Aetiology of thyroid nodules.
\r\n\tThis book will mainly cover work related to: (i) cells mechanosensing and mechanotransduction mechanisms (ii) computational and experimental techniques in mechanobiology, (iii) mathematical mechanobiological models of bone remodeling, (iv) bone mechano-transduction, (v) innovative tools for mechanobiology and the role of medical imaging in this field and (vi) any other proposals related to innovations, clinical application and perspectives of mechanobiology.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"0a38ccecc83b50d8b015a6dd2533049d",bookSignature:"Prof. Abdelwahed Barkaoui",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10255.jpg",keywords:"Nuclear Mechanotransduction, Mechanosensitivity, Fluids Mechanics, Multiscale Mechanobiology, Modeling Cellular Mechanics, Finite Elements Method, Bone Remodeling, Mechanics Stimulus, Multi-scale Modeling, Mechanobiology Tools, Cell Imaging, Cell-Substrate Interactions",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 2nd 2020",dateEndSecondStepPublish:"July 23rd 2020",dateEndThirdStepPublish:"September 21st 2020",dateEndFourthStepPublish:"December 10th 2020",dateEndFifthStepPublish:"February 8th 2021",remainingDaysToSecondStep:"9 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Assistant director of LERMA laboratory, head of mechanical discipline at ECINE and coordinator of the ECINE study program accreditation committee, a member of the editorial board of several international scientific journals, also a member of the American Society of Mechanical (ASME) Engineers European Society of Biomechanics (ESB) and the International Society of Biomechanics (ISB).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320631",title:"Dr.",name:"Abdelwahed",middleName:null,surname:"Barkaoui",slug:"abdelwahed-barkaoui",fullName:"Abdelwahed Barkaoui",profilePictureURL:"https://mts.intechopen.com/storage/users/320631/images/system/320631.jpg",biography:"Abdelwahed Barkaoui is an associate professor of Mechanical Engineering at International University of Rabat. He obtained his University habilitation from university of Tunis El Manar-Tunisia in 2017 and his PhD from university of Orleans-France 2012. He has a master's degree in mechanics obtained from the INSA of Lyon-France. He held a position of director of the department of sciences and techniques of engineers and was a Member of the Scientific Advisory Board of the Preparatory Institute for Engineering Studies of El Manar. Currently, Dr. Barkaoui is an assistant director of LERMA laboratory, head of mechanical discipline at ECINE and coordinator of the ECINE study program accreditation committee. His research mainly concerns problems in biomechanics, mechanobiology and biomedical engineering. He is a member of the editorial board of several international scientific journals as Series on biomechanics (2019-), Frontiers in Bioengineering and Biotechnology “biomechanics” (2017-), The Open Biomedical Engineering (2019-), EC Orthopedics (2017-) and Reviewer for several international journals known in the field of biomechanics and mechanics (Scientific Reports (nuture.com), Engineering Fracture Mechanics, Biomechanics and Modeling in Mechanobiology, etc). He is also a member of the American Society of Mechanical (ASME) Engineers European Society of Biomechanics (ESB) and the International Society of Biomechanics (ISB). 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Without time, there would be no physical substances, no space, and no life. In other words, time and substance have to coexist. In the chapter, I will start with Einstein’s relativity theory to show his famous energy equation, derived from in which we will show that energy and mass can be traded. Since mass is equivalent to energy and energy is equivalent to mass, we see that mass can be treated as an energy reservoir. We will show any physical space cannot be embedded in an absolute empty space and it cannot have any absolute empty subspace in it and empty space is a timeless (i.e., t = 0) space. We will show that every physical space has to be fully packed with substances (i.e., energy and mass), and we will show that our universe is a subspace within a more complex space. We see that our universe could have been one of the many universes outside our universal boundary. We will also show that it takes time to create a subspace, and it cannot bring back the time that has been used for the creation. Since all physical substances exist with time, all subspaces are created by time and substances (i.e., energy and mass). This means that our cosmos was created by time with a gigantic energy explosion, for which every subspace coexists with time. This means that without time the creation of substances would not have happened. We see that our universe is in a temporal (i.e., t > 0) space, and it is still expanding based on current observation. This shows that our universe has not reached its half-life yet, as we have accepted the big bang creation. We are not alone with almost absolute certainty. Someday, we may find a planet that once upon a time had harbored a civilization for a period of light-years. In short, the burden of a scientific postulation is to prove a solution exists within our temporal universe; otherwise it is not real or virtual as mathematics is.
Professor Hawking was a world renowned astrophysicist, a respected cosmic scientist, and a genius who passed away last year on March 14, 2018. As you will see, our creation of universe was started with the same root of the big bang explosion, but it is not a sub-universe of Hawking’s. You may see from this chapter that the creation of temporal universe is somewhat different from Hawking’s creation.
The essence of Einstein’s special theory of relativity [1] is that time is a relative quantity with respect to velocity as given by
where
We see that the time window
Equivalently, Einstein’s relativity equation can be shown in terms of relative mass as given by
where
With reference to the binomial expansion, Eq. (2) can be written as
By multiplying the preceding equation with the velocity of light c2 and noting that the terms with the orders of v4/c2 are negligibly small, the above equation can be approximated by
which can be written as
The significance of the preceding equation is that
What Einstein postulated, as I remembered, is that there must be energy associated with the mass even at rest. And this was exactly what he had proposed:
where
the energy of the mass at rest, where v = 0 and
We see that Eq. (6) or equivalently Eq. (7) is the well-known Einstein energy equation.
One of the most enigmatic variables in the laws of science must be “time.” So what is time? Time is a variable and not a substance. It has no mass, no weight, no coordinate, and no origin, and it cannot be detected or even be seen. Yet time is an everlasting existing variable within our known universe. Without time there would be no physical matter, no physical space, and no life. The fact is that every physical matter is associated with time which includes our universe. Therefore, when one is dealing with science, time is one of the most enigmatic variables that are ever present and cannot be simply ignored. Strictly speaking, all the laws of science as well every physical substance cannot exist without the existence of time.
On the other hand, energy is a physical quantity that governs every existence of substance which includes the entire universe. In other words without the existence of energy, there would be no substance and no universe! Nonetheless based on our current laws of science, all the substances were created by energy, and every substance can also be converted back to energy. Thus energy and substance are exchangeable, but it requires some physical conditions (e.g., nuclei and chemical interactions and others) to make the conversion start. Since energy can be derived from mass, mass is equivalent to energy. Hence every mass can be treated as an energy reservoir. The fact is that our universe is compactly filled with mass and energy. Without the existence of time, the trading (or conversion) between mass and energy could not have happened.
Let us now start with Einstein’s energy equation which was derived by his special theory of relativity [1] as given by
where
Since all the laws in science are approximations, for which we have intentionally used an approximated sign. Strictly speaking the energy equation should be more appropriately presented with an inequality sign as described by
This means that in practice, the total energy should be smaller or at most approaching to the rest mass
In view of Einstein’s energy equation of Eq. (8), we see that it is a singularity-point approximation and timeless equation (i.e., t = 0). In other words, the equation needs to convert into a temporal (i.e., t > 0) representation or time-dependent equation for the conversion to take place from mass into energy. We see that, without the inclusion of time variable, the conversion would not have taken place. Nonetheless, Einstein’s energy equation represents the total amount of energy that can be converted from a rest mass
where
One of the important aspects in Eq. (10) must be that energy and mass can be traded, for which the rate of energy conversion from a mass can be written in terms of electromagnetic (EM) radiation or Radian Energy as given by [4]
where
Similarly the conversion from energy to mass can also be presented as
The major difference of this equation, as compared with Eq. (11), must be the energy convergent operator −∇·S(
Incidentally, black hole [5, 6] can be considered as one of the energy convergent operators. Instead the convergent force is relied more on the black hole’s intense gravitational field. The black hole still remains an intriguing physical substance to be known. Its gravitational field is so intense even light cannot be escaped.
By the constraints of the current laws of science, the observation is limited by the speed of light. If light is totally absorbed by the black hole, it is by no means that the black hole is an infinite energy sink [6]. Nonetheless, every black hole can actually be treated as an energy convergent operator, which is responsible for the eventuality in part of energy to mass conversion, where an answer remained to be found.
In our physical world, every matter is a substance which includes all the elemental particles; electric, magnetic, and gravitation fields; and energy. The reason is that they were all created by means of energy or mass. Our physical space (e.g., our universe) is fully compacted with substances (i.e., mass and energy) and left no absolute empty subspace within it. As a matter of fact, all physical substances exist with time, and no physical substance can exist forever or without time, which includes our universe. Thus, without time there would be no substance and no universe. Since every physical substance described itself as a physical space and it is constantly changing with respect to time. The fact is that every physical substance is itself a temporal space (or a physical subspace), as will be discussed in the subsequent sections.
In view of physical reality, every physical substance cannot exist without time; thus if there is no time, all the substances which include all the building blocks in our universe and the universe itself cannot exist. On the other hand, time cannot exist without the existence of substance or substances. Therefore, time and substance must mutually coexist or inclusively exist. In other words, substance and time have to be simultaneously existing (i.e., one cannot exist without the other). Nonetheless, if our universe has to exist with time, then our universe will eventually get old and die. So the aspects of time would not be as simple as we have known. For example, for the species living in a far distant galaxy moving closer to the speed of light, their time goes somewhat slower relatively to ours [1]. Thus, we see that the relativistic aspects of time may not be the same at different subspaces in our universe (e.g., at the edge of our universe).
Since substances (i.e., mass) were created by energy, energy and time have to simultaneously exist. As we know every conversion, either from mass to energy or from energy to mass, cannot get started without the inclusion of time. Therefore, time and substance (i.e., energy and mass) have to simultaneously exist. Thus we see that all the physical substances, including our universe and us, are coexisting with time (or function of time).
Let us define various subspaces in the following, as they will be used in the subsequence sections:
An absolute empty space has no time, no substance, and no coordinate and is not event bounded or unbounded. It is a virtual space and timeless space (i.e., t = 0), and it does not exist in practice.
A physical space is a space described by dimensional coordinates, which existed in practice, compactly filled with substances, supported by the current laws of science and the rule of time (i.e., time can only move forward and cannot move backward; t > 0). Physical space and absolute empty space are mutually exclusive. In other words, a physical space cannot be embedded in an absolute empty space, and it cannot have absolute empty subspace in it. In other words, physical space is a temporal space in which time is a forward variable (i.e., t > 0), while absolute empty space is a timeless space (i.e., t = 0) in which nothing is in it.
A temporal space is a time-variable physical space supported by the laws of science and rule of time (i.e., t > 0). In fact, all physical spaces are temporal spaces (i.e., t > 0).
A spatial space is a space described by dimensional coordinates and may not be supported by the laws of science and the rule of time (e.g., a mathematical virtual space).
A virtual space is an imaginary space, and it is generally not supported by the laws of science and the rule of time. Only mathematicians can make it happen.
As we have noted, absolutely empty space cannot exist in physical reality. Since every physical space needs to be completely filled with substances and left no absolutely empty subspace within it, every physical space is created by substances. For example, our universe is a gigantic physical space created by mass and energy (i.e., substances) and has no empty subspaces in it. Yet, in physical reality all the masses (and energy) existed with time. Without the existence of time, then there would be no mass, no energy, and no universe. Thus, we see that every physical substance coexists with time. As a matter of fact, every physical subspace is a temporal subspace (i.e., t > 0), which includes us and our universe.
Since a physical space cannot be embedded within an absolute empty space and it cannot have any absolute empty subspace in it [7], our universe must be embedded in a more complex physical space. If we accepted our universe is embedded in a more complex space, then our universe must be a bounded subspace.
How about time? Since our universe is embedded in a more complex space, the complex space may share the same rule of time (i.e., t > 0). However, the complex space that embeds our universe may not have the same laws of science as ours but may have the same rule of time (i.e., t > 0); otherwise our universe would not be bounded. Nevertheless, whether our universe is bounded or not bounded is not the major issue of our current interest, since it takes a deeper understanding of our current universe before we can move on to the next level of complex space revelation. It is however our aim, abiding within our current laws of science, to investigate the essence of time as the enigma origin of our universe.
One of the most intriguing questions in our life must be the existence of time. So far, we know that time comes from nowhere, and it can only move forward, not backward, not even stand still (i.e., t = 0). Although time may somewhat relatively slow down, based on Einstein’s special theory of relativity [1], so far time cannot move backward and cannot even stand still. As a matter of fact, time is moving at a constant rate within our subspace, and it cannot move faster or slower. We stress that time moves at the same rate within any subspace within the universe even closer the boundary of our universe, but the difference is the relativistic time. Since time is ever existing, then how do we know there is a physical space? One answer is that there is a profound connection between time and physical space. In other words, if there is no time, then there would be no physical space. A physical space is in fact a temporal (i.e., t > 0) space, in contrast to a virtual space. Temporal space can be described by time, while virtual space is an imaginary space without the constraint of time. Temporal space is supported by the laws of science, while virtual space is not.
A television video image is a typical example of trading time for space. For instance, each TV displayed an image of (dx, dy) which takes an amount of time to be displayed. Since time is a forward-moving variable, it cannot be traded back at the expense of a displayed image (dx, dy). In other words, it is time that determines the physical space, and it is not the physical space that can bring back the time that has been expended. And it is the size (or dimension) of space that determines the amount of time required to create the space (dx, dy). Time is distance and distance is time within a temporal space. Based on our current constraints of science, the speed of light is the limit. Since every physical space is created by substances, a physical space must be described by the speed of light. In other words, the dimension of a physical space is determined by the velocity of light, where the space is filled with substances (i.e., mass and energy). And this is also the reason that speed of time (e.g., 1 s, 2 s, etc.) is determined by the speed of light.
Another issue is why the speed of light is limited. It is limited because our universe is a gigantic physical space that is filled with substances that cause a time delay on an EM wave’s propagation. Nevertheless, if there were physical substances that travel beyond the speed of light (which remains to be found), their velocities would also be limited, since our physical space is fully compacted with physical substances and it is a temporal (i.e., t > 0) space. Let me further note that a substance can travel in space without a time delay if and only if the space is absolutely empty (i.e., timeless; t = 0), since distance is time (i.e., d = ct, t = 0). However, absolute empty space cannot exist in practice, since every physical space (including our universe) has to be fully filled with substances (i.e., energy and mass), with no empty subspace left within it. Since every physical subspace is temporal (i.e., t > 0), in which we see that timeless and temporal spaces are mutually exclusive.
Strictly speaking, all our laws of physics are evolved within the regime of EM science. Besides, all physical substances are part of EM-based science, and all the living species on Earth are primarily dependent on the source of energy provided by the sun. About 78% of the sunlight that reaches the surface of our planet is well concentrated within a narrow band of visible spectrum. In response to our species’ existence, which includes all living species on Earth, a pair of visible eyes (i.e., antennas) evolved in us humans, which help us for our survival. And this narrow band of visible light led us to the discovery of an even wider band of EM spectral distribution in nature. It is also the major impetus allowing us to discover all the physical substances that are part of EM-based physics. In principle, all physical substances can be observed or detected with EM interaction, and the speed of light is the current limit.
Then there is question to be asked, why is the speed of light limited? A simple answer is that our universe is filled with substances that limit the speed of light. The energy velocity of an electromagnetic wave is given by [3]
where (
where (
In view of Eq. (13), it is apparent that the velocity of electromagnetic wave (i.e., speed of light) within an empty subspace (i.e., timeless space) is instant (or infinitely large) since distance is time (i.e., d = ct, t = 0).
A picture that is worth more than a thousand words [8] is a trivial example to show that EM observation is one of the most efficient aspects in information transmission. Yet, the ultimate physical limitation is also imposed by limitation of the EM regime, unless new laws of science emerge. The essence of Einstein’s energy equation shows that mass and energy are exchangeable. It shows that energy and mass are equivalent and energy is a form of EM radiation in view of Einstein’s equation. We further note that all physical substances within our universe were created from energy and mass, which include the dark energies [9] and dark matter [10]. Although the dark substances may not be observed directly using EM interaction, we may indirectly detect their existence, since they are basically energy-based substances (i.e., EM-based science). It may be interesting to note that our current universe is composed of 72% dark energy, 23% dark matter, and 5% other physical substances. Although dark matter contributes about 23% of our universe, it represents a total of 23% of gravitational fields. With reference to Einstein’s energy equation (Eq. (8)), dark energy and dark matter dominate the entire universal energy reservation, well over 95%. Furthermore, if we accept the big bang theory for our universe creation [11], then creation could have been started with Einstein’s time-dependent energy formula of Eq. (11) as given by
where [∇·S(v)] represents a divergent energy operation. In this equation, we see that a broad spectral band intense radian energy diverges (i.e., explodes) at the speed of light from a compacted matter M, where M represents a gigantic mass of energy reservoir. It is apparent that the creation is ignited by time and the exploded debris (i.e., matter and energy) starts to spread out in all directions, similar to an expanding air balloon. The boundary (i.e., radius of the sphere) of the universe expands at the speed of light, as the created debris is disbursed. It took about 15 billion chaotic light-years [12, 13, 14] to come up with the present state of constellation, in which the boundary is still expanding at the speed of light beyond the current observation. With reference to a recent report using the Hubble Space Telescope, we can see galaxies about 15 billion light-years away from us. This means that the creation process is not stopping yet and at the same time the universe might have started to de-create itself, since the big bang started, due to intense convergent gravitational forces from all the newly created debris of matter (e.g., galaxies and dark matter). To wrap up this section, we would stress that one of the viable aspects of Eq. (15) is the transformation from a spatially dimensionless equation to a space-time function (i.e., ∇·S); it describes how our universe was created with a huge explosion. Furthermore, the essence of Eq. (15) is not just a piece of mathematical formula; it is a symbolic representation, a description, a language, a picture, or even a video as may be seen from its presentation. We can visualize how our universe was created, from the theory of relativity to Einstein’s energy equation and then to temporal space creation.
Let us now take one of the simplest connections between physical subspace and time [15]:
where d is the distance, v is the velocity, and t is the time variable. Notice that this equation may be one of the most profound connections between time and physical space (or temporal space). Therefore, a three-dimensional (Euclidean) physical (or temporal) subspace can be described by
where (v
Thus, we see that time can be traded for space and space cannot be traded for time, since time is a forward variable (i.e., t > 0). In other words, once a section of time Δt is expended, we cannot get it back. Needless to say, a spherical temporal space can be described by
where radius r increases at the speed of light. Thus, we see that the boundary (i.e., edge) of our universe is determined by radius r, which is limited by the light speed, as illustrated in a composite temporal space diagram of Figure 1. In view of this figure, we see that our universe is expanding at the speed of light well beyond the current observable galaxies. Figure 2 shows a discrete temporal space diagram, in which we see that the size of our universe is continuously expanding as time moves forward (i.e., t > 0). Assuming that we have already accepted the big bang creation, sometime in the future (i.e., billions of light-years later), our universe will eventually stop expanding and then start to shrink back, preparing for the next cycle of the big bang explosion. The forces for the collapsing universe are mainly due to the intense gravitational field, mostly from giant black holes and matter that were derived from merging (or swallowing) with smaller black holes and other debris (i.e., physical substances). Since a black hole’s gravitational field is so intense, even light cannot escape; however, a black hole is by no means an infinite energy reservoir. Eventually, the storage capacity of a black hole will reach a limit for explosion, as started for the mass to energy and debris creation.
Composite temporal space universe diagram. r = ct, r is the radius of our universe, t is time, c is the velocity of light, and ε0 and μ0 are the permittivity and permeability of the space.
Discrete temporal universe diagrams; t is time.
In other words, there will be one dominant giant black hole within the shrinking universe, to initiate the next cycle of universe creation. Therefore, every black hole can be treated as a convergent energy sink, which relies on its intense gravitation field to collect all the debris of matter and energies. Referring to the big bang creation, a gigantic energy explosion was the major reason for the universe’s creation. In fact, it can be easily discerned that the creating process has never slowed down since the birth of our universe, as we see that our universe is still continuingly expanding even today. This is by no means an indication that all the debris created came from the big bang’s energy (e.g., mc2); there might have been some leftover debris from a preceding universe. Therefore, the overall energy within our universe cannot be restricted to just the amount that came from the big bang creation. In fact, the conversion processes between mass and energy have never been totally absent since the birth of our universe, but they are on a much smaller scale. In fact, right after birth, our universe started to slow down the divergent process due to the gravitational forces produced by the created matter. In other words, the universe will eventually reach a point when overall divergent forces will be weaker than the convergent forces, which are mostly due to gravitational fields coming from the newly created matter, including black holes. As we had mentioned earlier, our universe currently has about 23% dark matter, which represents about 23% of the gravitational fields within the current universe. The intense localized gravitational field could have been produced from a group or a giant black hole, derived from merging with (or swallowing up) some smaller black holes, nearby dark matter, and debris. Since a giant black hole is not an infinite energy sink, eventually it will explode for the next cycle of universal creation. And it is almost certain that the next big bang creation will not occur at the same center of our present universe. One can easily discern that our universe will never shrink to a few inches in size, as commonly speculated. It will, however, shrink to a smaller size until one of the giant black holes (e.g., swallowed-up sufficient physical debris) reaches the big bang explosive condition to release its gigantic energy for the next cycle of universal creation. The speculation of a possible collapsing universe remains to be observed. Nonetheless, we have found that our universe is still expanding, as observed by the Doppler shifts of the distant galaxies at the edge of our universe, about 15 billion light-years away [12, 13, 14]. This tells us that our universe has not reached its half-life yet. In fact, the expansion has never stopped since the birth of our universe, and our universe has also been started to de-create since the big bang started, which is primarily due to convergent gravitational forces from the newly created debris (e.g., galaxies, black holes, and dark matter).
Relativistic time at a different subspace within a vast universal space may not be the same as that based on Einstein’s special theory of relativity [1]. Let us start with the relativistic time dilation as given by
where Δt′ is the relativistic time window, compared with a standstill subspace, Δt is the time window of a standstill subspace, v is the velocity of a moving subspace, and c is the velocity of light. We see that time dilation Δt′ of the moving subspace, relative to the time window of the standstill subspace Δt, appears to be wider as velocity increases. For example, a 1-s time window Δt is equivalent to the 10-s relative time window Δt’. This means that a 1-s time expenditure within the moving subspace is relative to about a 10-s time expenditure within the standstill subspace. Therefore, for the species living in an environment that travels closer to the speed of light (e.g., at the edge of the universe), their time appears to be slower than ours, as illustrated in Figure 3. In this figure, we see an old man traveling at a speed closer to the velocity of light; his relative observation time window appears to be wider as he is looking at us, and the laws of science within his subspace may not be the same as ours.
Effects on relativistic time.
Two of the most important pillars in modern physics must be Einstein’s relativity theory and Schrödinger’s quantum mechanics [15]. One is dealing with very large objects (e.g., universe), and the other is dealing with very small particles (e. g., atoms). Yet, there exists a profound connection between them, by means of the Heisenberg’s uncertainty principle [16]. In view of the uncertainty relation, we see that every temporal subspace takes a section of time Δt and an amount of energy ΔE to create. Since we cannot create something from nothing, everything needs an amount of energy ΔE and a section of time Δt to make it happen. By referring to the Heisenberg uncertainty relation as given by
where h is the Planck’s constant. We see that every subspace is limited by ΔE and Δt. In other words, it is the h region, but not the shape, that determines the boundary condition. For example, the shape can be either elongated or compressed, as long as it is larger than the h region.
Incidentally, the uncertainty relationship of Eq. (21) is also the limit of reliable bit information transmission as pointed out by Gabor in [17]. Nonetheless, the connection with the special theory of relativity is that the creation of a subspace near the edge of our universe will take a short relative time with respect to our planet earth, since Δt’ > Δt. The “relativistic” uncertainty relationship within the moving subspace, as with respect to a standstill subspace, can be shown as
where we see ΔE energy is conserved. Thus a narrower time-width can be achieved as with respect to standstill subspace. It is precisely possible that one can exploit for time-domain digital communication, as from ground station to satellite information transmission.
On the other hand, as from satellite to ground station information transmission, we might want to use digital bandwidth (i.e., Δ
Or equivalently we have
in which we see that a narrower bandwidth Δ
Every physical (or temporal) subspace is created by substances (i.e., energy and mass), and substances coexist with time. In this context, we see that our universe was essentially created by time and energy and the universe is continuously evolving (i.e., changing) with time. Although relativistic time may not be the same at the different subspaces within our universe, the rule of time may remain the same. As for the species living closer to the speed of light, relativistic time may not be noticeable to them, but their laws of science within their subspace may be different from ours. Nonetheless, our universe was simultaneously created by time with a gigantic energy explosion. Since our universe cannot be embedded in an empty space, it must be embedded in a more complex space that remains to be found. From an inclusive point of view, mass is energy or energy is mass, which was discovered by Einstein almost a century ago [1]. And it is this basic fundamental law of physics that we have used for investigating the origin of time. Together with a huge energy explosion (i.e., big bang theory [11]), time is the igniter for the creation of our universe. As we know, without the existence of time, the creation of our universe would not have happened. As we have shown, time can be traded for space, but space cannot be traded for time. Our universe is in fact a temporal physical subspace, and it is continuously evolving or changing with time (i.e., t > 0). Although every temporal subspace is created by time (and substances), it is not possible for us to trade any temporal subspace for time. Since every physical substance has a life, our universe (a gigantic substance) cannot be excluded. With reference to the report from a recent Hubble Space Telescope observation [12, 13, 14], we are capable of viewing galaxies about 15 billion light-years away and have also learned that our universe is still by no means slowing down in expansion. In other words, our universe has still not reached its half-life, based on our estimation. As we have shown, time ignited the creation of our universe, yet the created physical substances presented to us the existence of time.
In view of the preceding discussion, we see that our universe is a time-invariant system (i.e., from system theory stand point); as in contrast with an empty space, it is a not a time-invariant system and it is a timeless or no-time space. We see that timeless solution cannot be directly implemented within our universe. Since science is a law of approximation and mathematics is an axiom of absolute certainty, using exact math to evaluate inexact science cannot guarantee its solution to exist within our temporal (i.e., t > 0) universe. One important aspect of temporal universe is that one cannot get something from nothing: There is always a price to pay; every piece of temporal subspace (or every bit of information [7]) takes an amount of energy (i.e., ΔE) and a section of time (i.e., Δt) to create. And the subspace [i.e., f(x, y, z; t), t > 0] is a forward time-variable function. In other words, time and subspace coexist or are mutually inclusive. This is the boundary condition and constrain of our temporal universe [i.e., f(x, y, z; t), t > 0], in which every existence within our universe has to comply with this condition. Otherwise it is not existing within our universe, unless new law emerges since laws are made to be broken. Thus we see that any emerging science has to be proven to exist within our temporal universe [i.e., f(x, y, z; t), t > 0]. Otherwise it is a fictitious science, unless it can be validated by repeated experiments.
In mathematics, we see that the burden of a postulation is first to prove if there exists a solution and then search for a solution. Although we hardly have had, there is an existent burden in science. Yet, we need to prove that a scientific postulation is existing within our temporal universe [i.e., f(x, y, z; t), t > 0]; otherwise it is not real or virtual as mathematics is. For example such as the superposition principle in quantum mechanics, in which we have proven [18] it is not existed within our temporal universe (i.e., t > 0), since Schrödinger’s quantum mechanics is timeless as mathematics is.
There is however an additional constrain as imposed by our temporal universe which is the affordability. As we have shown that everything (e.g., any physical subspace) existed within our universe has a price tag, in terms of an amount of energy ΔE and a section of time Δt (i.e., ΔE, Δt). To be precise, the price tag also includes an amount of “intelligent” information ΔI or an equivalent amount of entropy ΔS (i.e., ΔE, Δt, ΔI) [7]. For example, creation of a piece of simple facial tissue will take a huge amount of energy ΔE, a section of time Δt, and an amount of information ΔI (i.e., equivalent amount of entropy ΔS). We note that on this planet Earth, only humans can make it happen. Thus we see that every physical subspace (or equivalently substance) within our universe has a price tag (i.e., ΔE, Δt, ΔS), and the question is that can we afford it?
Within our universe, we can easily estimate there were billions and billions of civilizations that had emerged and faded away in the past 15 billion light-years. Our civilization is one of the billions and billions of current consequences within our universe, and it will eventually disappear. We are here, and will be here, for just a very short moment. Hopefully, we will be able to discover substances that travel well beyond the limit of light before the end of our existence, so that a better observational instrument can be built. If we point the new instrument at the right place, we may see the edge of our universe beyond the limit of light. We are not alone with almost absolute certainty. By using the new observational equipment, we may find a planet that once upon a time had harbored a civilization for a period of twinkle thousands of (Earth) years.
We have shown that time is one of the most intriguing variables in the universe. Without time, there would be no physical substances, no space, and no life. With reference to Einstein’s energy equation, we have shown that energy and mass can be traded. In other words, mass is equivalent to energy, and energy is equivalent to mass, for which all mass can be treated as an energy reservoir. We have also shown that a physical space cannot be embedded in an absolute empty space or a timeless (i.e., t = 0) space, and it cannot even have any absolute empty subspace in it. In reality, every physical space has to be fully packed with physical substances (i.e., energy and mass). Since no physical space can be embedded in an absolute empty space, it is reasonable to assume that our universe is a subspace within a more complex space, which remains to be found. In other words, our universe could have been one of the many universes outside our universal boundary, which comes and goes like bubbles. We have also shown that it takes time to create a physical space and the time that has been used for the creation cannot be brought back. Since all physical substances exist with time, all physical spaces are created by time and substances (i.e., energy and mass). This means that our cosmos was created by time and a gigantic energy explosion, in which we see that every substance coexists with time. That is, without time, the creation of physical substances would not have happened. We have further noted that our universe is in a temporal space and it is still expanding based on current observation. This shows that our universe has not reached its half-life yet, as we have accepted the big bang creation. And it is noted that we are not alone with almost absolute certainty. Someday, we may find a planet that once upon a time had harbored a civilization for a period of light-years. We have further shown that the burden of a scientific postulation is to prove it exists within our temporal universe [i.e., f(x, y, z; t), t > 0]; otherwise it is not real or virtual as mathematics is.
Finally, I would like to take this opportunity to say a few words on behalf of Professor Stephen Hawking, who passed away last year on March 14, 2018. Professor Hawking was a world-renowned astrophysicist, a respected cosmic scientist, and a genius. Although the creation of temporal universe started with the same root of the big bang explosion, it is not a subspace of Professor Hawking’s universe. You may see from the preceding presentation that the creation of temporal universe is somewhat different from Hawking’s creation. One of the major differences may be at the origin of big bang creation. My temporal universe was started with a big bang creation within a “non-empty” space, instead within of an empty space which was normally assumed.
A thyroid nodule is defined as a discrete radiologically distinct lesion from the surrounding thyroid parenchyma. Nodules which are palpable but do not correspond to distinct abnormalities on ultrasound do not fall under this category [1]. Clinically they can be identified by the doctor on examination or even noticed by the patient themselves. With the increasingly popular use of neck imaging modalities, thyroid nodules are being commonly identified during these imaging studies.
\nThe clinical importance lies in excluding malignancy in a thyroid nodule, assessing functional status, associated with pain at appearance and compressive symptoms (if large) and accordingly decide the line of management. The key guidelines included to cover this area include
The 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer.
AACE/ACE/AME Task Force on Thyroid Nodules. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules-2016 update [2].
ACR Thyroid Imaging, Reporting and Data System (TI-RADS): white paper of the ACR TI-RADS Committee [3].
European Thyroid Association guidelines for ultrasound malignancy risk stratification of thyroid nodules in adults: The EU-TIRADS [4].
This chapter thus provides a comprehensive coverage of the topic with an optimal approach in management of a thyroid nodule.
\nThyroid nodules are a common finding in general population. This is likely due to the increased use of diagnostic imaging for purposes unrelated to the thyroid. The prevalence of thyroid nodules in a population depends on the screening method used and the presence of risk factors for nodule development. The prevalence of thyroid nodules by palpation was found to be 4.2% in a population-based study in Framingham. The prevalence in females and males was 6.4 and 1.5%, respectively [5]. Clinically nonpalpable nodules are frequently identified on ultrasonography and are termed “incidentalomas.” The prevalence of thyroid nodules as detected by high resolution ultrasound can be as high as 67% [6]. The prevalence in this Californian study also had an asymmetrical distribution with 72 and 41% prevalence in females and males respectively. 22% patients had solitary nodules, whereas 45% had multiple nodules. In another Italian study by Bartollota et al., the prevalence of thyroid nodules by ultrasonography was 33.1%. Thus it becomes a difficult dilemma on what to do with incidentally detected thyroid nodules which are not malignant and not well-characterised.
\nAlso the number of detected nodules increases with age, with the highest prevalence in the seventh decade. Autopsy studies provide the true prevalence of the incidence in a population. An autopsy study in Mayo clinic revealed a prevalence of around 50% even in patients with no history of thyroid disease [7, 8]. This makes it even more complicated that many individuals would complete their lifespan without any intervention for their thyroid nodules.
\nThe prevalence of thyroid nodules is 4 times more common in females than in males. Gender disparity is postulated to occur secondary to influence of oestrogen and progesterone, as demonstrated by increased risk associated with pregnancy and multiparity [9]. The prevalence of thyroid nodules increases with age. Nodules occur more commonly in areas of iodine deficiency. Cigarette smoking can also predispose to development of nodular goitre. This can occur secondary to inhibition of iodine uptake and organification by thiocyanate, which is derived from cyanide in cigarette smoke, hence mimicking iodine deficiency [10]. Obesity has also been demonstrated to be associated with increased risk of goitre and thyroid nodules [11, 12]. Serum IGF-1, being a potent mitogenic factor, was postulated to be associated with development of thyroid nodules. A positive association was observed between serum IGF-1 levels and prevalence of thyroid nodules in males in a study by Volzke et al. In a study by Ying Jian Liu et al., serum IGF-1 levels were not found to be significantly different in patients with hot nodules, cystic cold and solid cold nodules. However, in subgroup analysis, patients with thyroid adenoma on FNA were found to be having significantly higher serum IGF1 levels compared to the control group comprising of healthy adults. However no such association was demonstrated in a study by Hsiao et al. [13, 14, 15]. On the other hand, alcohol intake has been associated with decreased prevalence of goitre and thyroid nodules [16].
\nAutoimmune thyroid diseases are commonly associated with thyroid nodules. Graves disease is associated with nodules in 10–31% of patients. In a Brazilian study, the prevalence of nodules in Graves disease was 27.8%; 19.5% of the nodules harboured thyroid carcinomas, yielding an overall malignancy prevalence of 5% in patients with Graves disease. Younger age and increased thyroid volumes were associated with increased risk for papillary thyroid carcinoma (PTC). This was in contrast to other studies where older age was a risk factor for malignancy [17, 18]. Small thyroid nodules are also commonly associated with Hashimotos thyroiditis. These should be differentiated form pseudonodules resulting from inflammatory infiltrate. Despite the concerns, the US Preventive Services Task Force (USPSTF), which reviews the effectiveness of screening programs in asymptomatic individuals, recommended against screening for thyroid cancer in adults without signs or symptoms of the disease [19].
\nThyroid nodular disease comprises of a wide range of disorders. Colloid nodules, cysts and thyroiditis comprise of 80% of cases, whereas benign follicular neoplasms and thyroid carcinomas account for 10–15% and 5% cases respectively [20]. These causes have been summarised in \nTable 1\n.
\nBenign causes | \nMalignant causes | \n
---|---|
Hashimotos thyroiditis Colloid adenomas Cysts Follicular adenomas Hurthle cell adenomas | \nPapillary thyroid carcinoma (PTC) Follicular thyroid carcinoma (FTC) Medullary thyroid carcinoma (MTC) Anaplastic thyroid carcinoma (ATC) Primary thyroid lymphoma Metastatic carcinomas (breast, renal, lung, head and neck) | \n
Aetiology of thyroid nodules.
Thyroid nodules can present as anterior neck swelling. Most nodules grow very slowly over years. Patients may also present with history of rapid increase in size, which can be suggestive of a malignancy, or a haemorrhage into a nodule, especially if associated with pain. Significant sized nodules can result in compressive symptoms based on the anatomical structure being compromised. Larger nodules can result in compression of underlying structures leading to symptoms like dyspnoea, dysphagia, and hoarseness of voice with compression of trachea, oesophagus and recurrent laryngeal nerves respectively. Patient can also present with thyroid dysfunction. Younger patients with adenoma and thyrotoxicosis (Toxic adenoma) tend to present with the classical symptoms of thyrotoxicosis like nervousness, weight loss despite increased appetite, tremors, palpitations, heat intolerance and sweating. On the other hand, thyrotoxicosis in elderly can present with non-specific symptoms like anorexia, atrial fibrillation, congestive heart failure, and is difficult to diagnose due to lack of classical symptoms. A hypothyroid presentation with fatigue, constipation, cold intolerance is more indicative of a diagnosis of autoimmune thyroiditis in patients with nodular goitre.
\nFindings suggestive of hyperthyroidism or hypothyroidism should be actively elicited during examination. Size of the gland and qualitative and quantitative description of palpable nodules and lymph nodes should be noted, including size, tenderness, consistency and fixity to surrounding anatomical structures. Smaller thyroid nodules <1 cm, and posteriorly or substernally located nodules can be difficult to palpate, and would be better characterised by imaging techniques.
\nIncreasingly nodules are being detected during neck imaging for other indications. The clinical importance of diagnosis of thyroid nodules lies in excluding malignancy in these patients. 4–6.5% of thyroid nodules can harbour malignancy [1]. History of rapid growth of the nodule, hoarseness of voice due to paralysis of vocal cords suggests a malignant aetiology. Examination features in such cases could include a hard consistency of the nodule, fixation to surrounding structures, presence of regional lymphadenopathy or distant metastases. The risk of a nodule being malignant increases with extremes of age and with male sex. The frequency of malignancy in patients with solitary nodules is not different from nodules seen in multinodular thyroid disease [21].
\nOther risk factors which impart increased risk of malignancy should be enquired in all patients. History of prior exposure to radiation for various indications like haematopoietic malignancies and stem cell transplantation, head and neck, mediastinal and CNS tumours should be sought, as this increases the likelihood of malignancy in thyroid nodules. Familial forms of thyroid cancers should be considered in differential diagnosis in the presence of supportive history. Most common form of familial thyroid cancers is seen in medullary thyroid carcinomas (MTC). Familial MTC can occur either as an isolated problem inherited in an autosomal dominant fashion, or as a component of MEN 2A (MTC, primary hyperparathyroidism, pheochromocytoma) MEN 2B (MTC, pheochromocytoma, ganglioneuromas, Marfanoid habitus, thickened corneal nerves). Familial papillary thyroid carcinoma (PTC) can occur as an autosomally dominantly inherited isolated form, or can be a component of Pendred syndrome or intestinal polyposis syndromes like Familial adenomatous polyposis (FAP), Gardner syndrome and Peutz Jeghers syndrome. Follicular thyroid carcinoma (FTC) can be associated with Cowden disease and Bannayan Riley Ruvalcaba syndrome. Carney complex type I can be associated with either PTC or FTC, whereas Werner’s syndrome can be associated with PTC, FTC or anaplastic thyroid carcinoma (ATC) [22]. Factors suggestive of an increased likelihood of malignancy have been summarised in \nTable 2\n.
\nHistory | \nFindings | \n
---|---|
Age < 20 years or > 70 years Male sex Increasing size/rapid growth Compressive symptoms: dyspnoea, dysphagia, hoarseness of voice Childhood H/O exposure to radiation Family H/O thyroid malignancies, MEN2, intestinal polyposis syndromes | \nNodules >4 cm in size Hard consistency Fixed nodule Vocal cord palsy Regional lymphadenopathy Distant metastases | \n
Risk factors for malignancy.
The initial evaluation in all patients presenting with a thyroid nodule should include a measurement of serum TSH. If TSH levels are low, possibility of subclinical or overt hyperthyroidism should be considered. Approximately 10% of solitary nodules can be associated with a subnormal TSH. Multinodular goitres, on the other hand, are frequently associated with suppressed TSH due to development of autonomy in the nodules. Serum free T4 levels and T3 levels should be obtained for documentation of hyperthyroidism; the latter may especially be obtained in areas with iodine deficiency due to preferential secretion of T3 over T4 in these circumstances. Patients with a thyroid nodule and subnormal TSH can be taken for a Nuclear Thyroid Scan to document the functional status of the nodule.
\nIn patients with elevated TSH, anti-thyroid peroxidase (anti-TPO) antibodies may be measured which point to a diagnosis of Hashimotos thyroiditis. However, positive anti-TPO does not obviate the need for a cytopathological evaluation, as a coexisting malignancy needs to be ruled out. A raised or even a normal TSH is associated with an increased risk of malignancy, as well as a more advanced stage of differentiated thyroid cancer [23, 24].
\nThyroglobulin (Tg) is a storage form of thyroid hormones, synthesised by thyroid follicular cells. Serum Tg levels are elevated in many benign and malignant thyroid disorders. An elevated level of serum Tg cannot differentiate malignancy in a thyroid nodule with certainty. Measurement of serum thyroglobulin has a role in postoperative monitoring for residual, recurrent or metastatic disease in patients with differentiated thyroid cancers.
\nCalcitonin is produced by the parafollicular C cells of the thyroid gland and is a marker for medullary thyroid cancer (MTC). Basal and pentagastrin stimulated serum calcitonin has a role in early diagnosis as well as post-operative monitoring of patients with MTC. Serum calcitonin is measured in patients with family history of MTC or MEN-2 syndrome. Unstimulated serum calcitonin levels >50–100 pg/ml are commonly associated with MTC. There are no recommendations for the routine use of calcitonin in evaluation of thyroid nodules in current recommendations.
\nHyper-functioning thyroid nodules comprise up to 10% of thyroid nodules. Currently ATA recommends performing a thyroid radionuclide scan in patients with thyroid nodule associated with subnormal TSH. Two radionuclides are primarily used for functional evaluation of thyroid nodules: I123 and Tc 99 m pertechnetate. Both the radioisotopes are taken up by thyroid follicular cells, but only radioiodine is organified and stored within the gland. A thyroid nodule can be classified as “hot/hyperfunctioning”, “warm/isofunctioning” and “cold/hypofunctioning” on scintigraphy. A functioning nodule is nearly always benign. 5% of nodules that appear hot or warm on pertechnetate scanning can appear cold on radioiodine scanning, up to 30% of which can be malignant [25].
\nOn the contrary, the risk of malignancy in non-functioning nodules is 4–6.5% [26, 27, 28, 29]. Since malignancy is rarely encountered in hyperfunctioning nodules, further cytological evaluation is not necessary if a corresponding hot nodule is identified on scintigraphy.
\nUltrasonography has become an indispensable tool for the evaluation of thyroid nodules. Ultrasound is easily available, non-invasive and invaluable for dileniation and prognostication in these patients. Ultrasound in the hands of an experienced sonologist enables accurate identification of size, number of nodules, composition, echogenicity, margins, presence and type of calcifications, shape if taller than wide, vascularity and status of cervical lymph nodes. The pattern of sonographic characteristics of a nodule confers a risk for malignancy. Categories of high suspicion nodules are then subjected to invasive modalities like Fine Needle Aspiration (FNA) and cytological evaluation is done. Features with the highest specificities (median > 90%) are microcalcifications, irregular margins and tall shape, even though the sensitivities are significantly low for any single feature.
\nUltrasound is also invaluable in assessing the risk of malignancy in lymph nodes. Location of the lymph nodes adds to the diagnosis. Malignant nodes are more likely to occur in levels III, IV and VI than in level II. PTC tumours arising in upper pole of the thyroid may be an exception as they have a propensity to demonstrate skip metastases to levels III and II. Size of >1 cm, ratio of long axis to short axis (also called as Solbiati index of <2), punctate calcification, presence of hyperechogenicity/mixed echogenicity/cystic changes, loss of hilum and peripheral hypervascularity are some of the features predictive of malignancy. While peripheral vascularity has the highest sensitivity of 86%, punctate calcifications are 100% specific for malignant involvement [30, 31]. However, no single sonographic feature is adequately sensitive for determining malignant involvement. Sonographically suspicious lymph nodes ≥8–10 mm in the smallest diameter should therefore undergo FNA to look for evidence of malignant involvement.
\nUltrasound Elastography is a novel modality performed with an ultrasound machine using an elastography computational module. It provides a measure of tissue stiffness, and is being used for malignancy risk assessment. In a study by Azizi et al., thyroid nodule stiffness by elastography was an independent predictor of thyroid carcinoma, with a PPV of 36%, comparable to that of microcalcifications. On the contrary, in another study by Moon et al., elastography alone or in combination with grey scale ultrasound showed an inferior performance compared to grey scale ultrasonographic assessment for differentiation of benign and malignant thyroid nodules [32]. Guidelines currently do not recommend universal use or widespread adoption of ultrasound elastography for malignancy risk assessment.
\nSince ultrasound is operator dependent and cannot adequately image deep anatomic structures and those acoustically shadowed by bone or air, preoperative cross sectional imaging like CT/MRI can be used as an adjunct in patients with clinical suspicion of advanced disease, like patients with an invasive primary tumour, or clinically apparent multiple or bulky nodal involvement. These modalities permit imaging beyond the routine cervical regions imaged by the ultrasound, like infraclavicular, retropharyngeal, parapharyngeal regions and the mediastinum. These also aid in preoperative planning to accurately delineate the inferior border, extent of laryngeal tracheal, oesophageal or vascular involvement.
\nCombined ultrasound and CT may have a higher sensitivity for macroscopic nodal metastasis detection preoperatively, compared to ultrasound alone [33, 34]. Contrast enhanced CT helps in the accurate delineation of the primary tumour and the metastatic disease with the surrounding areas. There exists a small risk of precipitating hyperthyroidism due to iodine content in the contrast agents. Iodine from the IV contrast agents is generally cleared within 4–8 weeks of the scan, as assessed by the urinary iodine levels returning to baseline. Hence a waiting period of atleast a month is advisable to allow urinary iodine levels to return to normal before moving forward to the use of diagnostic or therapeutic radioiodine post-operatively. There is no evidence to suggest this could translate into adverse outcome for thyroid cancer patients currently [31, 35]. MRI is prone to respiration artefacts and can be more difficult to interpret by surgeons in the operating room.
\nFunctional imaging with 18 F – FDG PET is currently not recommended routinely prior to initial surgery. However, it has been widely accepted as a modality for detecting recurrence of differentiated thyroid cancer, particularly in non-iodine avid disease. PET avidity has also been shown to be a strong predictor of poor outcome in metastatic thyroid cancer [31].
\nSonographic Scoring systems are used to stratify nodules according to risk of malignancy to allow centres for uniform reporting and reduce interobserver variability.
\nThe
Sonographic characteristics of thyroid nodules (Adapted from ATA guidelines for adult patients with thyroid nodules and differentiated thyroid cancer [
Sonographic pattern | \nUltrasound features | \nEstimated risk of malignancy | \nFNA size cutoff (largest dimension) | \n
---|---|---|---|
High suspicion | \nSolid hypoechoic nodule or solid hypoechoic component of a partially cystic nodule with one or more of the following Irregular margins (infiltrative, microlobulated) Microcalcifications Taller than wider shape Rim calcifications with small extrusive soft tissue component Evidence of extrathyroidal extension (ETE) | \n>70–90% | \n≥1 cm | \n
Intermediate suspicion | \nHypoechoic solid nodule with smooth margins, without microcalcifications, ETE, or taller than wider shape | \n10–20% | \n≥1 cm | \n
Low suspicion | \nIsoechoic or hyperechoic solid nodule, or partially cystic nodule with eccentric solid areas, without microcalcification, irregular margin or ETE or taller than wider shape | \n5–10% | \n≥1.5 cm | \n
Very low suspicion | \nSpongiform or partially cystic nodules without any of the sonographic features described as low, intermediate or high suspicion patterns | \n<3 | \n≥2 cm/ Observe | \n
Sonographic characteristics and FNA cutoffs of thyroid nodules Adapted from ATA guidelines for adult patients with thyroid nodules and differentiated thyroid cancer [1].
Similar to Breast reporting, the
The ACR-TIRADS scoring system of reporting for thyroid nodules (reproduced from
Patients with multiple thyroid nodules ≥1 cm should be evaluated similarly as delineated above for patients with solitary nodule. Each nodule in a multinodular gland carries an independent risk of malignancy, and FNA should be done in sequentially based on imaging characteristics. In case of multiple sonologically similar low or very low risk pattern nodules, aspiration can be done in the largest nodule ≥2 cm, or surveillance can be continued without FNA.
\nFNA is the single most valuable, cost effective and accurate method in the evaluation of a nodular goitre. It has demonstrated a sensitivity and specificity of 65–98 and 72–100%, respectively [22]. The use of FNA results in fewer surgeries, reduced cost of care, while improving the malignancy yield at thyroidectomy [37]. Selection of which nodule to subject to FNA is crucial for optimum yield of the procedure. This is based on the sonographic criteria and the size cut-offs depending on which guideline one follows.
\nFNA is done as an outpatient procedure under local anaesthesia or no anaesthesia. 23–27 guage needles are used to obtain samples for cytopathology. For nodules with a high likelihood of non-diagnostic cytology (>25–50% cystic component) or sampling error (difficult to palpate or posteriorly located), ultrasound guided FNA is preferred [29].
\nTo address variability in reporting thyroid cytopathology,
Diagnostic category | \nEstimated risk of malignancy by Bethesda system, % | \nActual risk of malignancy in surgically excised nodules, % median (range) | \n
---|---|---|
Non diagnostic or unsatisfactory | \n1–4 | \n20 (9–32) | \n
Benign | \n0–3 | \n2.5 (1–10) | \n
Atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) | \n5–15 | \n14 (6–48) | \n
Follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN) | \n15–30 | \n25 (14–34) | \n
Suspicious for malignancy | \n60–75 | \n70 (53–97) | \n
Malignant | \n97–99 | \n99 (94–100) | \n
The Bethesda system for reporting cytopathology: diagnostic categories and risk of malignancy [38].
PTC, MTC and ATC can be diagnosed by cytopathology preoperatively. However, cytopathology cannot differentiate between FTC and follicular adenoma as histopathological findings of vascular and capsular invasion distinguish these entities.
\nFNA specimens can also be investigated for molecular markers, mutations and rearrangements to assess the risk of malignancy, prognosis and decide further management strategies in cases of indeterminate cytology.
\nThyroglobulin and calcitonin in the washout fluid from FNA of cervical lymph nodes can serve as potential markers for metastatic well differentiated thyroid carcinoma and MTC respectively. TG levels of <1 ng/ml in the washout fluid is reassuring, with higher levels corresponding to increasing probability of N1 disease. This is particularly useful in cases in which lymph nodes are cystic, cases with inadequate cytological evaluation and sono-cytological discordance [1].
\nThe 2 most common molecular testing strategies are
Mutational analysis involves isolating DNA from thyroid follicular cells in the specimen and performing gene sequencing. For example, RET-PTC and AKAP9/BRAF rearrangements, BRAF mutations can be associated with PTC and ATC of PTC origin. PTCs with BRAF mutation tend to be more aggressive, with greater propensity for extrathyroidal invasion and a more advanced clinical stage. FTCs are commonly associated with PAX8/PPARγ fusion in 20–50% of cases, followed by RAS mutations. The presence of markers like calcitonin and RET protein are suggestive of MTC. RET mutations are associated with fMTC, MEN2A and MEN 2B [22]. The seven gene mutation and rearrangement panel comprising of BRAF, NRAS, HRAS and KRAS point mutations, and rearrangements of RET/PTC1 and 3, and PAX8/PPARγ has a high specificity of 86–100% and a PPV of 84–100%, but poor sensitivity of 44–100%. It is being used as a
The second type of molecular testing, gene expression classifier (GEC), uses a proprietary algorithm to analyse the expression of specific genes, the Afirma gene expression classifier (167 GEC), i.e. the mRNA expression of 167 genes, evaluates for the presence of a benign gene expression profile, with a high sensitivity of 92% and NPV of 93%, but low PPV and specificity of 48–53%. Hence it is used as a
Patients with toxic adenoma and toxic multinodular goitre (Toxic MNG) can be managed with either radioactive iodine ablation (RAIA) or surgery with surgery being preferred for Toxic MNG and RAIA for Toxic adenoma. For patients with toxic adenoma, the risk of treatment failure is <1% after surgical resection (ipsilateral thyroid lobectomy or isthmusectomy), whereas the risk of persistent hyperthyroidism and recurrent hyperthyroidism with radioiodine therapy is 6–18 and 3–5.5%, respectively. For patients with toxic multinodular goitre, the risk of treatment failure is <1% following surgery (near-total/total thyroidectomy), compared with 20% risk of need for retreatment following radioiodine therapy.
\nRadioiodine therapy may additionally be preferred in the following scenarios:
Advanced patient age
Comorbidities with increased surgical risk
Small goitre size
RAIU sufficient to allow therapy
Previously operated or irradiated necks
Lack of access to a high volume thyroid surgeon
Radioiodine therapy is contraindicated in pregnancy, lactation, coexisting thyroid cancer, inability to comply with radiation safety guidelines.
\nSurgery (near total/total thyroidectomy for multinodular goitre, ipsilateral thyroid lobectomy or isthmusectomy for toxic adenoma) can be preferred in the following scenarios:
Symptomatic compression or large goitres >80 g
Need for rapid correction of the thyrotoxic state
Substernal or retrosternal extension
Relatively low uptake of RAI
Documented or suspected thyroid malignancy
Large thyroid nodules, especially if >4 cm
Coexisting hyperparathyroidism requiring surgery
In patients who are poor candidates for either therapies, long term anti-thyroid drugs (ATDs) can be considered as an alternative [39].
\nIf a nodule is found benign on cytology, no further immediate diagnostic studies or treatment is required. Infact more than 90% of detected thyroid nodules need no intervention because they have no ultrasound features to suggest malignancy or because they are cytologically benign.
\nNodules with high suspicion pattern on ultrasound can be followed up with a repeat ultrasound and FNA within 12 months, whereas nodules with low to intermediate suspicion can have a repeat ultrasound at 12–24 months. If sonographic evidence of growth (>20% increase in atleast two nodule dimensions, with a minimal increase of 2 mm, increase in volume by 50%) or appearance of a suspicious sonographic pattern, FNA should be repeated or monitoring continued with repeat ultrasound, with repeat FNA in case of continued growth. Nodules with very low suspicion pattern can have a repeat ultrasound at ≥24 months if >1 cm, rest do not require a routine sonographic follow up. If a nodule has a second benign cytology on repeat ultrasound guided FNA, then further surveillance with ultrasound is not required. Surgery may be considered in growing nodules >4 cm, presence of compressive symptoms or cosmetic concern. There is no role of levothyroxine suppression therapy in benign thyroid nodules.
\nFor nodules with AUS/FLUS cytology, repeat FNA and molecular testing may be used to supplement malignancy risk assessment in addition to clinical and sonographic features. Mutational testing for BRAF in AUS/FLUS samples has high specificity, but low sensitivity for cancer. Testing for the seven gene panel of mutations and rearrangements (BRAF, NRAS, KRAS, HRAS, RET/PTC1, RET/PTC3, PAX8/PPARγ) offer a significantly higher sensitivity of 63–80%. On the other hand, molecular testing using the 167 GEC (gene expression classifier) in AUS/FLUS cytology has yielded a sensitivity and NPV of 90 and 95%, respectively, but only 53% specificity and 38% PPV for cancer. If repeat FNA and molecular testing are not performed or both are inconclusive, either surveillance or diagnostic surgical excision may be carried out based on clinical and sonographic risk factors and patient preference.
\nIf cytology is suggestive of FN/SFN, diagnostic surgical excision is the long-established standard of care. Clinical, sonographic pattern and molecular testing may be used to supplement the malignancy risk assessment. Testing for the seven gene panel of mutations in FN/SFN cytology has a sensitivity of 57–75%, specificity of 97–100%, PPV of 87–100%, NPV of 79–86%. Molecular testing with GEC is reported to have a 94% NPV, and a 37% PPV in the FN/SFN subgroup. If molecular testing is unavailable, a diagnostic surgical excision is the preferred treatment modality. No further treatment is required if the histopathology of surgical specimen is suggestive of a follicular adenoma. However, if the histopathology is suggestive of FTC, then a completion thyroidectomy may be required.
\nIf the cytology is suspicious of papillary carcinoma (SUSP), surgical management is similar to that of malignant cytology, depending on clinical risk factors, sonographic characteristics and mutational testing if available. BRAF testing is estimated to have 36% sensitivity and 100% specificity, whereas testing with seven gene panel is reported to have 50–68% sensitivity, 86–96% specificity, 80–95% PPV and 70–75% NPV in this subgroup. On the other hand, GEC testing has a PPV (76%) similar to cytology, and a NPV of 85%, hence is not indicated in this cytological diagnosis. Molecular testing may be done if expected to alter the surgical decision making.
\nFor a nodule with initial non diagnostic cytology, repeat FNA should be done with ultrasound guidance, and with on-site cytological evaluation if available. If the results are repeatedly non diagnostic, surgery should be considered for histopathological diagnosis in the presence of clinical and sonographic risk factors for malignancy, or growth of the nodule >20% in two dimensions detected during ultrasound surveillance.
\nSurgical management in cytologically indeterminate nodules (AUS/FLUS, FN/SFN, SUSP) can be either hemithyroidectomy or near total or total thyroidectomy based on clinical risk factors (nodule >4 cm, family history, history of radiation) and findings on sonography, cytology and molecular testing.
\nIf cytology is diagnostic of a primary thyroid malignancy, then thyroid surgery is the treatment of choice. The choice of surgery depends on the stage of the differentiated thyroid cancer. In tumours ≥4 cm, or with gross extrathyroidal invasion or clinically apparent nodal metastasis or distant metastasis, near total or total thyroidectomy is the treatment of choice. Therapeutic central compartment neck dissection should accompany the procedure in case of clinical involvement of central nodes. Therapeutic lateral neck compartmental neck dissection should be undertaken in case of biopsy proven metastatic lateral cervical lymphadenopathy. Prophylactic central compartment neck dissection can be considered in cases of papillary thyroid carcinoma with advanced primary tumour (T3/T4), or clinically involved lateral neck nodes.
\nFor thyroid cancers >1 cm and < 4 cm, with no gross extrathyroidal invasion/nodal or distant metastasis, either lobectomy or near-total/total thyroidectomy can be considered. In tumours <1 cm, without extrathyroidal extension and nodal involvement, the initial surgical procedure should be a lobectomy, unless there are clear indications to remove the contralateral lobe. Active surveillance can be chosen in very low risk tumours like micropapillary carcinoma (tumour ≤1 cm), patients at high surgical risk or limited life expectancy [1].
\nNewer minimally invasive methods like percutaneous ethanol ablation, radiofrequency, laser, microwave ablation, and high-intensity focused ultrasound have been tried and may be considered for treating clinically relevant benign thyroid nodules [40]. Recurrent cystic thyroid nodules with benign cytology can be considered for percutaneous ethanol injection (PEI) or surgical excision. Ethanol acts by coagulative necrosis and small vessel thrombosis.
\nThyroid nodules may enlarge slightly during pregnancy, though this does not imply malignant transformation. Patients with suppressed TSH beyond 16 weeks of pregnancy should be monitored until after delivery and cessation of lactation, followed by a radionuclide scan to assess the functional status of the nodule if TSH is still suppressed.
\nIn euthyroid and hypothyroid patients, FNA should be done if clinically and sonographically indicated similar to non-pregnant patients. If PTC is diagnosed by cytology during pregnancy, surgery should be considered during pregnancy only if there is substantial growth (>20% increase in atleast two nodule dimensions, with a minimal increase of 2 mm, increase in volume by 50%) before 24–26 weeks of gestation, or if ultrasound reveals cervical nodes suspicious of metastatic disease. The surgery should be carried out in second trimester before 24 weeks to minimise the risk of miscarriage. If the disease remains stable by mid gestation, or diagnosed in second half of the pregnancy, surgery may be deferred until after delivery. As higher TSH levels may correlate with a more advanced stage of cancer, thyroid hormone therapy can be initiated if TSH > 2 mIU/L, with a target TSH of 0.3–2 mIU/L for the remainder of gestation.
\nThyroid nodules pose a common clinical problem to physicians and surgeons alike. The primary concern in the evaluation of thyroid nodules is exclusion of malignancy while bearing in mind that most thyroid nodules are benign. With the advent and easy availability of high-resolution ultrasound, reliable of characterisation is possible while deciding on further testing for FNA. FNA is the single most valuable cost effective and reliable investigation for risk stratification, complemented by clinical risk factors. New molecular markers can aid in risk stratification in nodules with indeterminate cytology. Diagnostic surgical excision can be done in these patients if associated with high risk clinical and sonographic features. Patients with malignant cytology should undergo surgery. Evidence based practices should be followed while keeping in mind patient preferences thus giving individualized precision medical care for patients with thyroid nodule.
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