly active antiretroviral therapy (HAART) in the treatment of AIDS patients, a decrease in the incidence of GI lymphoma among AIDS patients and improved survival rates for relevant lymphoma patients have been achieved. Therefore, therapeutic strategies including ChTh, immunotherapy and HAART can be able to demonstrate promising results in response and survival rates [43].
The clinical course and prognosis of PGİL are dependent on histopathological subtype and stage at the time of initial diagnosis [11]. The best overall survival (OS) and progression-free survival (PFS) were observed in MALT lymphoma and FL, followed by DLBCL, and the poorest in EATL and other lymphomas of T-cell lineage [8]. Overall survival rates remain poor also in MCL [110].
Gastric MALT lymphoma is commonly an indolent, multifocal disease and because of that, it has a high rate of relapse after surgery. In 10% of cases, it can have synchronous involvement of intestinal and extraintestinal sites [91]. In the early stages, the disease may completely resolve following antibiotic therapy; however, transformation to DLBCL is not uncommon [25].
There are many prognostic systems for prognostication of DLBCL of which the International Prognostic Index (IPI) is the most valuable and main clinical tool widely employed [101]. GEP is a new evolving approach to diagnose, classify and prognosticate DLBCL. According to GEP two prognostically significant types of DLBCL have been identified [12, 83, 101, 161]. The molecular subgroups include GCB and ABC, which are associated with different chromosomal aberrations. GCB group has a better prognosis than the ACB group [101]. GEP is considered the “gold standard” to identify the molecular subtypes of DLBCL, however, is not available in routine diagnostics due to its cost-ineffectiveness. Several studies have attempted to define the molecular subtypes (GCB and non-GCB) by IHC using a limited panel of available antibodies [12]. The Hans algorithm which used antibodies to CD10, BCL6, and IRF4/MUM1 has been the most widely used in clinical trials [83] with nearly 80% concordance with the GEP [161]. According to the results of most of the relevant studies, IHC algorithms can predict the prognosis in DLBCL, however, all researchers believe that these methods cannot perfectly substitute GEP. Taking into consideration of the possible prognostic significance of cell lineage and the incremental efforts to adjust the treatment strategy based on molecular characteristics, 2016 revised WHO classification recommends distinguishing the above-mentioned molecular subtypes of DLBCL. Therefore, the application of IHC algorithms is now considered an acceptable and effective tool by many experts [12].
BL, a type of non-Hodgkin BCL, is a substantially aggressive mature B cell neoplasm and the fastest growing human cancer that is seen mainly in children and young adults [15, 109]. Despite very aggressive biology most of the cases of BL can be cured by modern ChTh [156]. BL comprises up to 20% of HIV-associated lymphomas and is usually associated with higher median CD4 counts when compared with many other lymphoma types. In a recently presented multicenter study, there were no differences in survival between HIV-negative and HIV-positive counterparts [155].
Primary GI MCL is highly aggressive and survival is poor compared to nodal MCL involving the GIT. Patients respond poorly to CHOP chemotherapy [157]. Despite the improved response rate of ChTh for MCL, current overall survival rates remain poor because of the advanced stage in most of the cases and the early relapse. Median survival with standard treatment for MCL patients remains between 1.5 and 4 years [110, 113]. For risk prediction, the MCL International Prognostic Index (MIPI) that include also pretreatment Ki-67 proliferation rate, an important determinant of risk, is employed [157]. MIPI might be helpful to allow individualized, risk-adapted treatment decisions in patients with MCL.
GI FL has poorer outcomes than previously suggested [138]. Anatomical location within the GIT may have prognostic implications, with primary duodenal and small intestinal disease having a significantly higher progression-free survival rate than non-duodenal presentations [138, 139]. For risk stratification of FL patients, FLIPI (FL International Prognostic Index) and FLIPI2 have been developed as prognostic indexes. Despite the usefulness of these risk assessment criteria in nodal cases, no studies have been conducted on intestinal FL patients [115, 137]. Most of the GI FL cases are assessed as low risk or intermediate risk, but it is not confirmed by larger studies if these criteria are suitable for GI cases [115].
MLP may be one of the GI lymphomas with a poor prognosis, even though several regimens of systemic ChTh have been adapted for its treatment [23].
EATL and MEITL is clinically aggressive disease, with frequent early dissemination and a median survival of several months [28, 162].
EBV-positive MCU has an indolent clinical course and may spontaneously regress in some cases [41, 42].
ITLPD is a nonaggressive disease and its clinical course is chronic and relapsing, with rarely reported disseminated disease, including bone marrow and peripheral blood involvement, usually after many years [121, 122].
GIT is the most common extranodal site involved in lymphoma. Histopathologically, almost 90% of PGILs are of B-cell lineage. PGILs represent a heterogeneous group of malignant neoplasms which are different entities in terms of cancerogenesis, cell lineage, pathological characteristics, immunoprofile, biological behavior, response to modern treatment approaches and prognosis. In most cases, pathogenesis of primary PGIL is associated with infectious agents such as
The authors declare no conflict of interest.
“
Firstly, classical mechanics is a theory in physics studying the macroscopic objects motion whether they are parts of machinery or projectiles or objects in astronomy like for example planets or spacecrafts or galaxies or stars. As it was established, classical mechanics is deterministic that means that we can predict the motion of objects in the future when we know their present state. It is also reversible and that means we can know the motion of objects in the past when we know their present state also [1].
Since classical mechanics was developed at the beginning by Sir Isaac Newton therefore it is usually referred to as Newtonian mechanics. It comprises the mathematical methods and the employed physical concepts developed, as we have mentioned, by Newton, Gottfried Wilhelm Leibniz and others in the seventeenth century to study the bodies motion under the effect of a set of forces. The theory was more developed later on to embody more abstract methods which have led to the reformulations of classical mechanics and hence to the establishment of Hamiltonian mechanics and Lagrangian mechanics. These developments which were done in the eighteenth and nineteenth centuries are substantial extensions beyond the work of Newton because they used more particularly analytical mechanics. After doing some modifications, modern physics makes use of them in all its areas [2].
Moreover, exceptionally precise results are provided by classical mechanics when considering objects with velocities far from the speed of light and when they do not possess extreme masses. It is mandatory to make use of quantum mechanics which is a sub-field of mechanics when studying objects which have an atom diameter size. Additionally, we need Albert Einstein’s special relativity when considering speeds near the velocity of light. Furthermore, Einstein’s general relativity is applied when objects have huge masses. It is important to note that many modern sources include in classical physics the relativistic mechanics which represents according to them the most precise, developed, and complete form of classical mechanics [3].
Furthermore, we now present classical mechanics fundamental concepts. The theory assumes that the objects of the real world are of negligible size that means that they are point particles. And it also characterizes the point particle motion by few parameters which are: its mass, its position, and the applied forces to it. We will discuss each of these parameters in turn [4].
In fact, and in reality, classical mechanics can describe always the kind of objects that have a non-zero size. Whereas, very small particles like electrons are described more accurately by the physics of quantum mechanics. Additionally, hypothetical point particles have more simplified behavior than non-zero size objects like for example a baseball that can spin when it is in motion. Moreover, such non-zero objects are considered as composite objects constituted of a large number of point particles acting collectively; hence, the point particles results can be used in such large objects study [5].
Common sense notions are used by classical mechanics of how matter and forces interact and exist. Its basic assumption is that energy and matter have knowable and definite attributes such as speed and location in space. Additionally, it is assumed by non-relativistic mechanics the instantaneous action of forces or instantaneous action at a distance [6].
The bodies motion study is very ancient, this makes classical mechanics one of the largest and oldest subjects in engineering, technology, and science [7].
Aristotle, one among antiquity Greek philosophers and who is the founder of Aristotelian physics, may have been the first to postulate that theoretical principles can assist nature understanding and to assume that “everything happens for a reason”. Many of these ideas preserved are considered as eminently reasonable by a modern reader but there is an obvious lack of controlled experiment and mathematical theory as we know it. In fact, modern science was formed by these later decisive factors and classical mechanics came to be known as their early application [8].
The medieval mathematician Jordanus de Nemore introduced in his Elementa demonstrationem ponderum the “positional gravity” concept and the component forces use [9].
Johannes Kepler published in 1609 Astronomia nova which was the first published causal explanation of the planets motion. Based on the observations made by Tycho Brahe on Mars orbit, he concluded that the orbits of the planet were ellipses. This epistemological revolution occurred at the same time when Galileo was proposing for objects motion abstract mathematical laws. Perhaps he may have performed the historical experiment of the two cannonballs of different weights dropping from Pisa tower. Hence, he showed that these two cannonballs hit the ground simultaneously. We doubt in fact the reality of that particular experiment, but Galileo conducted quantitative experiments which were to roll balls on an inclined plane. From such experiments results he derived his accelerated motion theory [10].
Sir Isaac Newton laid down classical mechanics foundations by founding his natural philosophy principles on three laws of motion proposed by him: the inertia first law, the acceleration second law, and the action and reaction third law. A proper mathematical and scientific treatment in Philosophiae Naturalis Principia Mathematica of Newton was given to his second and third laws. They are in fact different from the attempts laid earlier to explain similar phenomena and which were either incorrect, incomplete, or they lack a precise mathematical expression. Moreover, the principles of conservation of angular momentum and momentum were postulated by Newton. Additionally, the universal gravitational law of Newton was also provided by him to give the first accurate mathematical and scientific formulation of gravity. The most accurate and fullest description of classical mechanics was provided by the combination of the laws of motion and gravitation of Newton. Newton showed that his three laws can be applied to the objects of everyday as well to heavenly objects. Particularly, Newton derived a theoretical explanation of the planets’ laws of motion of Kepler [11].
Newton performed the mathematical calculation by inventing previously the mathematical calculus. In fact, calculus eclipsed his book, the Principia, which was formulated totally in terms of geometric methods which were long established and to gain hence acceptability. Moreover, the notation of the integral and of the derivative which are preferred today were developed by Leibniz however [12].
All phenomena, including light in the form of geometric optic, can be explained by classical mechanics as it was assumed by Newton and most of his contemporaries, with the notable exception of Christiaan Huygens. Newton maintained his own corpuscular light theory even when they discovered the wave interference phenomenon or the so-called Newton’s rings [13].
Classical mechanics became a major field of study in physics as well in mathematics and this after Newton. A far greater number to problems solutions were allowed by several progressive reformulations of his mechanics. Joseph Louis Lagrange was the first to reformulate in 1788 Newtons’ mechanics. William Rowan Hamilton in his turn reformulated Lagrangian mechanics in 1833 [14].
More modern physics resolved some difficulties that were discovered in the late nineteenth century. Compatibility with the theory of electromagnetism and the famous Michelson-Morley experiment were some of these difficulties. Often still considered as a part of classical mechanics, the special relativity theory was led by the resolution of these problems [15].
Explaining all thermodynamics, raised another set of difficulties and problems with classical mechanics. Gibbs paradox of classical statistical mechanics was the result of the combination of classical mechanics with thermodynamics. In this paradox, entropy is not a quantity which was well defined. We introduced quanta to explain the black-body radiation otherwise this was not possible. Classical mechanics was unable to explain, not even approximately, such basic things as the sizes of the atoms, the photo-electric effect, and the energy levels and this when experiments delved into the atomic world. Quantum mechanics was the result of the efforts to resolve these problems [16].
Classical mechanics has no longer been considered as an independent theory since the end of the twentieth century. We consider classical mechanics now as an approximate theory to quantum mechanics which is a more general theory. The desire to understand the fundamental forces of nature has shifted our emphasis in our research and investigation and has led to the Standard Model and also has directed the studies to a unified theory of everything. For the study of the motion of low-energy, of non-quantum mechanical particles in weak gravitational fields, it is useful to make use of classical mechanics. Additionally, we were successful to extend classical mechanics to the complex domain. In fact, this extended complex classical mechanics behaves very similarly to quantum mechanics [17].
At the end, and to conclude, this research work is organized as follows: After the introduction in section 1, Newton’s laws of classical mechanics are stated in section 2, then the purpose and the advantages of the present work are presented in section 3. Afterward, in section 4, the extended Kolmogorov’s axioms and hence the complex probability paradigm with their original parameters and interpretation will be explained and summarized. Moreover, in section 5, the complex probability paradigm axioms are applied to classical mechanics which will be hence extended to the imaginary and complex sets. Additionally, in section 6, the resultant complex random vector
The classical mechanics foundation was laid down by Isaac Newton’s three physical laws of motion. These laws define and describe the forces acting upon a body as well as the response of the body to those forces. Moreover, and more precisely, the first law defines the force qualitatively, the second law measures the force quantitively. The third law states that an isolated single force does not exist [18, 19, 20, 21]. Throughout nearly three centuries, these three laws have been stated in many different ways and we will summarize them as follows:
First law
In an inertial frame of reference, an object either remains at rest or continues to move at a constant velocity, unless acted upon by a force.
Second law
In an inertial frame of reference, the vector sum of the forces
Third law
When one body exerts a force on a second body, the second body simultaneously exerts a force equal in magnitude and opposite in direction on the first body.
Isaac Newton was the first to state in his Mathematical Principles of Natural Philosophy (Philosophiae Naturalis Principia Mathematica), first published in 1687, the three laws of motion. Many systems and physical objects were investigated and explained by the three laws of motion of Newton. As an example, the planetary motion laws of Johannes Kepler were proved and demonstrated by Newton’s laws when combined with the universal gravitational law, in the third volume of the text [22, 23, 24, 25].
Fourth law
Some also describe a Fourth law which states that forces add up like vectors, that is, that forces obey the principle of superposition.
A single point masses idealize the objects to which we apply the laws of Newton, that means that the object body shape and size are to be ignored in order to concentrate on the body’s motion more easily. This is achieved when the rotation and the deformation of the body are negligible and when the object is too small compared to the distances that the analysis involves. Hence, in the planet orbital motion around a star analysis, even a planet can be idealized as a particle [26, 27, 28, 29].
Moreover, deformable bodies and the rigid bodies motion are not characterized by the original form of the laws of motion of Newton which reveal to be inadequate. Additionally, a generalization of the laws of motion of Newton for rigid bodies was introduced and achieved by Leonhard Euler in 1750 and they were called accordingly Euler’s laws of motion. They were applied later on to deformable bodies which were postulated to be a continuum. Euler’s laws can be derived from the laws of Newton if we represent a body as an assemblage of discrete particles where every particle is governed by the motion laws of Newton. Independently of the structure of any particle, the laws of Euler can be considered, however, as axioms that describe the motion laws of extended bodies [30, 31, 32, 33].
Newtonian inertial reference frames are a certain set of frames that verify and confirm Newton’s laws. The first law defines what an inertial frame of reference is and this according to some authors interpretation. Therefore, the first law cannot be demonstrated as special case of the second law since the second law is only valid when an inertial frame of reference is used in the observation. The second law is considered as a corollary of the first law by other authors. It was long after Newton’s death that we have developed the inertial frame of reference explicit concept [34, 35, 36, 37].
Furthermore, we assume that, momentum, acceleration, and most importantly force to be quantities defined externally in the given interpretation. This is not the only interpretation, but the most common way one can consider the definition of these quantities by Newton’s laws [38, 39, 40, 41].
Additionally, when the speeds considered are much closer to the speed of light, then Albert Einstein’s special relativity replaces Newtonian mechanics which is still useful as an approximation of the studied phenomenon [42, 43, 44].
The crucial job of the theory of classical probability is to compute and to assess probabilities. A deterministic expression of probability theory can be attained by adding supplementary dimensions to nondeterministic and stochastic experiments. This original and novel idea is at the foundations of my new paradigm of complex probability. In its core, probability theory is a nondeterministic system of axioms that means that the phenomena and experiments outputs are the products of chance and randomness. In fact, a deterministic expression of the stochastic experiment will be realized and achieved by the addition of imaginary new dimensions to the stochastic phenomenon taking place in the real probability set
The advantages and the purpose of this current work are to:
Extend the theory of classical probability to encompass the complex numbers set, hence to bond the theory of probability to the field of complex variables and analysis in mathematics. This mission was elaborated and initiated in my earlier seventeen papers.
Apply the novel probability axioms and paradigm to Newton’s classical mechanics.
Show that all nondeterministic phenomena can be expressed deterministically in the complex probabilities set which is
Compute and quantify both the degree of our knowledge and the chaotic factor of all the forces acting on a body in classical mechanics and
Represent and show the graphs of the functions and parameters of the innovative paradigm related to Newton’s mechanics.
Demonstrate that the classical concept of probability is permanently equal to one in the set of complex probabilities; hence, no randomness, no chaos, no ignorance, no uncertainty, no nondeterminism, no unpredictability, and no disorder exist in:
Prove an important property at the foundation of statistical physics after applying
Prepare to implement this creative model to other topics in prognostics and to the field of stochastic processes. These will be the job to be accomplished in my future research publications.
Concerning some applications of the novel founded paradigm and as a future work, it can be applied to any nondeterministic phenomenon using classical mechanics whether in the continuous or in the discrete cases. Moreover, compared with existing literature, the major contribution of the current research work is to apply the innovative paradigm of complex probability to Newton’s classical mechanics and to statistical physics as well.
The next figure displays the major purposes and goals of the Complex Probability Paradigm (
The diagram of the complex probability paradigm major goals.
The simplicity of Kolmogorov’s system of axioms may be surprising. Let
hence, we say that
And we say also that:
Moreover, we can generalize and say that for
And we say also that for
Now, we can add to this system of axioms an imaginary part such that:
We can see that by taking into consideration the set of imaginary probabilities we added three new and original axioms and consequently the system of axioms defined by Kolmogorov was hence expanded to encompass the set of imaginary numbers [45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61].
As a summary of the new paradigm, we declare that in the universe
The
In this section we will relate and link Newton’s mechanics to the complex probability paradigm with all its parameters by using four novel concepts which are: the real stochastic force
The real stochastic force is defined by:
Here
Since
If
If
The imaginary stochastic force is defined by:
Here
Since
If
If
We have:
And since
And we can deduce that:
Therefore,
We define the resultant complex stochastic force by:
Here
Since
If
If
Since
where
Additionally, since
where
We define the deterministic real force by:
Since from
Here
Furthermore,
Since
Since
Since
Since
If
If
The second case shows and proves that if
Additionally, since
And
Since
And since
Furthermore, according to
which is a second-degree equation in terms of
Since
But according to
And if
And if
Consequently,
But
The graphs of the reduced real force
We have
The graphs of the reduced real force
We have
The graphs of the reduced real force
We can deduce also from
The graphs of the reduced real force
And we can infer using the fact that
The graphs of the reduced real force
Also, we can calculate (Figure 8):
The graphs of the reduced real force
But according to
As we have computed:
And since
We have
The graphs of the reduced imaginary force
And we can deduce that (Figure 10):
The graphs of the reduced imaginary force
And we can infer that (Figure 11):
The graphs of the reduced imaginary force
We can deduce also that (Figure 12):
The graphs of the reduced imaginary force
And we can compute (Figure 13):
The graphs of the reduced imaginary force
And we can calculate (Figure 14):
The graphs of the reduced imaginary force
But according to
Analogously, and since
And
And
We can deduce also that:
And
And
But according to
The graphs of the reduced real force
And since the deterministic force in
In this cube (Figure 15), we can notice the simulation of the complex resultant reduced force
We have:
But from
According to
Since also
Since we have:
And
Furthermore, since
Hence, we can conclude that no chaos, no ignorance, no disorder, no unpredictability, no chance, and no randomness exist in the probability universe
A powerful tool will be described in the current section which was developed in my personal previous research papers and which is founded on the concept of a complex random vector that is a vector combining the real and the imaginary probabilities of a random particle, defined in the three added axioms of
First, let us consider the following general Bernoulli distribution and let us define its complex random vectors and their resultant (Table 1):
Outcome | |||
---|---|---|---|
In | |||
In | |||
In |
A general Bernoulli distribution in
Where,
We have:
and
Where
The complex random vector corresponding to the random outcome
The complex random vector corresponding to the random outcome
The resultant complex random vector is defined as follows:
The probability
This is coherent with the three novel complementary axioms defined for the
Similarly,
The probability
Where
By analogy, for the case of one random vector
In general, for the vector
Where the degree of our knowledge of the whole distribution is equal to
Notice, if
which is coherent with the calculations already done.
To illustrate the concept of the resultant complex random vector
The resultant complex random vector
As a general case, let us consider then this discrete probability distribution with
Outcome | |||||
---|---|---|---|---|---|
In | |||||
In | |||||
In |
A discrete uniform distribution with
We have here in
Moreover, we can notice that:
And
Where
Therefore, the degree of our knowledge corresponding to the resultant complex vector
and its relative chaotic factor is:
Similarly, its relative magnitude of the chaotic factor is:
Thus, we can verify that we have always:
What is important here is that we can notice the following fact. Take for example:
We can deduce mathematically using calculus that:
From the above, we can also deduce this conclusion:
As much as
We have:
Where
= the mean of all the
Therefore,
Additionally, we have:
= the mean real random force acting on the whole macrosystem in
Moreover,
= the mean imaginary random force acting on the whole macrosystem in
Furthermore,
= the mean resultant complex random force acting on the whole macrosystem in
Also, we have:
And
Correspondingly, we can deduce the following result:
Therefore, this means that in the first case the mean real force acting on the macrosystem in the real set
That means that the mean norm of the resultant force acting on the whole macrosystem is totally deterministic in both cases in the probability set
Similarly, we can deduce also the following similar result:
Therefore, this means that in the first case the mean real force acting on the macrosystem in the real set
That means that the mean norm of the resultant force acting on the whole macrosystem is totally deterministic in both cases in the probability set
In addition, for
This means that we have a random experiment with only one outcome or vector, hence,
The law of large numbers states that:
“As
We can deduce now the following conclusion related to the law of large numbers:
We can see, as we have proved, that as much as
Hence, what we have done here is that we have proved the law of large numbers (already discussed in the published papers [46, 50, 57, 61]) as well as an important property of statistical mechanics using
The following flowchart summarizes all the procedures of the proposed complex probability prognostic model where
In this section, the simulation of the novel
The probability density function (
Note that in the simulation we have considered:
The cumulative distribution function (
Note that:
If
If
The mean or average or expectation is:
The variance is:
The standard deviation is:
The median
Since the distribution is uniform then it has no mode.
The real probability
The imaginary complementary probability
The real complementary probability
The complex probability or random vector and force are:
The Degree of Our Knowledge:
The Chaotic Factor:
The Magnitude of the Chaotic Factor
At any value of
then,
Hence, the prediction of all the probabilities and forces of the stochastic experiment in the universe
The graphs of
In the first cube (Figure 20), the simulation of
The graphs of
In the second cube (Figure 21), we can notice the simulation of the real reduced force
The graphs of
In the third cube (Figure 22), we can notice the simulation of the complex resultant reduced force
The graphs of the reduced forces
The probability density function (
I have taken the domain for the binomial random variable to be:
Taking in our simulation
The mean of this binomial discrete random distribution is:
The standard deviation is:
The median is
The mode for this symmetric distribution is = 6 =
The cumulative distribution function (
Note that:
If
If
The real probability
The imaginary complementary probability
The real complementary probability
The complex probability or random vector and force are:
The Degree of Our Knowledge:
The Chaotic Factor:
The Magnitude of the Chaotic Factor
At any value of
then,
Hence, the prediction of all the probabilities and forces of the stochastic experiment in the universe
The graphs of
In the first cube (Figure 24), the simulation of
The graphs of
In the second cube (Figure 25), we can notice the simulation of the real reduced force
The graphs of
In the third cube (Figure 26), we can notice the simulation of the complex resultant reduced force
The graphs of the reduced forces
The probability density function (
For the Poisson discrete random variable:
I have taken in the simulation the domain for the Poisson random variable to be equal to:
The mean of this Poisson discrete random distribution is:
The standard deviation is:
The median
The mode is =
Since
The cumulative distribution function (
Note that:
If
If
The real probability
The imaginary complementary probability
The real complementary probability
The complex probability or random vector and force are:
The Degree of Our Knowledge:
The Chaotic Factor:
The Magnitude of the Chaotic Factor
At any value of
then,
Hence, the prediction of all the probabilities and forces of the stochastic experiment in the universe
The graphs of
In the first cube (Figure 28), the simulation of
The graphs of
In the second cube (Figure 29), we can notice the simulation of the real reduced force