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How Cancer Arises Based on Complexity Theory
Nat L. Pernick, M.D.
Last revised 10 December 2017
In memory of Eric Arons, Mindy Goldberg and Jim Overholt.
Thanks to Vic Doucette and Kristi Z. Marie for their review of the manuscript.
This manuscript has not received any outside funding.
Executive summary
1. Cancer is an inevitable tradeoff of human biologic design. It will always be with us, particularly as life expectancy increases.
However, we can often prevent it, we can detect it earlier and we can treat it more effectively.
2. Chronic cellular stress is the underlying cause of most cancer, by disturbing the delicate balance that exists in our
interconnected biologic networks. In the correct microenvironment, it pushes susceptible stem or progenitor cells into
increasingly dysregulated and unstable network trajectories that are ultimately associated with cancer. It is foreseeable
that some chronic cellular stressors will cause cancer but which stressors will be important, where the cancers will arise
and what their molecular and histologic features will be is not predictable.
3. There are nine important sources of chronic cellular stress which cause cancer, which often interact to provide the
multiple “hits” that produce malignancy:
* Chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, obesity and other causes)
* Exposure to carcinogens
* Reproductive hormones
* Western diet (high fat, low fiber, low vegetable consumption)
* Aging
* Radiation
* Immune system dysfunction
* Germ line changes
* Random chronic stress / bad luck
These sources of chronic stress typically create a field effect, because they affect cells throughout an organ or organ
system.
4. Complexity theory helps us better understand how cancer arises:
A. To understand cancer, it is important to think about how life arose from cellular networks, because the same principles guide the
pathophysiology of cancer. Focusing too much on specific details of the networks ignores the overriding theme, namely that the
emergence of generic network features is independent of these details.
B. Living systems require delicately balanced cellular networks to enable major transitions from fertilization to embryogenesis to
maturity to reproduction; to respond to environmental threats (infection, infestation, external and internal trauma); to physiologic
threats (chronic inflammation and internal system errors) and to maintain homeostasis. Living systems must also have enough
flexibility to promote and tolerate evolutionary change.
C. We can acquire new insights about malignancy by analyzing patterns of network behavior, which are more uniform than changes
to downstream oncogenes.
D. Self-organized criticality describes how enormous transformations (“catastrophes”) occur over short time scales. Malignant
change does not occur through gradualism but by bursts of activity.
E. Malignancies arise due to a build up of hierarchies, in which combination of agents (biomarkers and networks) at one level
become agents at the next level. Hierarchies are identifiable by patterns of molecular changes; in some but not all cases there are
accompanying histologic changes called intermediate states.
Introduction
This paper proposes a model of how cancer arises based on complexity theory. Chronic cellular stress is the underlying cause of
most cancers by disturbing the delicate balance that exists in cellular networks necessary for the major functions of the organism:
homeostasis; transition from fertilization to embryogenesis to maturity to reproduction; response to environmental changes; repairing
external or internal damage; and providing genetic flexibility to allow evolutionary change. It is foreseeable that cancer will
occasionally arise from these chronic cellular stressors although the site of disease and its histologic and molecular features are not
a priori predictable. Future papers will discuss the top 20 causes of cancer death in the U.S. and the chronic stressors which cause
them.
In his 1971 State of the Union address, President Richard M. Nixon announced the beginning of the “war on cancer” in the United
States (see President Nixon's 1971 State of the Union at 15:03). Despite U.S. government expenditures of more than $100 billion
on related research (Kolata: Grant System Leads Cancer Researchers to Play It Safe, New York Times, 27Jun09) and
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testimonials that the war on cancer “did everything it was supposed to do” (NCI: National Cancer Act of 1971, accessed 2Nov17),
cancer is still the #2 cause of death in the U.S. and is projected to be #1 by 2020 (Centers for Disease Control and Prevention:
Heart Disease and Cancer Deaths - Trends and Projections in the United States 1969–2020, 2016), with high mortality from
common cancers of the lung, colon, pancreas and breast (Cancer Facts and Figures 2017). This suggests an underlying flaw in
our understanding of the disease.
The limits of reductionism
Traditional biology relies on the reductionist approach, which assumes that for all systems, including human physiology, the behavior
of the whole is equal to the sum of the behavior of the parts. This means that sophisticated systems are merely combinations of
simpler systems, which can themselves be reduced to simpler parts (Mazzocchi 2008), and disease is just due to flawed parts or
systems. We reject reliance on reductionism, and believe that principles of complexity theory and self-organization create a more
robust framework for understanding the origins and dynamics of cancer. We previously summarized the laws of complexity and self-
organization as they relate to neoplasia, the process of abnormal tissue growth which includes cancer (Pernick 2017):
The Laws of Complexity and Self-Organization as a Framework for Understanding Neoplasia
1. In life, as in other complex systems, the whole is greater than the sum of the parts.
2. There is an inherent inability to predict the future of complex systems.
3. Life emerges from non-life when the diversity of a closed system of biomolecules exceeds a threshold of complexity.
4. Much of the order in organisms is due to generic network properties.
5. Numerous biologic pressures push cellular pathways towards disorder.
6. Organisms resist common pressures towards disorder through multiple layers of redundant controls, many related to
cell division.
7. Neoplasia arises due to failure in these controls, with histologic and molecular characteristics related to the cell of
origin, the nature of the biologic pressures and the individual’s germ line configuration.
These seven “laws” shift the emphasis on understanding cancer from cataloging a list of molecular alterations towards focusing on
biologic stressors (pressures) that transform essential physiologic networks into lethal pathways.
Complexity theory
A system is considered complex if the properties of the entire system are greater than the sum of the properties of each part of the
system. This is due to emergence of novel properties which cannot be predicted, based on interactions between the parts. Life can
be considered to be a complex adaptive system with biologic networks composed of numerous independent agents, such as genes
and proteins. These agents interact with each other through many connections, and behave as a unified whole to learn from
experience and adjust to changes in the environment (BusinessDictionary.com: Complex adaptive system, accessed 2Nov17).
Complex adaptive systems lack the fixed properties of planetary motion and their behavior cannot be solved with partial
differentiation equations. They are best understood by analyzing patterns of behavior (Bak, How Nature Works 1999), which
provides new insights into understanding pathophysiology and may ultimately lead to more effective treatment.
How life arose
To fully understand cancer, it is useful to consider how life arose, because the same principles may guide the pathophysiology of
cancer. According to Kauffman, life is an emergent property of a modestly complex mix of biomolecules, confined to a small space to
promote interactions, which ultimately crystallize in a phase transition and catalyze their own reproduction (Kauffman, The Origins
of Order 1993, Chapter 7). In small groups, these biomolecules are relatively inert. However, as the number of biomolecules in the
mix increases, there are more reactions and a greater probability that some biomolecules will catalyze the formation of other
biomolecules (Kauffman, The Origins of Order 1993, page 309). Above some threshold of complexity, a network of biomolecules
with catalytic closure is likely to arise (i.e. the formation of each biomolecule is catalyzed by other network members).
Kauffman and others have demonstrated that order is a common emergent property of molecular networks, based on structural
network properties not dependent on details of the particular biomolecules (Kauffman 1993). These properties include the
localization of cell networks to a small subset of their possible state space, and the stabilization of networks by genes with
canalyzing Boolean functions (Pernick 2017). In addition natural selection produces redundant control systems which further
constrain network behavior. Chronic cellular stress can overcome these controls but typically requires years or decades to do so.
The impact of chronic stressors may be countered by evolution but only if they are relatively common, affect reproductive capacity
and have persisted for at least 1 million years (Uyeda 2011).
Life as a complex adaptive system embraces the principle of universality, that the formation of necessary structures is not sensitive
to particular details (Bak, How Nature Works 1999, Holland, Complexity: A Very Short Introduction 2014). Many alternative
pathways are possible to produce these results but only one is necessary (Kauffman, The Origins of Order 1993, Chapter 8).
Focusing too much on details ignores the overriding theme, that life has generic features even if details are not predictable
(Kauffman, At Home in the Universe, page 18). As Bak notes, “The theory of life is likely to be a theory of a process, not a detailed
account of utterly accidental details of that process (Bak, How Nature Works 1999, page 10). Similarly, the emergence of
intermediate states and ultimately cancer is predictable but does not depend on particular details although those details may be
important for individualized treatment.
Self-organized criticality
Cancer is an assault on the order typically maintained in cells. There are two overlapping theories that explain how disorder arises in
biologic systems - self-organized criticality and the “edge of chaos”. Self-organized criticality was first described by Danish physicist
Per Bak in 1987 as the tendency of large systems with many components, living or non living, to evolve into a critical state or
“tipping point” (Bak, How Nature Works 1999). The evolution to this delicate critical state arises spontaneously, without interference
from an outside agent, due to dynamic interactions among individual elements of the system. Remarkably, without any manager
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tuning the network elements, “a system that obeys simple, benign local rules can organize itself into a poised state” (Bak, How
Nature Works 1999, page 33). Although the precise mechanism of the self-organization is unknown, it is based on local interactions
between many components in an open system (Krink and Thomsen 2001). At this critical state, minor disturbances cause events
whose impact and frequency follow a power law distribution, with a high frequency of minor impact events and a small tail of major
impact events. Rarely, an apparently trivial event triggers a large scale systemic response, leading to a major reconfiguration of the
system (Bak, How Nature Works 1999).
Self-organized criticality is illustrated by dropping one grain of sand at a time on the center of a table to create a sand pile. Initially,
the grains stay where they land. As the slope increases, a single grain is likely to cause other grains to topple. At this point, the
system has been transformed from one in which individual grains cause predictable patterns to one where the dynamics are global,
a self-organized critical state. Although a single grain of sand may cause an avalanche affecting the entire pile, we are incapable of
predicting its impact, because it is contingent on extensive knowledge of minor details of the sand pile’s configuration (Bak, How
Nature Works 1999, page 59). The emergence could not have been anticipated based on properties of the individual grains (Bak,
How Nature Works 1999, page 51). This system cannot be understood by focusing on isolated parts, because the dynamics
observed are due to the entire system as a whole. The sandpile itself is the functional unit, not the individual grains, so reductionism
is illogical in this context. The configuration of the sandpile does not change gradually but by means of large avalanches (Bak, How
Nature Works 1999, page 61). Thus, self-organized criticality may be nature’s mechanism of making large transformations over
short time scales, an approach which is useful in understanding how cancer arises.
Hierarchies
Living systems arise based on hierarchies, in which combination of agents (genes, proteins, processes) at one level become agents
themselves at the next level. Hierarchies include the transcription and translation of DNA to produce proteins, proteins interacting to
form organelles, clustering of organelles to create cells, cells combining to form tissues, tissues forming organs, organs forming
systems, systems working together to form individuals, and individuals interacting to form communities (Holland, Complexity: A
Very Short Introduction 2014, page 32). In a similar way, a biologic network can be considered to have a specific purpose, such as
phosphorylating a protein moiety. Multiple networks working together contribute to a more general biologic purpose, such as
metabolizing a substance. Networks with these purposes then cooperate to create important cell functions, such as mitosis,
apoptosis and morphogenesis, which can then work together, at a higher level, to form cells or create an organism.
Hierarchies explain how malignant change occurs through bursts of activity, not through gradualism. Tumors characterized by
multistep progression (Vogelstein 1993) appear to arise through the formation of increasingly unstable hierarchies (hyperplasia,
dysplasia) that may lead to malignancy. However, the process is not necessarily linear, and the formation of the hierarchies
themselves may be discontinuous. For example, it appears that breast cancer does not typically progress continuously from
hyperplasia to low grade DCIS to high grade DCIS to invasive carcinoma; instead, multiple parallel, genetically distinct pathways
may be present (Tang 2006). Similarly, malignancy in the prostate does not progress continuously from low grade to high grade
prostatic intraepithelial neoplasia to adenocarcinoma (Bostwick 2004, Braun 2011).
The origin of cancer begins with isolated network alterations, which may be mutations or simply changes in a network’s “rhythm” (i.e.
how it associates with other networks). These changes are often in response to chronic stressors which find or create “weak spots”
in a network to cause it to deviate from its usual physiologic state. These local network changes may interact to create, within the
context of other chronic stressors, a hierarchy of new biologic properties, which may be identifiable by altered patterns of molecular
expression. Kauffman describes how cells maintain a stable phenotype, called an attractor, through large numbers of mutually
regulating genes (Kauffman, The Origins of Order 1993, page 467). Similarly, hierarchies may have their own version of stability
due to “cancer attractors” (Huang 2009), and be identifiable as an intermediate state. Intermediate states may interact with each
other and with chronic stressors to create new hierarchies of more chaotic networks with new patterns of molecular expression, and
eventually lead to malignancy. The intermediate state is defined by patterns of molecular or network expression but there need not
be an associated histologic change. This explains why some malignancies, such as well differentiated pancreatic adenocarcinoma,
have molecular properties distinct from benign conditions, such as chronic pancreatitis, even though they are similar morphologically
(Hruban 2007, Logsdon 2003).
The edge of chaos
Disorder can also be understood based on the concept of human biologic networks being at the edge of chaos, a self-organized
critical state between order and chaos, which represents a state of biologic tension, analogous to a transition state in physics,
although the details differ. Positioning networks in this manner: (a) provides flexibility to coordinate complex activities such as
transcription, translation, mitosis and apoptosis, (b) helps coordinate global functions such as fertilization, embryogenesis and
response to environmental and physiologic threats (Kauffman, At Home in the Universe, page 86) and (c) maximizes an
organism’s evolutionary advantages, because rigid order would doom species that could not adapt to a changing and competitive
environment (Kauffman and Johnsen 1991, Langton 1990).
Part of the tradeoff for maintaining a self-organized critical state is that catastrophic systemic failure is predictable. This failure has
been described for man made and natural systems (Clearfield 2013, Rietkerk 2004, Scheffer 2001), as well as for human
physiology and cancer (Hogenboom, BBC Earth 2016, Simpson 1998, Maley 2017). Thus, we believe that cancer is an inevitable
feature of human biologic design, and will always be with us. We can prevent many cases of cancer by targeting chronic stressors
and risk factors, we can diagnose it earlier and we can treat it more effectively but the mission of the American Cancer Society for a
“world without cancer” will never be achieved.
Chronic cellular stress is the underlying cause of most cancers
This paper proclaims that chronic cellular stress is the underlying cause of most cancers. It disturbs the delicate balance
that exists in biologic networks involving susceptible stem or progenitor cells and pushes them into dysregulated and
unstable network trajectories associated with increased and relatively uncontrolled cell division. These new network states
are based not only on gene changes but altered cellular processes, which may be difficult to reverse:
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“Because the cell must be inherited, and because its processes cannot always be constructed de novo from genetic
instructions (Cavalier-Smith 2004), genes often manipulate ongoing cellular behavior. DNA is the cell's information-
storage device, but only some information is stored. The basic mechanisms of life must be inherited as ongoing
processes. Thus, if life evolved as a coupled set of interconnected processes, then it has remained so ever since (Nicolis
and Prigogine 1977, Kauffman, The Origin of Order 1993, Newman et al. 2006). Therefore, the perspective on
evolution that focuses solely on shuffling genes propagating through time is limited because the cell propagates as a
whole and its processes are the engines of life” (Johnson and Lam 2010, The Nobel Prize in Chemistry 1977 Award
Presentation Speech, accessed 16Nov17).
These sources of chronic stress typically create a field effect, because they affect cells throughout an organ or organ
system.
This paper deemphasizes the importance of oncogenes in understanding how cancer initially arises (The Nobel Prize in
Physiology or Medicine 1989, Press Release, accessed 26Nov17), because alterations in their control or function are
foreseeable downstream effects of the chronic cellular stress. In contrast to Emmanuel Farber (Farber 1984), we consider
permanent DNA damage to typically be a late effect, not cancer’s initiating event.
We have identified nine chronic cellular stressors which act in combination to destabilize networks and cause cancer:
* Chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, obesity, diabetes and other causes)
* Exposure to carcinogens
* Reproductive hormones
* Western diet (high fat, low fiber, low vegetable consumption)
* Aging
* Radiation
* Immune system dysfunction
* Germ line changes
* Random chronic stress / bad luck
If time limited, these stressors typically have little malignant potential, for several reasons. First, as complex adaptive
systems, cells have inherent stability. Control of cell networks tends to be highly dispersed, so a single alteration is
typically insufficient to produce marked network changes (Waldrop, Complexity: The Emerging Science at the Edge of
Order and Chaos, page 145). Second, inactive genes in biologic networks can be considered to be “frozen” and resistant
to minor perturbations (Kauffman, At Home in the Universe, pages 87-90, Pernick 2017). Third, to add biologic
sophistication, evolution has added intricate control systems to existing genes and pathways, which are not easily
disrupted (Molecular Biology of the Cell (4th Ed), How Genomes Evolve, accessed 3Nov17, Glassford 2015).
However, when the stress continues for years or decades, pummeling weak spots in the network similar to ocean waves
hitting the shore, there is an increased probability of disrupting networks in susceptible cells. A simple network change
may provide a niche for other changes, which may further increase network instability, and under the proper
circumstances, this may push the cell towards a malignant phenotype.
Due to the complex, nonlinear interactions which characterize living systems, one typically cannot predict which types of
chronic stress will be associated with malignancy at all, what malignant patterns will arise, which cells will be affected and
what molecular pathways or gene products will be altered.
This model of cancer as due to chronic cellular stress is an extension of current views about DNA damage and repair.
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions
and double strand breaks. This induces activity in multiple genes, cell cycle arrest and inhibition of cell division, with the
ultimate goal of macromolecular repair and bypass of lesions that stall transcription or apoptosis. Similar to HIV infection,
this process may reflect a dynamic between destabilizing forces (the chronic cellular stress) and stabilizing (repair) forces
(Nowak and McMichael 1995, Goulder 1997), and ultimately, the magnitude of DNA damage or its chronic nature may
overtake the organism’s repair capacity (Friedberg 2003). Cofactors include germ line changes which limit the
effectiveness of repair or make damage more likely, cell states that are particularly susceptible to these changes and
deficiencies in the immune system. These processes also apply to malignancy.
This concept of chronic cellular stress triggering cancer has similarities to the paradigm of a pathogenic stimulus, followed
by chronic inflammation and the ultimate development of a “cancer cell” (Brücher and Jamall 2014), as well as the
concept of an etiologic field effect (Lochhead 2015).
Modeling cancer as due to chronic stressors may provide an alternative approach to classify and treat cancer.
Conceptually, it may make sense to group malignancies together if they are due to the same stressor even if they have
different morphologies, comparable to how tumors are considered similar if arising from the same cytogenetic
translocation.
Focusing on the chronic stressors also alters our consideration of treatment, which should not only target the tumor’s
morphologic and molecular patterns and microenvironment but also its chronic stressors or macro environment, to the
extent possible. Even when treatment eradicates most or all existing disease, the continued presence of these chronic
stressors makes it more likely that residual tumor cells will grow or a new tumor will arise. In addition acknowledging the
role of complexity in cancer pathophysiology suggests that targeting some of its features may be helpful, as described
below.
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Exclusions from model
This model specifically excludes acute types of cancer - when tumor cells are close to their genetic events, such as
childhood tumors due to known germ line changes (Childhood Cancer Genomics (PDQ®), accessed 25Nov17), which
are not due to chronic stressors. In these cases, treating only the existing tumor is often curative. In contrast, adult tumors
may also require minimizing the chronic stressors to prevent recurrence or relapse. This echoes the view of Savage, who
argues that malignancies can be functionally divided into 2 groups: those that arise in cells with naturally heightened
apoptotic potential due to their proximity to unique genetic events, which are generally chemotherapy curable, and those
that arise in cells of standard apoptotic potential, that are not curable with classical cytotoxic drugs (Savage 2015,
Savage 2016).
Of note, even apparently “straightforward” pediatric malignancies such as retinoblastoma do not follow a reductionist
model; its development involves oxidative stress, additional mutations and appears to occur in a nonlinear manner
(Kandalam 2010, Vandhana 2012).
The chronic stressors that cause cancer and their mechanism of action
We describe nine chronic stressors that cause cancer, recognizing that most malignancies are due to interactions of multiple
stressors. Although the mechanisms of these stressors are distinctive enough to be described separately, some risk factors have
features of multiple stressors (e.g. infections trigger chronic inflammation but also carry mutagenic proteins) and some stressors are
related to each other (e.g. diet influences obesity, which triggers chronic inflammation).
Remarkably, chronic stressors which can cause cancer only do so in a small percentage of those exposed, and only at a limited
number of sites. The explanation may be that the sources of order described above make networks resilient to many stresses, and
that cancer requires not only chronic stress but the appropriate amount and type of stress, the correct context (organ / tissue /
microenvironment), an inadequate immune response and a suitable germ line configuration to overcome a network’s inherent
stability.
Table of Contents (TOC)
Section 1.0 Chronic inflammation
Section 1.1 General
Section 1.2 Infections
Section 1.3 Antigen driven lymphoproliferation - infections
Section 1.4 Antigen driven lymphoproliferation - autoantigens
Section 1.5 Bacterial driven carcinoma
Section 1.6 Parasite driven carcinoma
Section 1.7 Trauma related
Section 1.8 Excess weight related
Section 1.9 Other
Section 2.0 Exposure to carcinogens
Section 2.1 General
Section 2.2 Carcinogens associated with bacteria and parasites
Section 2.3 Viral carcinogens causing lymphoma
Section 2.4 Viral carcinogens causing carcinoma or sarcoma
Section 2.5 Tobacco use
Section 2.6 Occupational exposure to carcinogens
Section 2.7 Alcohol
Section 3.0 Reproductive hormones
Section 3.1 Breast carcinoma due to chronic estrogenic stimulation
Section 3.2 Endometrial carcinoma due to estrogens
Section 3.3 Prostate adenocarcinoma due to androgens / estrogens
Section 3.4 Cancer due to other hormones
Section 4.0 Western diet (high fat, low fiber, low vegetable consumption)
Section 4.1 Diet and specific cancers
Section 5.0 Aging
Section 5.1 Specific malignancies
Section 6.0 Radiation
Section 6.1 Skin cancer (basal cell carcinoma, squamous cell carcinoma and melanoma) due to ultraviolet radiation
Section 6.2 Radon and lung cancer
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Section 7.0 Immune system dysfunction
Section 7.1 Normal physiology
Section 7.2 Runaway immune system / nonspecific immune system dysfunction
Section 7.3 Cancer due to HIV infection
Section 7.4 Cancer due to other immunodeficiency
Section 8.0 Germ line changes
Section 9.0 Random chronic stress / bad luck
Section 1.0 Chronic inflammation
In this section, we describe how chronic inflammation associated with microorganisms (bacterial and viruses), parasites,
autoantigens, trauma and excess weight contributes to malignancy. The chronic inflammation affects existing cells by pressuring
networks to veer towards malignant pathways and by creating a more supportive microenvironment for malignant change
(Mbeunkui 2009). This process is not reductionist - it involves complex combinations of germ line variations of numerous genes and
multiple alterations to interacting networks of susceptible cells. It is also affected by the existing microenvironment and immune
response, which it also manipulates.
Prevention and treatment are described below, and include drugs to treat infectious organisms, behavioral changes to reduce
excess weight and trauma, and anti-inflammatory agents; these measures are typically more useful for premalignant than
aggressive invasive disease, which is treated in a traditional manner with surgery, chemoradiation therapy and immunotherapy. For
autoimmune disorders other than celiac disease, watchful waiting is recommended, as treatment side effects are too severe.
Additional discussion of chronic inflammation related effects appears in sections 4.0 (proinflammatory diet) and 7.0 (immune system
dysfunction).
Section 1.1 General
Chronic inflammation has long been considered a major cause of cancer. In 1863, Virchow noted that cancer occurs at
sites of chronic inflammation, speculating that some irritants enhance cell proliferation via tissue injury and associated
chronic inflammation (Balkwill 2001, Schottenfeld 2006). The current paradigm is that cancer is also accompanied by
DNA damaging agents and occurs in the context of a permissive microenvironment that contains growth factors
(cytokines, chemokines) and activated stroma (Coussens 2002).
Inflammation associated cancer, described at most body sites (Kanda 2017, Table 1), is considered the seventh hallmark
of cancer (Colotta 2009), in addition to self-sufficiency in growth signals, insensitivity to inhibitory growth signals, evasion
of apoptosis, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis (Hanahan 2000).
Cancer may arise when the chronic inflammatory process persists over years. Tumors have been described as wounds that do not
heal (Dvorak 1986, Drovak 2015). In typical wounds, tissue injury causes inflammation and cell proliferation which induce network
changes resulting in less stable states. When the trauma ceases and the repair is complete, the inflammation also subsides and the
microenvironment returns to its initial, more stable condition. However, when the inciting cause persists, the inflammation also
persists with its pro-carcinogenic production of reactive oxygen and nitrogen species, growth factors, pro angiogenesis factors and
attenuation of local cell mediated immunity (Kanda 2017, Figure 3, Rasch 2014). When mutated cells arise, this microenvironment
nurtures them, helps them escape immune surveillance (Dalgleish 2006) and ultimately promotes invasion by subverting
physiologic “invasion” of wounded epithelium through the extracellular matrix (Bleaken 2016, Coussens 2002).
Germ line variations in inflammatory mediators, such as macrophage migration inhibitory factor (Zhang 2015), interleukin 1A,
interleukin 4, NFκB1 and protease activated receptor 1 may also promote inflammation associated cancer (Amador 2016).
Section 1.2 Infections
Infections are a major contributor to chronic inflammation related cancer. In 2012, 15.4% (2.2 million) of the 14 million new cancer
cases worldwide were attributed to infections, including Helicobacter pylori (770,000 cases), human papillomavirus (640,000 cases),
hepatitis B virus (420,000 cases), hepatitis C virus (170,000 cases) and Epstein-Barr virus (120,000 cases). In sub-Saharan Africa,
Kaposi sarcoma was the second largest contributor to new cancer cases (Plummer 2016). The attributable fraction for cancers due
to infection varies from less than 5% in the United States, Canada, Australia, New Zealand and some countries in western and
northern Europe, to more than 50% in some countries in sub-Saharan Africa (Plummer 2016, Oh 2014, Schottenfeld 2015).
The International Agency for Research on Cancer (IARC), the specialized cancer agency of the World Health Organization (WHO),
has classified numerous infectious agents as Group 1 carcinogens, meaning there is sufficient evidence of carcinogenicity in
humans. They include bacteria: Helicobacter pylori, parasites: Clonorchis sinensis, Opisthorchis viverrini, Schistosoma
haematobium and viruses: Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency
virus type 1 (HIV1), human papillomavirus (HPV) (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59), human T cell lymphotropic
virus type 1 (HTLV1) and Kaposi sarcoma herpesvirus (HHV8) (IARC Monograph on the Evaluation of Carcinogenic Risks to
Humans 2017, Ohnishi 2013). Bacteria and parasites which promote carcinogenesis primarily through chronic inflammation are
described in this section. Viruses other than Hepatitis C are described in sections 2.3 and 2.4 because they promote carcinogenesis
primarily through oncogenic proteins.
Chronic infections promote the continuous release of inflammatory mediators, including the NFκB family of transcription factors.
Epithelial cells also produce reactive oxygen species and nitric oxide in response to inflammation, which promote mutations (Nath
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2010). Bacterial toxins also modify cellular processes that control DNA damage, proliferation, apoptosis and differentiation (Nath
2010, Table 2), and are discussed in section 2.2.
Section 1.3 Antigen driven lymphoproliferation - infections
We describe four chronic bacterial infections and one viral infection which typically cause MALT lymphoma or other low grade non
Hodgkin lymphoma through a process called antigen driven lymphoproliferation. This mechanism appears to account for a high
percentage of MALT lymphoma arising in the stomach (92% have H. pylori infection, Wotherspoon 1991) and ocular adnexae (up
to 80% contain C. psittaci DNA, Ferreri 2004), and occasional cases in the skin, small intestine and other sites. However, these
microorganisms are not a major cause of lymphoma, as only 8% of all non Hodgkin lymphoma is MALT subtype (The Non-
Hodgkin's Lymphoma Classification Project 1997).
In general, chronic infection is not associated with malignancy. Antigen driven malignancy requires a specific type of infection, with a
response by susceptible cells, within the correct tissue context. For example, M. tuberculosis infects 2 billion people worldwide
(Centers for Disease Control and Prevention 2017), and if untreated, typically persists as a chronic infection but does not induce
B cell proliferation or other malignancy. Bacterial or mycobacterial infections may induce proliferation of neutrophils, macrophages or
inflammatory cells other than B cells but these inflammatory cells have a limited potential to attain clonality and malignancy.
Gastric MALT lymphoma due to chronic Helicobacter pylori infection
Gastric MALT lymphoma due to chronic Helicobacter pylori gastritis is the paradigm of antigenic driven lymphoproliferation, with
these features: (a) the persistence of bacteria that cannot be killed by the immune system causes chronic immune stimulation,
which ultimately directs cellular networks affecting B lymphocytes towards a less stable state, which over years may become clonal
and overtly malignant, (b) the immune stimulation is directed at countering the bacteria, and is not a generalized proliferation, (c)
these network changes are typically not permanent, (d) removal or antagonism of the bacterial stimuli by antibiotics may cause
reversion towards the original non malignant state (Suarez 2006).
Gastric MALT lymphoma is rare, with an incidence of 0.2 to 3.8 per 100,000, and is declining due to reductions in the incidence of H.
pylori infection (Luminari 2010, Khalil 2014). H. pylori induces chronic gastritis, which causes ongoing stimulation of antigen
presenting T cells, leading to a reactive B cell infiltrate. In a small percentage of patients, it promotes B cell clonal expansion through
a multistage process. Although the stomach is normally devoid of organized lymphoid tissue, marginal zone lymphocytes are
attracted by the presence of H. pylori, mediated through chemokine BCA1 (CXCL13) and its chemokine receptor CXCR5
(Mazzucchelli 1999, Winter 2010). These lymphocytes are anatomically positioned in the spleen, lymph nodes and mucosa
associated lymphoid tissue to constitute a first line of defense against invading pathogens, with a low activation threshold (Suarez
2006). The immune system cannot destroy H. pylori (Bende 2009), leading to chronic lymphoid proliferation, which makes these
inherently unstable lymphocytes more prone to additional network alterations, and increases the risk of transformation of clones that
are dependent on antigenic stimulation (Suarez 2006). MALT lymphoma is considered to arise at a relatively late stage in
lymphocyte development, when the lymphocyte is responding to antigenic stimulation by modifying diversity within its antigen
receptors (Malcolm 2016). These changes are mediated by high levels of cytokines and chemokines produced by infiltrating
macrophages induced by H. pylori and H. pylori specific T cells (Russo 2016, Munari 2011, Kuo 2010).
Both B and T lymphocytes have distinctive traits: (a) they repeatedly rearrange their DNA to produce a unique and functional antigen
receptor, (b) via this receptor or its precursor, they can undergo massive clonal expansion, and (c) they can be extremely long lived
as memory cells. These traits are fundamental to their role in the adaptive immune response to infectious agents, but also make
these cells unstable and vulnerable to transformation (Malcolm 2016).
Antibiotics directed against Helicobacter pylori (“eradication therapy”) lead to long term regression in 75-80% of low grade gastric
MALT lymphoma (Nakamura 2012), apparently due to elimination of the bacterial driven lymphoproliferative signals. Surprisingly,
antibiotics also cause regression of some low stage H. pylori negative cases of MALT lymphoma (Raderer 2006, Park 2010, Asano
2012, Asano 2015), which is attributed to: (a) their association with antibiotic sensitive Helicobacter heilmannii (Morgner 2000, Joo
2007), (b) false negative H. pylori testing (Gisbert 2006) or (c) the antiproliferative effect of macrolide antibiotics which are part of
the eradication therapy, such as clarithromycin (Ohe 2013, Van Nuffel 2015). Eradication therapy may also be useful for other H.
pylori associated lymphoma. For example, some patients with H. pylori positive gastric diffuse large B cell lymphoma, either with or
without histological evidence of MALT lymphoma, have achieved long term complete remission after first line H. pylori eradication
therapy (Kuo 2013, Kuo 2012, Paydas 2015).
Helicobacter pylori infection may also cause gastric MALT lymphoma by translocating its cytotoxin associated gene A
(CagA) protein into B cells, which stimulates their proliferation (Wang 2013, Krisch 2016) and promotes a more potent
inflammatory response (Zucca 2014). In addition germ line variations of the TNF alpha T 857 allele (Hellmig 2005) and
Interleukin 22 (Liao 2014) are associated with an increased risk of gastric MALT lymphoma.
Immunoproliferative small intestinal disease due to chronic Campylobacter infection
In the small intestine, persistent infection by Campylobacter jejuni (Lecuit 2004) or less commonly Campylobacter coli (Criscuolo
2014) or H. pylori (Dutta 2010) cause immunoproliferative small intestinal disease (IPSID), an antigen driven lymphoproliferative
disorder with features similar to H. pylori associated gastric MALT lymphoma. IPSID, also known as alpha chain disease, was first
described in 1968 (Seligmann 1968). It is most prevalent in the Middle East and Africa, particularly in developing countries where C.
jejuni infection is hyperendemic due to environmental and food contamination (Coker 2002).
The WHO considers IPSID a variant of MALT lymphoma that arises in small intestinal mucosa associated lymphoid tissue due to
infiltration by plasma cells which secrete a monotypic truncated immunoglobulin alpha heavy chain lacking both the light chain
region and the first constant domain (Al-Saleem 2005). The corresponding mRNA lacks the variable heavy chain and the constant
heavy chain 1 sequences and contains deletions as well as insertions of unknown origin. Cytogenetic studies demonstrate clonal
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rearrangements involving predominantly the heavy and light chain genes, including a t(9;14) translocation involving the PAX5 gene
(Al-Saleem 2005).
Chronic C. jejuni infection can elicit a strong IgA mucosal response, which leads to sustained stimulation of the mucosal immune
system. This may eventually cause expansion of IgA secreting clones, and selection of a clone which secretes alpha heavy chains
and eludes antibody antigen Fc dependent down regulation (Lecuit 2004), due to the absence of variable region determinants.
As with gastric MALT lymphoma, IPSID is often eradicated by antibiotics, which appear to stop the proliferative signals to
lymphocytes. Early stage disease is treated by tetracycline, possibly with the addition of metronidazole (Pervez 2011), with 30-70%
complete remissions. In cases refractory to antibiotics, or in advanced disease such as diffuse large B cell lymphoma, CHOP
chemotherapy is indicated (Economidou 2006).
C. jejuni also secretes CDT (cytolethal distending toxin), the first bacterial genotoxin described, which hijacks the control system of
eukaryotic cells (Ohara 2004) to induce cytoplasm distention and cell cycle arrest, which may ultimately promote malignant change
(Lara-Tejero 2000).
Ocular adnexal MALT lymphoma due to chronic Chlamydia psittaci infection
In the ocular adnexa, chronic Chlamydia psittaci infection is variably associated with MALT lymphoma. Ocular adnexal lymphoma
(OAML) accounts for 1 to 2% of non Hodgkin lymphoma cases, and 80% are MALT subtype. They show a mature B cell phenotype,
derived from post germinal center B cells. C. psittaci is an obligate intracellular bacterium responsible for psittacosis (ornithosis) in
birds; humans are infected by inhaling aerosolized bacteria when exposed to infected birds, contaminated feathers, fecal material or
carcasses. C. psittaci infection is typically asymptomatic with repeated infection cycles in humans, but mainly involves the
respiratory tract (Perrone 2016).
Chlamydia psittaci infections have more geographic variability than Helicobacter pylori and Campylobacter infections. An
international study detected C. psittaci DNA in biopsies of 89% of newly diagnosed stage I OAML patients from Chile, Italy, Spain
and Switzerland (results were not reported separately by country, Ferreri 2012) but another international study showed lower rates
in Germany (47%), the U.S. east coast (35%), The Netherlands (29%), Italy (13%), U.K. (12%), and Southern China (11%)
(Chanudet 2006). Studies focusing on single countries showed prevalence rates varying from 80% in Italy (Ferreri 2004), Korea
79% (Yoo 2007), Austria 54% (Aigelsreiter 2008) to 0% in Kenya (Carugi 2010), Florida (Rosado 2006) and China (Cai 2012).
These variable rates may be due to differing prevalences of Chlamydia psittaci as well as EBV coinfection, differences in genetics or
other host factors (Mosleh 2011a, Moslehi 2011b, Perrone 2016).
Chronic antigenic stimulation by Chlamydia psittaci may lead to clonal expansion and proliferation of post germinal center memory B
cells (Coupland 1999). This process, initially dependent on ongoing antigenic stimulation, may eventually progress to genetic
instabilities with successive chromosomal abnormalities, causing transformation of a clone of normal lymphoid cells to MALT
lymphoma (Stefanovic 2009, Suarez 2006).
Antibiotic treatment, primarily doxycycline, is often effective, with response rates of 45% (Kiesewetter 2013) to 65% (Ferreri 2012).
Due to the geographic variability of the association, blanket antibiotic therapy is advised only when there is proof of Chlamydia
psittaci involvement (Cohen 2009). As with gastric MALT lymphoma, some OAML cases not associated with Chlamydia psittaci
nevertheless respond to doxycycline (Ferreri 2006).
Primary cutaneous lymphoma due to chronic Borrelia burgdorferi infection
Primary cutaneous lymphoma is associated with Borrelia burgdorferi infection but the association is much weaker than with the prior
three infectious agents. It is strong in areas endemic for Lyme disease, including the Scottish Highlands (Goodlad 2000), Austria
(Cerroni 1997) and Yugoslavia (Jelić 1999). However, no association was found in Asia (Li 2003), Central Italy (Goteri 2007) and
Northern Italy (Ponzoni 2011). Reports from the U.S. show varied results (association present: de la Fouchardiere 2003,
association not present: Takino 2008, Wood 2001).
B. burgdorferi infection may cause chronic inflammation of the skin with a dense lymphocytic infiltration followed by atrophy.
However, some patients have no clinical findings (Garbe 1991). B. burgdorferi is thought to provoke chronic antigen stimulation,
similar to H. pylori, C. jenuni and C. psittaci, leading to primary cutaneous lymphoma.
Antibiotics are effective in many but not all cases in treating the lymphoma, apparently by reducing the stimulus for the chronic
antigenic stimulation (Roggero 2000, Monari 2007). Disappearance of the microorganism, accompanied by the unequivocal
decrease of most indicators of active T and B cell immune response, strongly supports a pathogenetic role for B. burgdorferi in
sustaining an antigen driven process (Kütting 1997) even if no clinical or molecular evidence of B. burgdorferi is present (Kempf
2014).
Hepatic lymphoma due to Hepatitis C
Hepatitis C virus (HCV) infects 180 million people, or 3% of the global population (Forghieri 2012). Chronic HCV infection is
associated with B cell lymphoma (Khoury 2014), including splenic marginal zone lymphoma (De Re 2012) and diffuse large B cell
lymphoma (Bronowick 2003, Kikuma 2012). This association appears strongest in highly endemic areas such as Italy, Japan and
the southern U.S. (Arcaini 2012, Khoury 2014). The etiologic fraction of non Hodgkin lymphoma attributable to HCV varies by
country, and may approach 10% in Italy and other areas where HCV prevalence is high, compared with <1% in low prevalence
areas (Dal Maso 2006), where the lack of an association may be due to small sample sizes of HCV positive subjects (Datta 2012).
Although no clear mechanism has consistently been demonstrated, chronic antigen stimulation of B cells by HCV appears to be
important based on: (a) immunoglobulin variable region genes of non Hodgkin lymphoma B cells from HCV positive patients exhibit
somatic mutations indicative of an antigen selection process, (b) the histology of these cells is often typical of germinal center (GC)
and post germinal center B cells (Quinn 2001), (c) HCV infection is not associated with lymphoma subtypes that do not originate
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from germinal center or post germinal center B cells, such as mantle cell, Burkitt and T cell lymphoma (de Sanjose 2008) and (d)
chronic HCV infection is strongly associated with mixed cryoglobulinemia type II and vigorous polyclonal B lymphocyte activation
due to persistent immune stimulation (Oliveira 2014, Agnello 1992), with massive clonal expansion of marginal zone B cells that
recognize the HCV E2 protein of HCV (Visentini 2013). Analogous to Helicobacter pylori related lymphomagenesis, it is conceivable
that progressive independence from the antigen driven mechanism will develop, possibly due to chromosomal translocations or
other genetic aberrations (Zignego 2012). However one study found that lymphoma in HCV infected patients appears not to arise
from B cells aimed at eliminating the virus (Ng 2014).
Antiviral therapy is associated with an overall response rate up to 77% in indolent B cell lymphoma associated with HCV infection
(Arcaini 2014). Prospective studies demonstrate that antiviral therapy is associated with improved survival and support the current
recommendation of antiviral therapy as a first line option in asymptomatic patients with HCV associated indolent non Hodgkin
lymphoma (Michot 2015, Merli 2016).
Section 1.4 Antigen driven lymphoproliferation - autoantigens
Antigen driven lymphoproliferation due to autoantigens
Antigen driven lymphoproliferation may also occur due to autoantigens, with a pathophysiology similar to cases due to
microorganisms. Since B and T cell activation are important in the pathogenesis of autoimmunity, it is not surprising that
longstanding chronic inflammation is a risk factor for lymphoma in patients with autoimmune disease (Baecklund 2014). Similar to
the lymphomas described above, the B or T cell proliferations appear to be directed against the autoantigens; i.e. the lymphoma is
not due to a generic stimulation of B or T cells. Various cofactors are important in these entities, some related to the primary
autoimmune disorder itself, including germ line changes related to NFκB and other inflammatory mediators.
In contrast to antigen driven lymphoproliferation due to infections, treatment is directed at the lymphoma itself with various
combinations of surgery or chemoradiation therapy. It typically is not directed at suppressing autoantigens, with the exception of
celiac disease, because the side effects of therapy outweigh the possible benefits of preventing a primary or relapsing indolent
lymphoma.
MALT lymphoma of thyroid gland due to autoimmune (Hashimoto) thyroiditis
Autoimmune (Hashimoto) thyroiditis, the most common cause of hypothyroidism in iodine sufficient regions (UpToDate:
Pathogenesis of Hashimoto thyroiditis, accessed 24Nov17), is a major risk factor for primary thyroid lymphoma, including MALT
lymphoma, with a relative risk of 67 to 80 times those with an uninvolved thyroid (Holm 1985, Hyjek 1988). Hashimoto thyroiditis is
a T cell mediated disease characterized by lymphocytic infiltration that leads to thyroid cell loss and hypothyroidism. It has an
incidence of 0.3 to 1.5 cases per 1,000 population per year, and is 15 to 20 times more frequent in women than men. It typically
occurs between ages 30 to 50, but may be seen in any age group, including children (Endotext [Internet]. Hashimoto's
Thyroiditis, accessed 4Nov17). Many patients need no treatment because the disease is asymptomatic and the resulting goiter is
small. If the goiter causes local pressure symptoms or is unsightly, thyroid hormone is given (Endotext [Internet]. Hashimoto's
Thyroiditis, accessed 4Nov17).
Primary thyroid lymphoma is rare, accounting for 1-5% of thyroid malignancies (Chai 2015). Hashimoto thyroiditis may have clonal
bands with a polyclonal smear pattern (Saxena 2004), but is not considered malignant. However, the sequence similarity between
the clonal bands in Hashimoto thyroiditis and subsequent thyroid lymphoma suggests that it is a precursor lesion (Moshynska
2008). This progression is not well understood, but involves the NFκB pathway (Troppan 2015), an important regulator of numerous
inflammatory genes, with both pro and anti inflammatory roles (Lawrence 2009).
In the thyroid gland, MALT lymphoma is considered low grade with an excellent prognosis after treatment with various combinations
of surgery or chemoradiation therapy (Chai 2015, Cha 2013, Oh 2012). As a result, no treatment for Hashimoto thyroiditis is
provided prior to or even after the diagnosis of MALT, to reduce the risk of primary or recurrent disease.
MALT lymphoma of salivary gland due to lymphoepithelial sialadenitis of Sjögren syndrome
Patients with lymphoepithelial sialadenitis of Sjögren syndrome have a 44 times increased risk of developing lymphoma, 80% of
which are marginal zone / MALT type, typically of salivary gland origin (Harris 1999). Sjögren syndrome is a chronic, systemic
autoimmune disorder of unknown etiology with an incidence of 3.9 to 5.3 per 100,000 per year. It is nine times more common in
women than men, with a peak onset during menopause (Mavragan 2014). It is characterized by marked B cell hyperactivity,
hypergammaglobulinemia and serum autoantibodies, including antinuclear antibodies, rheumatoid factor, cryoprecipitable
immunoglobulins and antibodies against ribonucleoprotein complexes Ro/SSA and La/SSB.
Sjögren syndrome is characterized histologically by a benign lymphoid infiltrate with lymphocytic epitheliotropism in salivary glands.
Lymphoepithelial sialadenitis (LESA) is common, and exhibits markedly hyperplastic lymphoid tissue with loss of most acinar
structures. Altered ducts are infiltrated by lymphoid cells, and monocytoid B cells may be prominent within the ducts themselves,
even in the absence of lymphoma (Jaffe 2002). In up to 50% of cases of benign LESA, some foci of intraepithelial B cell infiltration
are clonal, as demonstrated by PCR for Ig heavy chain gene rearrangement. Despite clonality, the infiltrates usually have a benign
clinical course, analogous to lymphocytic gastritis associated with Helicobacter pylori, which can show monoclonality by PCR
without overt lymphoma. Thus, clonality is insufficient to diagnose MALT lymphoma in the salivary gland in the absence of other
evidence of malignancy (Jaffe 2002).
MALT lymphoma in the salivary glands typically arises due to autoimmunity associated inflammation, which causes a proliferation of
B cells directed against the autoantigen, as with LESA. This occasionally leads to clonal overgrowth, and, after acquiring secondary
genetic changes, to MALT lymphoma (Jaffe 2002). In contrast to gastric MALT, salivary gland cases usually have no translocations
involving the MALT1 gene (Mulligan 2011, Ye 2003).
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Germ line changes, such as TNFAIP3 polymorphisms in patients with primary Sjögren syndrome, are associated with an increased
risk for MALT and other lymphoma. TNFAIP3 encodes the A20 protein that plays a key role in controlling NFκB activation (Nocturne
2013). Germ line abnormalities of TNFAIP3 lead to decreased control of the NFκB pathway, promoting survival of B cells and
oncogenic mutations (Nocturne 2015).
LESA is routinely treated symptomatically and with surgery if nothing else works. Unlike gastric MALT lymphoma, therapy is not
directed towards reducing the risk of lymphoma, because it is usually low grade and indolent (median overall survival is18.3 years,
Jackson 2015), and the risk of therapy likely outweighs any possible benefit. The lymphoma is effectively treated with surgery,
radiotherapy or rituximab based regimens (Matutes 2017).
Enteropathy associated T cell lymphoma due to celiac sprue
Enteropathy associated T cell lymphoma (EATL) is a rare lymphoma subtype strongly associated with celiac disease, an
autoimmune disease triggered by gluten ingestion. Its incidence has increased significantly in the U.S., which may reflect an
increasing seroprevalence of celiac disease or better recognition of rare T cell lymphoma subtypes. The incidence may continue to
rise given the large number of undiagnosed individuals (Sharaiha 2012). EATL is aggressive, with a 5 year survival of 8-60%
(Nijeboer 2015, Delabie 2011). EATL type II, now known as monomorphic epitheliotropic intestinal T cell lymphoma (Swerdlow
2016) is rarer, and has no known association with celiac disease (Sharaiha 2012).
Celiac disease has a 1% prevalence in Western populations and may have no clinical symptoms (Brito 2014). It is usually
diagnosed by demonstrating gluten enteropathy in a small bowel biopsy or anti tissue transglutaminase antibodies in serum (Webb
2015).
EATL occurs in 14% of celiac disease patients. Patients have HLA-DQ2 and DQ8 haplotypes (Bao 2012) and increased
immunological responsiveness to prolamins such as dietary wheat gliadin and similar proteins in barley, rye and possibly oats. In
these patients, gliadin becomes cross linked to transglutaminase to create a neoantigen, which leads to an immune response and
accumulation of intraepithelial cytotoxic T cells and helper T cells in the small bowel lamina propria. Chronic exposure promotes
antigen driven lymphoproliferation affecting T cells, and an increased risk of EATL (Kooy-Winkelaar 2017, Kim 2015). A
dysregulated microbiome may drive aberrant type 1 IFN or IL15 expression and contribute to celiac disease but the evidence is not
yet definitive (Kim 2015).
Treatment of celiac disease is adherence to a strict gluten free diet for life, which is usually effective (Holmes 1989) although rare
cases are refractory (Woodward 2016). EATL is an aggressive lymphoma, with a 5 year survival of 8 to 60% (Nijeboer 2015,
Delabie 2011). There is no standardized treatment, and optimal therapy is unknown. Typically, local debulking is the first step,
followed by anthracycline based chemotherapy, possibly followed by high dose chemotherapy and autologous stem cell
transplantation (Nijeboer 2015).
Lymphoma due to rheumatoid arthritis
Rheumatoid arthritis is associated with diffuse large B cell lymphoma, as well as other subtypes of leukemia / lymphoma (Parodi
2015, Hellgren 2017, Hashimoto 2015) but the association is strongest for those with severe disease (Baecklund 2006). The risk
does not appear to be familial (Ekström 2003). The driving force is apparently immunostimulation not immunosuppression
(Baecklund 2006, Gridley 1994). Treatment with methotrexate is associated with lymphoma in some (Kamel 1983, Mariette 2002),
but not all studies (Hellgren 2017). The lymphoma itself may be effectively treated with methotrexate withdrawal or steroid pulse
therapy; however some lymphomas require aggressive chemotherapy (Ikeda 2016, Tokuhira 2017).
Hepatic lymphoma due to autoimmune disease
Although primary hepatic lymphoma is rare (0.016% of non Hodgkin lymphoma), persistent inflammatory processes associated with
Hepatitis B or C infection or autoimmune disease (primary biliary cholangitis, Sjögren syndrome and autoimmune hepatitis) may
play independent roles in the lymphomagenesis of hepatic B cells (Kikuma 2012). Other risk factors are chemical exposure,
cirrhosis (Ugurluer 2016) and gastric Helicobacter pylori infection (Nagata 2015, Iida 2007). Occasionally, no risk factor is found
(Shiozawa 2015). The most common subtype is diffuse large B cell lymphoma.
Chronic antigenic stimulation due to primary biliary cholangitis or other disorders may induce the accumulation of reactive lymphoid
hyperplasia (Okada 2009, Ishida 2010, Higashi 2015), leading to various subtypes of lymphoma (MALT: Prabhu 1998, diffuse large
B cell: Kanellopoulou 2011, lymphoplasmacytic: Koumati 2011).
Treatment is typically CHOP-like (cyclophosphamide, doxorubicin, vincristine and prednisone) or radiotherapy (Ugurluer 2016), and
is not directed at the antigen driven lymphoproliferation.
Section 1.5 Bacterial driven carcinoma
Carcinoma due to chronic bacterial infection
Chronic bacterial infections promote cancer of epithelial cells through changes associated with chronic inflammation as well as via
bacterial mutagenic toxic proteins (Cummins 2013, Table 1). This process has similarities to antigen driven lymphoproliferation in
that the bacteria and associated inflammation induce chronic stress, which leads to unstable states in the stem / progenitor cells of
the epithelium. Elimination of the bacteria reduces this stress. However, unlike lymphocytes which undergo apoptosis when no
longer triggered by antigen, the stem / progenitor cells persist and may accumulate additional mutations due to their increasing
instability.
Gallbladder cancer due to chronic Salmonella typhi infection
Gallbladder carcinoma, projected to cause 3,830 deaths in the U.S. in 2017, is associated with chronic carriage of Salmonella typhi,
the cause of typhoid fever, with an increased risk compared with non carriers of 4.3 to 14 (Nagaraja 2014, Gonzalez-Escobedo
2013). The association is strongest among women in Southeast Asia and South America, including Delhi, India (21.5 per 100,000
Page 11
women), Karachi, Pakistan (13.8) and Quito, Ecuador (12.9), compared with low rates (<3) in Northern Europe and North America
(Randi 2006, Nath 2010). In contrast, no association between S. typhi and biliary cancer was found in Shanghai, China, attributed
to the very low prevalence of chronic S. typhi carriers in this population (Safaeian 2011). PCR may be the most sensitive diagnostic
tool for S. typhi infection (Tewari 2010), because the bacterial culture isolation rate is very poor in the gallbladder (Nath 2010).
Bile is typically sterile (Ikeda 1990, Suna 2014) but in typhoid fever, 3-5% of patients become chronic carriers of S. typhi. The
bacteria typically persist in the liver and are excreted intermittently into the gallbladder (Nath 2010). S. typhi bacteria may survive in
the gallbladder niche by forming biofilms on cholesterol gallstones. Chronic infections can persist for decades and although highly
contagious through fecal spread, patients are typically asymptomatic (Gonzalez-Escobedo 2013). Recommended follow up
consists of careful monitoring with ultrasound or cholecystectomy.
S. typhi appears to mediate gallbladder carcinogenesis through both chronic inflammation and direct bacterial genotoxins. Persistent
bacterial infections cause chronic inflammation with production of cyclooxygenase 2, which can cause molecular disturbances in the
cell cycle of gallbladder mucosa. The bacteria also metabolize primary bile acids to produce potentially carcinogenic toxins and
metabolites, including bacterial β glucuronidase, a glycosidase which produces cytolethal distending toxin, described previously
under IPSID, as well as mutagenic intermediates and other primary and secondary bile acid metabolites (Nath 2010).
Other bacterial species associated with gallbladder cancer include Helicobacter bilis and Helicobacter hepaticus, Escherichia coli
(Nath 2010) and non typhoidal Salmonella species (Iyer 2016), some of which produce their own toxins (Nath 2010). Other risk
factors associated with chronic inflammation in the gallbladder include chronic cholelithiasis, chronic infection and obesity (Nath
2010).
Gallbladder carcinoma has been linked with genetic disorders including multiple familial polyposis / Gardener syndrome, Peutz-
Jegher syndrome, porcelain gallbladder and anomalous pancreaticobiliary ductal union (Nath 2010).
Gallbladder cancer has a five year survival rate of less than 5%. Prevention is based on treating typhoid fever, as well as diagnosis
and management of non typhoidal Salmonella species to reduce the chronic carrier state (Gonzalez-Escobedo 2013).
Colorectal carcinoma due to chronic Escherichia coli infection
A diet high in saturated fats (Reddy 2002) and low in fiber, coupled with obesity, a sedentary lifestyle and germ line susceptibility,
may lead to a change in the gut microbial community to promote carcinogenesis (Cho 2016, Mehta 2014). Dietary fiber undergoes
bacterial fermentation in the colon to yield butyrate, a short chain fatty acid and histone deacetylase inhibitor that may protect
against colorectal tumorigenesis (Bultman 2016, O'Keefe 2016).
The gut microbiota exist in a balanced community which maintains homeostasis through symbiotic interactions with intestinal
epithelium (Sheflin 2014) but alterations to the microbiome (dysbiosis) caused by diet and infection can promote colorectal
carcinoma (Gagnière 2016, Sun 2016). Specifically, subclinical colorectal mucosal colonization with Escherichia coli and other
Proteobacteria is associated with and may be a risk factor for colorectal carcinoma (Swidsinski 1998, Yang 2014, Jobin 2013).
Alteration in bacteria flora may contribute to an expanded community of “alpha bugs” which harbor virulence traits that drive colon
cancer development (Elinav 2013, Grivennikov 2013, Schwabe 2013, Coleman 2016). The alpha bug hypothesis proposes that
some microbiome members can remodel the colonic bacterial community to enhance induction of alpha bugs, which coopts other
members of the microbial community (Sears 2011) and may “crowd out” cancer protective microbial species (Yang 2014). The
alpha bugs include E. coli harboring the polyketide synthase (pks) island (Arthur 2012, Bonnet 2014, Cougnoux 2014, Raisch
2014), enterotoxigenic Bacteroides fragilis (Wu 2009) and Fusobacterium nucleatum (Kostic 2014, Rubinstein 2013).
The proposed pathophysiology is: (a) persistent asymptomatic bacterial infection of the colon leads to bacterial penetration of the
inner mucus layer, which may induce chronic inflammation and generate a pro carcinogenic microenvironment (Dejea 2013), (b)
inflamed epithelial cells under the stress of bacterial toxin exposure or chronic bacterial infection generate reactive oxygen species
and nitric oxide, which induces mutations (Dejea 2013), (c) microbial activation of innate immune pathways can also promote cancer
development (Schwabe 2013).
The change in microbiome, associated chronic inflammation and exposure to bacterial toxins induce local network changes that
slowly produce changes identified morphologically as steps in the dysplasia to carcinoma pathway (Sears 2014). Initially, bacteria
may induce increased permeability of tight junctions (Soler 1999, Grivennikov 2012), allowing delivery of bacterial toxins directly to
the epithelium (Sears 2014), which may ultimately lead to a new hierarchy of adenomatous epithelium. Dysplastic mucosa is usually
goblet cell depleted, lacks overlying mucus and has sparse underlying glycocalyx, which facilitates bacterial contact with the
mucosal surface to induce additional network and molecular alterations, leading to malignancy (Prorok-Hamon 2014).
Human host polymorphisms modulating the inflammatory response may affect microbiota influence on colorectal carcinoma
pathogenesis (Dejea 2013). In addition polymorphisms within DNA repair process genes can decrease their efficiency and promote
increased susceptibility to resident E. coli producing genotoxins (Buc 2013).
Treatment of colorectal carcinoma is based on stage (American Cancer Society, accessed 20Nov17), and includes surgery,
chemoradiation therapy, immunotherapy and targeted therapy. A diet high in vegetables, fruit and whole grains is recommended to
minimize recurrence and maintain optimal health although this diet may not have any specific antitumor properties (Mehra 2017).
Gastric carcinoma due to chronic Helicobacter pylori infection
Chronic gastric infection by Helicobacter pylori is a major cause of gastric carcinoma, the world’s fourth largest cause of cancer
death (after lung, liver and colorectal cancer, World Health Organization 2017 accessed ???). Helicobacter pylori, discovered by
Marshall and Warren (Marshall 1984), is classified by the IARC as a group 1 (definite) carcinogen in relation to gastric carcinoma
(IARC 1994). A 2001 prospective study demonstrated that only patients with H. pylori infection develop gastric carcinoma (Uemura
2001).
Page 12
H. pylori has a prominent chronic inflammatory component that is considered necessary but insufficient to cause gastric
carcinogenesis. H. pylori gains access to the gastric mucosa and triggers the production of cytokines that recruit acute inflammatory
cells, probably involved in tissue damage. Infection triggers a cascade of proinflammatory signals, including activation of NFκB and
AP1 and release of IL8 and tumor necrosis factor α (Hoffmann 2015). Chronic inflammation also promotes a tumor
microenvironment favoring angiogenesis and recruitment of inflammatory mediators and inflammatory cells which generate reactive
oxygen and nitrogen species. This leads to inflammatory related histologic changes (gastric atrophy, intestinal metaplasia,
dysplasia) that may lead to cancer (Zabaleta 2012, Castaño-Rodríguez 2014).
In addition H. pylori has a direct oncogenic effect on gastric epithelium; it induces mutations in mitochondrial DNA and the nuclear
genome (Machado 2010) including mismatch repair (Fishel 1995) and deficient MutYH DNA glycosylase activity (Raetz 2012,
Kidane 2014).
Cofactors that increase the risk of gastric carcinoma include cag PAI strains of H. pylori (Hanada 2014) which disrupt cell polarity
(Osman 2013, Zhang 2016) and a proinflammatory diet (Shivapp 2016). In addition 10-15% of diffuse histology cases are
hereditary (Zanghieri 1990), often due to mutations in CDH1 (E cadherin) (Hansford 2015, van der Post 2015) or other genes
(Huang 2015, Gaston 2014).
The American College of Gastroenterology and others recommend H. pylori eradication confirmed by the carbon 13 labeled urea
breath test for patients with endoscopic resection of early gastric cancer, as well as gastric MALT lymphoma (Chey 2007, Howden
2014). Eradication therapy reduces recurrence in early gastric cancer treated with endoscopic resection in some (Fukase 2008), but
not all studies (Kim 2016a, Kim 2016b, Tahara 2016). In addition eradication therapy is recommended for atrophic gastritis,
metaplasia or dysplasia although it may be only partly effective at reversing these high risk conditions (Rokkas 2007, Ohba 2016).
Other chronic bacterial infections
Other chronic bacterial infections are associated with cancer, but are not risk factors. As noted, to overcome the sources of order
within cells requires not only chronic stress, but a microenvironment sensitive to this stress. Streptococcus gallolyticus subsp
gallolyticus endocarditis is not common, but is so strongly linked to colorectal cancer (McCoy 1951, Klein 1997, Boleij 2013,
Paritsky 2015, Cummins 2013) that its presence may warrant colonoscopic examination. This association may be due to disruption
of tight junction permeability (Boleij 2011). Bartonella henselae, a facultative intracellular pathogen, causes bacillary angiomatosis
and bacillary peliosis, two vasculoproliferative but non neoplastic disorders. The bacteria may induce production of vascular
endothelial growth factor, an angiogenic factor leading to endothelial cell proliferation (Kempf 2001).
Section 1.6 Parasite driven carcinoma
Gallbladder carcinoma due to infestation by liver flukes
Three trematode parasites, Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium are classified as Group 1
biological carcinogens (IARC 1994, IARC Monograph on the Evaluation of Carcinogenic Risks to Humans 2017). However,
infestation with their phylogenetic relatives, also major human pathogens, is not carcinogenic (Brindley 2015), perhaps because the
correct chronic combination of chronic stressors in the proper microenvironment are needed to push physiologic networks onto
malignant pathways.
Cholangiocarcinoma due to liver flukes
Liver fluke infestation is strongly associated with cholangiocarcinoma, the most common biliary tract malignancy, which has a
relatively poor prognosis (Yusoff 2012, Buettner 2017). Incident rates are markedly elevated in Thailand (84.6 per 100,000)
compared with Korea (7.4 per 100,000), Japan (2.8), Singapore (1.0) and Western countries (0.2 to 0.7) (Lim 2011). The tradition of
eating ground, raw freshwater and salt fermented fish on a daily basis, particularly in Thailand, results in repeated exposure to liver
flukes and nitrosamine contaminated food beginning in childhood (Pairojku 1991), and more commonly in men (Haswell-Elkins
1994).
Opisthorchis viverrini and Clonorchis sinensis live in bile ducts and damage bile duct epithelia via several mechanisms. First, the
feeding parasites cause mechanical damage. Second, their presence leads to chronic inflammation, including recurrent suppurative
cholangitis and bile duct stones (Lim 2011), with release of cytokines and generation of reactive oxygen intermediates and nitric
oxide (Ohshima 1994). Third, fluke secreted proteins directly induce proliferation of biliary progenitor (“oval”) cells and inhibit DNA
repair and apoptosis (Lee 1997).
Nitrosamines may be necessary for the development of cholangiocarcinoma (Pairojku 1991). Syrian golden hamsters developed
cholangiocarcinoma only with dimethylnitrosamine plus fluke infestation; either alone was insufficient (Lee 1993). Other established
risk factors include alcohol (Miwa 2014) and biliary tract stone disease (Cai 2011, Chang 2013). Germ line polymorphisms appear
to be important, specifically those with a proinflammatory phenotype (Sripa 2012) such as IL6R (Prayong 2014).
Treatment of liver fluke infestation by praziquantel has been very successful but this is dependent on early accurate diagnosis and
correct species identification (Huang 2012) . Community wide prevention programs are also helpful (Sripa 2015).
Bladder squamous cell carcinoma due to Schistosome haematobium
Infestation by Schistosoma haematobium, a blood fluke which resides in venules and capillaries of the bladder and other pelvic
organs, is strongly associated with bladder squamous cell carcinoma (Khaled 2013). First identified in 1851 by Theodor Bilharz, S.
haematobium infestation is endemic in Africa and the Middle East, including Egypt. In one study from Egypt, 82% of patients with
bladder carcinoma had S. haematobium eggs in the bladder wall (El-Bolkainy 1981). In 1994, the IARC confirmed that S.
haematobium was carcinogenic (IARC 1994).
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The mechanism of carcinogenesis in S. haematobium is similar to liver flukes - the parasite causes chronic inflammation, leading to
epithelial metaplasia. The presence of nitrosamines (exogenous in liver flukes, endogenous with schistosomiasis) acts as a cofactor.
Adult S. haematobium commonly invade the venous plexus around the urinary bladder. The adult worms release eggs which cause
chronic granulomatous inflammation in the bladder mucosa and submucosa, leading to squamous metaplasia of the urothelium.
Chronic granulomatous inflammation also leads to bladder fibrosis, which causes urine stasis and bacteria superinfection. The
bacteria convert dietary nitrates and nitrites into nitrosamines, which are then excreted in the urine. These nitrosamines are
carcinogenic and act on the metaplastic epithelium, with subsequent progression to squamous cell carcinoma (Sheweita 2004).
Schistosomiasis is not implicated in the etiology or pathogenesis of any other malignant disease (Khaled 2013). Despite endemics
in 52 countries causing 206 million people to receive preventative treatment in 2016 (World Health Organization,
Schistosomiasis Fact Sheet, accessed 26Nov17), less than 25 cases of Schistosomiasis have been reported to be associated
with prostatic adenocarcinoma (Figueiredo 2015, Mazigo 2010).
Bladder cancer is still the most common malignant tumor among men in Egypt and some African and Middle East countries.
However, its frequency has declined significantly during the last 25 years due to control of Schistosomiasis (Khaled 2013).
Treatment is discussed in section 2.5 (tobacco).
Section 1.7 Trauma related
Trauma, whether physiologic or external is associated with inflammation and repair and occasionally with malignancy, particularly in
the esophagus (due to reflux and hot beverages), skin (burns, sinuses / fistulas and various dermatoses), stomach (wood dust, iron
files) and bladder (stones).
Esophageal adenocarcinoma due to gastroesophageal reflux
Gastroesophageal reflux is the major cause of esophageal and gastric cardia adenocarcinoma (Yang 2016). Its pathophysiology is
dominated by functional and anatomic defects at the gastroesophageal junction (Ness-Jensen 2016). Initially it causes Barrett
esophagus (Barrett metaplasia), which results in replacement of esophageal stratified squamous epithelium with columnar
epithelium, with a high rate of progression to dysplasia and then adenocarcinoma (Goldblum 2003). In the U.S., the incidence of
esophageal cancer has been stable for many years (American Cancer Society - Key Statistics for Esophageal Cancer,
accessed 6Nov17) but as with lung carcinoma, the incidence of esophageal adenocarcinoma has been markedly increasing while
rates for squamous cell carcinoma have been decreasing.
Esophageal adenocarcinoma, a classic example of inflammation associated cancer (O'Sullivan 2014), is typically caused by
cytokine mediated inflammatory injury, not caustic chemical (acid) injury. Refluxed acid and bile stimulate the release of
inflammatory cytokines from esophageal squamous cells, recruiting lymphocytes first to the submucosa and later to the luminal
surface (Souza 2016). Healing of reflux esophagitis may lead to Barrett metaplasia, a process facilitated by reflux related nitric oxide
production and Sonic Hedgehog secretion by squamous cells (Souza 2016). Barrett esophagus is an intermediate step or a
hierarchy between the common reflux esophagitis and the rare esophageal adenocarcinoma.
Other risk factors for esophageal adenocarcinoma include cigarette smoking, obesity (Long 2014, Zakaria 2017) and diet (high fat,
low vegetables and fruit, Neto 2016). A high fat diet may produce changes in the esophageal microbiota (Kaakoush 2017) as it
does in the colon; it is also associated with obesity which directly causes reflux (see section 1.8).
The risk of Barrett esophagus and esophageal adenocarcinoma is influenced by many germ line genetic variants of small effect (Ek
2013), including VSIG10L (Fecteau 2016) and MGST1 (Buas 2017).
Prevention is particularly important due to the poor prognosis of esophageal adenocarcinoma (O'Sullivan 2014) and focuses on
early detection and treatment of premalignant lesions. Lifestyle modifications include increasing physical activity, consumption of
vegetables and fruits, losing weight and reducing smoking, alcohol and meat consumption (Yang 2016), which reduce the risk of
gastroesophageal reflex and subsequent adenocarcinoma (Ness-Jensen 2016).
Esophageal squamous cell carcinoma is also associated with chronic inflammation but via a different mechanism, see the
discussion in sections 2.5 (tobacco), 2.7 (alcohol) and 4.2 (diet). Its highest incidence occurs in the “Asian esophageal cancer belt”,
from Iran east to China and north to Russia. The degree of chronic inflammation correlates with esophageal precursor lesions.
Persistent chronic inflammation may trigger oxidative DNA damage (Lin 2016), which may be mediated by COX2 (Zhang 2011,
Yang 2005).
Cutaneous squamous cell carcinoma due to chronic inflammation
Rarely, cutaneous squamous cell carcinoma arises at the site of chronic inflammation due to various types of tissue trauma,
including ulcers, sinus tracts, osteomyelitis (Horvai 2006, Li 2015), radiation dermatitis and others (Alam 2001).
Marjolin ulcer is a well described squamous cell carcinoma which develops after a prolonged latent period in posttraumatic scars
and chronic wounds, including deep burns (Saaiq 2014). Although the precise mechanism of malignant transformation is unknown,
these lesions are chronically inflamed and undergo continuous mitotic activity due to regeneration and repair, which leads to
unstable network states which may eventually overcome growth controls and trigger malignant transformation. Impaired healing in
chronic wounds occurs secondary to flaws in blood supply, angiogenesis and matrix turnover, as well as infection and continued
trauma, which themselves disturb the intricate balance of cytokines, growth factors, proteases and cellular and extracellular
elements necessary for proper wound healing (Saaiq 2014, Pekarek 2011). In addition scar tissue may have impaired immunologic
reactivity to tumor cells due to obliterated lymphatics (Visuthikosol 1986).
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Treatment is early excision and grafting. Radiotherapy has an important adjunctive role due to the tumor’s aggressive clinical
behavior (Saaiq 2014).
Section 1.8 Excess weight related
Being overweight (BMI of 25 or more) or obese (BMI of 30 or more) causes an estimated 20% of cancer cases, with the increased
risk influenced by diet, weight change, body fat distribution and physical activity. According to the IARC and World Cancer Research
Fund, the malignancies with the strongest association with excess weight are adenocarcinoma of the esophagus, colorectum and
postmenopausal breast, and carcinoma of the endometrium and kidney (De Pergola 2013, Ramos-Nino 2013).
In the U.S. in 2012, being overweight or obese caused 3.5% of new cancer cases in men (28,000) and 9.5% in women (72,000)
(National Cancer Institute: Obesity and Cancer, accessed 6Nov17), compared with worldwide figures of 1.9% of new cancer
cases in men and 5.4% of new cancer cases in women; attributable fractions vary from 6% for rectal cancer to 33% for esophageal
adenocarcinoma in men and 4% for rectal cancer to 34% for endometrial cancer and esophageal adenocarcinoma in women
(Arnold 2015).
Obesity, defined physiologically as abnormal excess accumulation of fat in adipose tissue, is a chronic low grade inflammation
associated with a high risk of developing type 2 diabetes, metabolic syndrome (Reaven 1988, Zhang 2014) and cardiovascular
disease, as well as various types of cancer (Divella 2016). Obesity is associated with diet (see section 4.0), sedentary behavior
(Sugiyama 2016) and lack of physical activity (Siddarth 2013).
The low grade inflammation tends to occur in white adipose tissue due to chronic activation of the innate immune system, which can
lead to insulin resistance, impaired glucose tolerance and even diabetes. Adipose tissue hypoxia may also lead to insulin resistance,
infiltration of macrophages, adipocyte death and mitochondrial dysfunction (Divella 2016). These changes are associated with
alteration of other factors which directly or indirectly drive tumor progression, including insulin, glucose, free fatty acids, insulin-like
growth factor 1 and 2, adipose tissue derived proinflammatory factors, adipokines (adiponectin and leptin), vascular endothelial
growth factor, sex hormones, gut microbiota and secondary bile acids (Ungefroren 2015, Tilg 2014, Bastard 2006). Obesity is also
associated with altered estrogen levels (Engin 2017), a chronic stressor described in section 3.1.
Breast cancer due to obesity
The World Cancer Research Fund estimates that 17% of U.S. breast cancer cases could be prevented by maintaining a healthy
weight (World Cancer Research Fund: Second Expert Report: Food, Nutrition, Physical Activity and the Prevention of
Cancer: a Global Perspective 2007), which is important because two thirds of U.S. women are overweight or obese (Matthews
2016). Postmenopausal women who are metabolically unhealthy or have central adiposity may be at increased risk for breast
cancer even with a normal BMI (Park 2017). Obesity is also a risk factor for breast cancer in men (Brinton 2014). Regular use of
NSAIDs appears to reduce breast cancer risk, particularly among overweight women (Cui 2014).
Colorectal carcinoma due to obesity
In Europe, 11% of colorectal cancer cases have been attributed to excess weight (Bardou 2013). Obesity is associated with a
30-70% increased risk of colon cancer in men but the association is less consistent in women. Abdominal obesity seems to be more
important than subcutaneous fat obesity. The underlying mechanisms are not straight forward, but metabolic syndrome, insulin
resistance and modifications in levels of adipocyte cytokines seem to be important, as is cross talk between pre neoplastic epithelial
cells and immune cells (Riondino 2014), most likely by destabilizing associated networks. Sedentary behavior is also associated
with colon carcinoma risk, and may be mediated through obesity (Schmid 2014).
Esophageal adenocarcinoma due to obesity
Abdominal visceral obesity is a risk factor for gastroesophageal reflux although the mechanism is unknown (El-Serag 2008).
Visceral obesity increases the risk of Barrett esophagus and adenocarcinoma via reflux dependent and independent mechanisms
(Long 2014). In Canada in 2010, an estimated 42% of cases of esophageal adenocarcinoma were attributable to excess body
weight (Zakaria 2017). Weight loss, in addition to the combined use of a statin, aspirin or another cyclooxygenase inhibitor, is
associated with a significantly reduced cancer incidence in patients with Barrett esophagus (Long 2014).
Hepatocellular carcinoma due to obesity
The current obesity epidemic has caused an increase in nonalcoholic fatty liver disease (NAFLD), found in 75-100% of obese and
overweight adults and children. The most severe form of NAFLD is nonalcoholic steatohepatitis (NASH), which is associated with
cirrhosis and hepatocellular carcinoma (Ip 2013, Page 2009), as well as carcinoma of the colon, esophagus, stomach and
pancreas, renal cell carcinoma in men and breast carcinoma in women (Sanna 2016).
NAFLD progression from steatosis to NASH to hepatocellular carcinoma is a multistep process, beginning with hepatocyte damage,
followed by inflammation and cycles of necrosis and regeneration (Sun 2012). Hepatic inflammation and injury in NASH activate
hepatic stellate cells, which promote cirrhosis by replacing hepatocytes with scar tissue rich in type I collagen. This creates an
environment permissive to genetic modulations, leading to malignant transformation.
Green tea catechins and branched chain amino acids may prevent obesity related hepatocellular carcinoma by improving metabolic
abnormalities. Acyclic retinoid, a pharmaceutical agent, may also reduce risk (Sakai 2016).
It has been suggested that weight loss strategies should consider disparities in genetic and environmental factors, focusing on the
specific ancestry of each population and the convenience of consuming traditional ethnic food (Roman 2015).
Pancreatic adenocarcinoma due to obesity
Pancreatic ductal adenocarcinoma is projected to become the second most common cause of cancer related death by 2030 due to
an epidemic in obesity and metabolic syndrome (Rahib 2014). Obesity, particularly android obesity (central obesity or fat excess
Page 15
primarily in the abdominal wall and visceral mesentery) and pancreatic fatty infiltration are risk factors for pancreatic precancerous
lesions. This risk may be mediated through insulin resistance and an altered adipokine milieu, or through its associated chronic low
grade inflammation with production of inflammatory mediators (Rebours 2015).
Other risk factors for pancreatic adenocarcinoma in addition to chronic inflammation and tobacco (discussed in section 2.5) include
diabetes and family history (McWilliams 2016). Alcohol consumption is not a significant risk factor (Andersson 2016).
Statins may reduce pancreatic cancer risk or improve survival in patients with pancreatic cancer and metabolic syndrome, possibly
by blocking the synthesis of intermediates important for both prenylation and activation of the Ras/mitogen activated protein kinase
1 signaling pathway (Gong 2017).
Section 1.9 Other
Cancer due to diabetes
Patients with diabetes have a 20% increased risk of cancer (Scappaticcio 2017), highlighted by reports of antidiabetic drugs
treating (Fukumura 2016) or promoting cancer, which suggests cross talk between the multiple pathways at the interface of the
diabetes-cancer link (Tudzarova 2015).
Diabetes mellitus is associated with a moderately increased risk of bladder cancer, particularly in men (Zhu 2013, Fang 2013)
although some confounding by tobacco or body mass index may partly explain the association (Turati 2015). The risk may be
greater in those taking oral hypoglycemics and with greater disease duration (MacKenzie 2011, Mamtani 2012). The mechanism is
unknown but there appears to be an important interaction between hyperglycemia, hyperinsulinemia, peripheral insulin resistance
and central adiposity, creating a low grade chronic inflammatory state (Gristina 2015).
Colorectal carcinoma due to inflammatory bowel disease
Patients with long standing ulcerative colitis and Crohn disease have an increased risk of colorectal cancer although the incidence
has been decreasing in western countries (Kim 2014). The risk increases with greater duration and extent of colitis, as well as more
prominent inflammation, the presence of primary sclerosing cholangitis and family history of colorectal cancer (Triantafillidis 2009).
Histologic changes apparently progress from no dysplasia to indefinite dysplasia, low grade dysplasia, high grade dysplasia and
finally to invasive adenocarcinoma although steps can be skipped (Triantafillidis 2009). As noted above, the changes appear to be
due to establishment of new hierarchies of molecular patterns, which may not have associated histologic changes.
Host inflammation affects the composition and functional capabilities of gut microbiota (Arthur 2013). Inflammatory mediators TNF,
IL17A and IL23 and byproducts such as reactive oxygen and nitrogen species produce genetic and epigenetic modifications that
may lead to carcinogenesis although it may be difficult to establish if specific bacteria are a cause or effect of the intestinal
inflammation (Arthur 2013).
During intestinal inflammation, some bacteria adjust to and exploit the inflamed environment to gain a growth advantage (see the
alpha bug discussion in section 1.5), which may lead to marked alterations in gut microbial composition (Yang 2014, Kostic 2014).
Key epigenetic mechanisms also link chronic inflammation to colitis associated cancer (Däbritz 2014).
Pancreatic adenocarcinoma due to chronic inflammation
The risk of pancreatic cancer is significantly elevated in patients with chronic pancreatitis, with a standardized incidence ratio of 26.3
The cumulative risk of pancreatic cancer in subjects is 1.8% at 10 years and 4.0% at 20 years (Lowenfels 1993), which persists
after adjusting for tobacco and alcohol use (Ling 2014). However, the population attributable fraction of chronic pancreatitis is only
1.3% (Duell 2012). In autoimmune pancreatitis, the incidence of subsequent pancreatic cancer ranges from 0 to 4.8% (Ikeura
2016).
Possible mechanisms are: (a) inflammation related reactive oxygen species and reactive nitrogen intermediates, enhanced by
growth factors and cytokines, may induce malignancy through DNA damage and abortive repair (Ling 2014), (b) in response to
macrophage secreted inflammatory cytokines, pancreatic acinar cells undergo acinar to ductal metaplasia, which induces
differentiation to a duct-like phenotype and contributes to pancreatic intraepithelial neoplasia and pancreatic adenocarcinoma
(Guerra 2007, Strobel 2007), mediated by NFκB and matrix metalloproteinases (Liou 2013), (c) the inflammatory process creates a
tumor microenvironment in which the immune response is actively suppressed (Evans 2012), (d) chronic inflammation is associated
with epithelial to mesenchymal transition and possibly pancreatic cancer cell dissemination prior to pancreatic tumor formation
(Rhim 2012) although this process is not well understood (McDonald 2012).
Regular use of aspirin may reduce the risk of pancreatic cancer (Streicher 2014, Risch 2017 but see Amin 2016), possibly
mediated through its inhibition of COX1 and COX2.
Lung carcinoma due to chronic inflammation
The overwhelming contribution of smoking to lung cancer makes it difficult to determine additional risk factors but a prior history of
chronic obstructive pulmonary disease or pneumonia is associated in most studies with an increased risk (smokers and
nonsmokers: McHugh 2013, Shen 2014, Koshiol 2009, Ho 2017; smokers only: Wang 2012; never smokers: Brenner 2011).
Additional risk factors are recurrent pneumonia in AIDS patients (Shebl 2010, Hessol 2015 but see Koshiol 2010), tuberculosis in
male smokers (Shiels 2011), Chlamydia pneumoniae infection (Zhan 2011), and elevated acute phase reactants, including C
reactive protein (Zhou 2012, Chaturvedi 2010) and others (Shiels 2013, Keeley 2014). There are variable conclusions on whether
NSAIDs protect against lung cancer risk (yes in smokers - Harris 2002, yes in women - Van Dyke 2008 but see Jiang 2015).
Section 2.0 Exposure to carcinogens
In this section, we describe how exposure to carcinogens, whether from bacteria, parasites, viruses, tobacco, alcohol or work
related, is associated with malignancy. Although these substances may directly be mutagenic, the malignant process is not
Page 16
straightforward and reductionist; it requires additional chronic stressors and indirect methods of overcoming network controls and
the immune response. Prevention and treatment are described in each section.
Section 2.1 General
Carcinogens are substances or exposures that lead to cancer; their mechanisms of action are described below. Due to network
stability (see below), we cannot predict in advance which carcinogens will induce change in which networks, and whether or not this
will propel stem or progenitor cells along a malignant pathway. Cellular networks do exhibit marked changes over time in response
to signals from each other, accounting for the marked differences in activity and the phenotypic changes associated with
progression from a fertilized egg through embryogenesis, fetal development, prepubertal and pubertal growth and adult activities,
with further changes due to inflammation and repair and other internal or external signals. Some pathways are more sensitive to
disruption than others, and some disruptions, while damaging to the cell, will dampen out, and are unlikely to influence interacting
networks to promote cancer.
Predicting the effect of changes to any particular gene or network is difficult for several reasons. First, based on self-organized
criticality, we can predict that some network changes will reverberate and be catastrophic (Bak, How Nature Works 1999) but we
cannot identify them in advance. Second, complex organisms tend to reuse genes and networks and to increase sophistication via
small changes and additional controls (Mattick 2001, Glassford 2015), which makes it extremely difficult to follow the flow of
activity, even in an isolated network. Third, evolution has taken advantage of physical laws that promote nonlinear results. For
example, rapid cell growth is associated with dedifferentiation, whether during embryogenesis or malignancy, because the shorter
interphase and lack of mitotic gap phases prevents the relatively time consuming polymerization of lengthy transcripts. This
activates numerous other networks in a manner that can be evaluated conceptually but is difficult to follow specifically.
Section 2.2 Carcinogens associated with bacteria and parasites
Numerous bacterial or parasitic toxins are associated with carcinogenesis (Nath 2010, Table 2), often as cofactors with antigen
driven lymphoproliferation or other chronic inflammation. For example, Helicobacter pylori infection promotes gastric MALT
lymphoma by translocating its cytotoxin associated gene A protein (CagA) into B cells. After tyrosine phosphorylation, it deregulates
intracellular signaling pathways, stimulates B cell proliferation (Wang 2013, Krisch 2016) and promotes a more potent inflammatory
response (Zucca 2014). Campylobacter jejuni secretes the CDT toxin, whose DNase activity produces chromosomal DNA damage
(Lara-Tejero 2000, Méndez-Olvera 2016). Salmonella typhi metabolizes primary bile acids to produce bacterial β-glucuronidase,
which then produces CDT, mutagenic intermediates and bile acid metabolites that promote gallbladder carcinogenesis (Gonzalez-
Escobedo 2013, Nath 2010).
In the colon, alpha bugs that promote intestinal carcinogenesis in animal models include: (a) E. coli harboring the polyketide
synthase (pks) island that encodes a putative genotoxin called Colibactin (Arthur 2012, Bonnet 2014, Raisch 2014), (b)
enterotoxigenic Bacteroides fragilis (Wu 2009) and (c) Fusobacterium nucleatum (Kostic 2014, Rubinstein 2013). Colibactin may
promote tumorigenesis by inducing DNA damage and genomic instability (Arthur 2012).
In Schistosomiasis haematobium, chronic granulomatous inflammation in the urinary bladder produces urine stasis and bacterial
superinfection, which produces nitrosamines that act on metaplastic epithelium (Sheweita 2004). Soluble antigens from S.
haematobium eggs may also promote malignancy (Botelho 2013).
As described in sections 1.3, 1.5 and 1.6, treatment is directed against the bacteria and parasites, not the possible toxins. When not
effective, treatment is directed against the malignancy itself.
Section 2.3 Viral carcinogens causing lymphoma
Viruses often drive lymphomagenesis directly by activating proliferation pathways. Of particular importance are Hepatitis C, Epstein-
Barr virus, HTLV1 and HHV8.
Hepatic lymphoma due to Hepatitis C
Although Hepatitis C virus promotes hepatic B cell lymphoma indirectly by antigen directed lymphoproliferation (see section 1.3),
HCV can also directly activate B cells by: (a) reducing the threshold of B cell activation through the binding of HCV E2 to CD81 on B
cells (Forghieri 2012), (b) inducing permanent damage to tumor suppressor genes and proto-oncogenes due to a transiently
intracellular virus infection that may quickly leave the cell (‘‘hit and run’’ theory, Forghieri 2012, Rossotti 2015), (c) directly
activating antiapoptotic pathways within B cells (Agnello 1992, Mele 2003) and (d) activating proinflammatory cytokines (de
Sanjose 2008). As Hepatitis C virus lacks reverse transcriptase or oncogenes, immediate malignant transformation of B or T cells is
unlikely (Pozzato 1994). When present, Sjögren syndrome may a cofactor in HCV lymphomagenesis (Ramos-Casals 2007).
Antiviral treatment with interferon induces regression of indolent lymphoma in 75% of cases, particularly marginal zone lymphoma,
with loss of serum HCV RNA and complete remission of lymphoma (Hermine 2002, Merli 2016, Arcaini 2012, Vallisa 2005).
Chemotherapy is necessary for associated high grade lymphoma (Tasleem 2015).
Lymphoma due to Epstein-Barr virus
Epstein-Barr virus (EBV) is a ubiquitous γ herpes virus which infects 95% of the adult population worldwide through oral secretions
and is also associated with an astounding 2% of cancer deaths worldwide, primarily gastric cancer (48% of EBV cancer deaths) and
nasopharyngeal carcinoma (44% of EBV cancer deaths) (Khan 2014). It has an important role in almost all cases of endemic Burkitt
lymphoma, lymphomatoid granulomatosis, extranodal NK/T cell lymphoma nasal type, pyothorax associated lymphoma,
angioimmunoblastic T cell lymphoma and post transplant lymphoproliferative disorder. It is associated with Hodgkin lymphoma (80%
of mixed cellularity and 30% of nodular sclerosis cases, Houldcroft 2015) and sporadic Burkitt lymphoma (30% of cases). Its role in
post transplant lymphoproliferative disorder, diffuse large B cell lymphoma associated with chronic inflammation, Hodgkin lymphoma
and Burkitt lymphoma (sporadic) is discussed in section 7.0.
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EBV is a potent growth transforming agent for primary B cells through stimulation of the NFκB pathway and increased expression of
antiapoptotic genes (Rowe 2014). After primary infection, it remains in a latent state within resting B cells for the lifetime of the host.
Cytotoxic T cells (CTL), both CD8+ and CD4+, and natural killer (NK) cells are primarily responsible for containing the infection. If
the host cellular immune system fails to control EBV activity, infected B cells can transform from their latent state into malignant
cells, which are typically aggressive (Roschewski 2012). EBV also plays a complex and multifaceted role in T/NK cell lymphoma by
promoting Th2 skewed T cell responses and increasing the expression of immune checkpoint ligand PDL1 (Gru 2015).
EBV has three distinct patterns of latency. Type I has selective expression of EBNA1 and is seen in Burkitt lymphoma. Type II
expresses EBNA1, LMP1 and LMP2 and is seen in Hodgkin lymphoma and peripheral T cell lymphoma. Type III expresses all nine
latent cycle EBV antigens and is commonly seen in post transplantation lymphoproliferative disorder (Roschewski 2012).
Typically the treatment approach for these tumors is similar whether they are EBV positive or negative (Kanakry 2013) although for
immunodeficiency related EBV tumors, treatment aims to restore the host immune response to EBV and may include specific
cytotoxic T cell therapy (see section 7.4). There is no specific anti-EBV medication.
Burkitt lymphoma-endemic due to EBV
EBV appears to be actively involved in all stages of endemic Burkitt lymphoma development. In a Ugandan prospective study,
children who subsequently developed Burkitt lymphoma had significantly higher titers of EBV-VCA IgG antibodies up to 6 years
before lymphoma onset; chronic rather than acute EBV infection appears to be relevant to lymphomagenesis (de-Thé 1978, van
den Bosch 2012).
EBV potentiates lymphomagenesis by directly stimulating and maintaining B cell proliferation, which increases the size of the B cell
pool and the risk of translocation or other cytogenetic changes (van den Bosch 2012). EBV-LMP1 acts as an oncogene by
mimicking the CD40 ligand and binding the B cell CD40 receptor, causing constitutive activation of the NFκB pathway and providing
a growth signal to B cells (Roschewski 2012). EBV also promotes genomic instability by inducing oxidative stress (Kamranvar
2007) and protects cells damaged by mutations from destruction by apoptosis (Mancao 2005).
Although EBV is widespread in all human communities, only a very small number of infected individuals develop Burkitt lymphoma
or any other cancer linked to the virus. Endemic Burkitt lymphoma is primarily a childhood cancer in parts of Africa and Brazil, and is
associated with the t(8;14) IgH-Myc translocation (Bernheim 1981).
Malaria appears to be a common cofactor in the pathogenesis of endemic Burkitt lymphoma (Magrath 2012). In sub-Saharan Africa,
90% of children are infected with EBV by age 2 and develop immune tolerance to it. Malaria produces polyclonal B cell activation,
inhibition of EBV specific cytotoxic T cells and an increase in EBV transformed B cells (Whittle 1990, van den Bosch 2012). The
combination of EBV and holoendemic malaria amplifies the incidence of endemic Burkitt lymphoma in African children approximately
a hundredfold, from 0.04–0.08/100,000 in Western Europe, 1-2/100,000 in Algeria to 10/100,000 in the African lymphoma belt (van
den Bosch 2012). Burkitt lymphoma has a germinal center cell immunophenotype (BCL6
+
, CD10
+
), and persistent malarial infection
may promote the hyperactivation of these germinal centers and increase the risk of somatic hypermutation and Myc translocation
(Roschewski 2012).
Although EBV and malaria are the most common infections associated with endemic Burkitt lymphoma, other cofactors have been
described including infections with HIV, human herpesvirus 5, human herpesvirus 8 (Abate 2015) and Chikungunya virus and the
presence of the EBV activating plant Euphorbia tirucalli (van den Bosch 2012, MacNeil 2003).
Treatment of Burkitt lymphoma is highly effective in the West and cure rates are >90% using short, intensive, rotational multiagent
chemotherapy including rituximab (Dozzo 2016). In Africa, long term cure rates have remained at 25-30% due to limited resources
and poor patient compliance (Mbulaiteye 2013).
Lymphomatoid granulomatosis due to EBV
Lymphomatoid granulomatosis is a rare angiodestructive EBV driven lymphoproliferative disease comprised of atypical clonal EBV
+
B cells in an inflammatory background. Most patients have lung involvement (Chavez 2016).
Typically there is no known immunodeficiency at diagnosis but there may be defective immune surveillance of EBV infected B cells,
particularly by CD8+ T cells (Roschewski 2012). As a result, the EBV infection leads to uncontrolled growth of infected B cells.
Treatment with interferon (grades 1/2) or dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and
rituximab (grade 3 disease) improved progression free survival to 56% for grades 1/2 (median followup 5.1 years) and to 44% for
grade 3 disease (median followup 32 months) (Song 2015).
Extranodal NK/T cell lymphoma, nasal type due to EBV
Extranodal NK/T cell lymphoma, nasal type is an aggressive extranodal non Hodgkin lymphoma most commonly found in East Asia
and Latin America but increasing in the U.S., where it is more common among Asian Pacific Islanders and Hispanics (Haverkos
2016). It accounts for 15% of all non Hodgkin lymphoma in southwest China, 7.8% in Guatemala, 6.1% in Korea, 2.8% in Taiwan,
2.6% in Japan, 2.6% in Chile, 2.4% in Peru and less than 0.1% in Europe and North America (Gru 2015). EBV is associated with
virtually all cases and is the only factor implicated in its pathogenesis although Asian and South American patients often have
antecedent lymphoproliferative disorders (Haverkos 2017). If in situ hybridization for EBV is negative, one should question the
diagnosis. EBV viral load detected by polymerase chain reaction is intimately tied to prognosis, clinical course and disease relapse
(Roschewski 2012).
Although the precise mechanism of action of EBV in this tumor is unknown, important factors appear to be the microenvironment,
cross talk with surrounding cell types and clinically unapparent immune dysregulation (Haverkos 2016).
Page 18
Pegaspargase, gemcitabine and oxaliplatin combined with radiotherapy produced a 94% response rate in one study (Wei 2017).
Another study recommended combined chemotherapy and radiotherapy for stage I/II disease and non anthracycline regimens
containing L-asparaginase for stage III/IV disease. Up to 90% of “good risk” stage I/II patients may achieve durable remission but
treatment of high risk stage I/II and stage III/IV patients remains challenging (Tse 2017).
Pyothorax associated lymphoma due to EBV
Pyothorax associated lymphoma is a distinct type of diffuse large B cell lymphoma associated with chronic inflammation which
develops in patients who received an artificial pneumothorax for pulmonary tuberculosis 30 to 40 years previously (Nishiu 2004)
although lymphomas with similar features are also recognized in other chronic inflammatory conditions (Xie 2015). EBV is detected
in lymphoma cells of most cases (Nakatsuka 2002). Patients often have a very large tumor (>10 cm) confined to the thoracic cavity,
which helps distinguish it from primary effusion lymphoma (Roschewski 2012).
Pyothorax associated lymphoma tumor cells typically derive from crippled post germinal center cells at the differentiation stage,
before antigen selected maturation has occurred, which differs from most B cell lymphomas (Miwa 2002). EBV appears to induce B
cell transformation and escape from cytotoxic T cells (Roschewski 2012, Takakuwa 2008).
Prognosis is poor, with a 5 year survival (as of 2007) of only 35% (Narimatsu 2007).
Angioimmunoblastic T cell lymphoma due to EBV
Angioimmunoblastic T cell lymphoma (AITL) is a distinct peripheral T cell lymphoma associated with EBV infection in almost all
cases (Roschewski 2012). It originates from the follicular T helper cell, a CD4+ T cell of germinal center origin and is characterized
by the RHOA G17V mutation together with genetic alterations in TET2 (Lemonnier 2017), DNMT3A and IDH2 (Cortés 2016), which
most likely promote T cell differentiation and malignant transformation (Wang 2017). AITL is the second most frequent peripheral T
cell lymphoma worldwide after peripheral T cell lymphoma not otherwise specified.
The exact role of EBV in AITL lymphomagenesis is not completely understood. Of note, it is the background B cells that are partially
infected by EBV, not the malignant T cells (Roschewski 2012). AITL tissues are characterized by massive infiltration of B cells
partially infected by EBV, follicular dendritic cells and high endothelial venules, promoted by cytokines and chemokines released
from tumor cells (Sakata-Yanagimoto 2016). EBV+ B cells may upregulate CD28 ligand, which leads to activation of follicular T
helper cells and production of CXC13 and other chemokines. Chronic stimulation of the follicular T helper cells through this
mechanism may eventually lead to an antigen independent clone (Roschewski 2012).
Outcomes with anthracycline containing regimens are poor; autologous transplantation at first remission is recommended (Broccoli
2017, Lunning 2017).
Lymphoma due to Human T cell Lymphotropic virus type 1 (HTLV1)
HTLV1 is a type 1 carcinogen associated with lymphoproliferative diseases collectively termed adult T cell leukemia / lymphoma
(Morales-Sánchez 2014). It is endemic in Japan, the Western African coast, Central America and the Caribbean, with 15 million to
25 million people infected worldwide. Transmission is by sexual contact, breast feeding or intravenous exposure. The virus infects T
and B lymphocytes and dendritic cells and binds to their GLUT1 receptor (Maeda 2015).
Most HTLV1 infected patients carry tens of thousands of clones of HTLV1 infected T lymphocytes, each distinguished by a unique
integration site of provirus into the host genome. However only 5% of those infected develop adult T cell leukemia / lymphoma,
typically those infected by breast feeding and usually more than 50 years after becoming infected (Bangham 2015). Compared with
HIV1, HTLV1 varies little in sequence, and the genotypes of patients with adult T cell leukemia / lymphoma, HTLV1 associated
myelopathy or HTLV1 associated tropical spastic paraparesis are similar to those from asymptomatic carriers. The efficiency or
“quality” of the specific cytotoxic T lymphocyte (CTL) response to HTLV1 is a major determinant of the HTLV1 proviral load and the
risk of disease. The chief factors that determine a high quality anti-HTLV1 CTL response are the host genotype in HLA Class 1 and
killer immunoglobulin-like receptor loci (Bangham 2015).
The HTLV1 viral oncoprotein Tax directly leads to leukogenesis and immortalization of T lymphocytes by: (a) inducing NFκB activity,
which stimulates cytokine expression, which triggers T cell proliferation and may amplify the pool of HTLV1 infected cells (Morales-
Sánchez 2014), (b) transcriptionally repressing DNA polymerase β, involved in base excision repair (Jeang 1990) and (c)
independently suppressing the nucleotide excision repair mechanism, which together lead to faulty chromosomal segregation and
aneuploidy in HTLV1 infected cells. In addition Tax can also modulate the host innate immune response to favor virus replication and
oncogenesis (Hyun 2015).
Prognosis is poor, with 4 year overall survival rates of 11%, 16%, 36% and 52% for the acute, lymphoma, chronic and smoldering
types (Ishitsuka 2017).
Primary effusion lymphoma due to HHV8
Primary effusion lymphoma is a rare, aggressive B cell lymphoma universally associated with HIV infected patients and human
herpesvirus 8 (HHV8), the oncogenic virus associated with Kaposi sarcoma. It typically presents in adults with a median age of 41
years (El-Fattah 2016) as a malignant serous effusion of the pleura, pericardium or peritoneum with no tumor mass although solid
variants have been described (Pielasinski 2014, Guillet 2011). Cases are occasionally observed in transplantation and elderly
patients in areas where HHV8 is endemic, such as the Mediterranean and sub-Saharan Africa (Kaplan 2013).
HHV8 may promote lymphomagenesis through viral IL6, a lytically produced cytokine capable of mediating paracrine signaling to
promote cell growth and survival in addition to proinflammatory and angiogenic responses (Chen 2014). There is no effective
treatment, and the overall median survival is 6 months (Kaplan 2013).
Multicentric Castleman disease, plasmablastic variant, due to HHV8
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Human herpesvirus 8 also causes multicentric Castleman disease (MCD) in immunocompromised individuals, such as HIV infected
patients, although >50% of MCD cases are negative for HIV and HHV8 (Yu 2017, Kaplan 2013).
Multicentric Castleman disease is often referred to as human interleukin 6 syndrome, since overproduction of IL6 is present
(Carbon 2015). In idiopathic MCD, defined as HHV8 negative disease, numerous mechanisms increase IL6 (Wang 2016); rarely it
is caused by immune reconstitution inflammatory syndrome (Siegel 2016).
Treatment with rituximab with or without chemotherapy results in significantly better overall survival (Kaplan 2013). Siltuximab, an
anti-IL6 monoclonal antibody, has also demonstrated durable tumor responses (van Rhee 2015, Sarosiek 2016).
Section 2.4 Viral carcinogens causing carcinoma or sarcoma
Hepatocellular carcinoma due to Hepatitis B and Hepatitis C
Hepatocellular carcinoma (HCC) is a leading cause of cancer related death worldwide (Forner 2012, Baumert 2017), and the
fastest growing cause of cancer related death in the U.S. (El-Serag 2011). In the U.S., in persons age 68 or older, population
attributable risks for HCC are diabetes / obesity (37%), alcohol related disorders (24%), hepatitis C virus (22%), hepatitis B virus
(6%) and rare genetic disorders (3%) (Weizel 2013).
Most HCV infected patients are unaware of their status, and 85% progress to chronic HCV infection and cirrhosis. The risk of HCC
for patients with HCV related cirrhosis is 2-6% per year (de Oliveria Andrade 2009). HCV is a RNA virus with no ability to integrate
into the host genome (Goossens 2015). It promotes malignancy by activating liver fibrogenic pathways and by interacting with
immune and metabolic systems. Germ line changes are also important in immune system, metabolic and growth signaling pathways
(Goossens 2015).
Direct acting antivirals have improved the HCV hepatitis cure rate to above 90% although this is limited by high cost. Due to under
diagnosis among baby boomers, inmates and injection drug users, HCC incidence even in high resource countries is predicted to
increase (Baumert 2017, El-Serag 2002).
In Africa and East Asia, 60% of HCC cases are attributable to hepatitis B, compared with 20% in the developed Western world (Di
Bisceglie 2009). HBV encoded X protein (HBx) plays a pivotal role in the pathogenesis of viral induced HCC by modulating
transcription, cell cycle progression, DNA damage repair, cell proliferation and apoptosis (Ali 2014). Universal hepatitis B
immunization is effective in reducing HCC incidence due to HBV (Chang 2003).
Gastric adenocarcinoma due to EBV
EBV associated gastric cancer is the largest group of EBV associated malignancies, primarily because gastric cancer is the third
leading cause of cancer related mortality worldwide, after lung and liver cancer. Ten percent of gastric carcinoma cases worldwide
contain EBV; in these cases, typically all tumor cells harbor the clonal EBV genome (Nishikawa 2014). EBV associated gastric
cancer is one of four subtypes based on gene expression profiles; the others are microsatellite unstable, genomically stable and
chromosomal instability (Cancer Genome Atlas Research Network 2014). EBV associated gastric carcinoma occurs
predominately in younger men, typically with a diffuse histology rich in lymphocytes (Nishikawa 2014).
Gastric cancer arises due to dysregulated differentiation of stem and progenitor cells caused by a chronic inflammatory
environment. However, the situation in the stomach is considered rather complex, consisting of two types of gastric units which
show bidirectional self renewal from an unexpectedly large variety of progenitor / stem cell populations (Hoffmann 2015). Genetic
and epigenetic changes characteristic of EBV associated gastric cancer alter gene expression related to cell proliferation, apoptosis,
migration and immune signaling, and include mutations in PIK3CA and ARID1A, amplification of JAK2 and PDL1/L2 and global CpG
island hypermethylation, which induces epigenetic silencing of tumor suppressor genes (Shinozaki-Ushiku 2015).
Cofactors for EBV associated gastric carcinoma include salty food and exposure to wood dust or iron filings, which may induce
mechanical injury to the gastric epithelia (Nishikawa 2014).
EBV subtype of gastric carcinoma has favorable survival compared with other subtypes, especially in Asians (Liu 2015). To date,
treatment for gastric carcinoma is similar for EBV positive and negative cases although new therapies based on epigenetic
regulation (Nishikawa 2017), immunotherapy (Tashiro 2017) and developing lytic induction therapy (Kraus 2017, Kenney 2014)
are being explored.
Nasopharyngeal carcinoma due to EBV
Nasopharyngeal carcinoma is a squamous cell or undifferentiated carcinoma caused by a combination of EBV infection,
environmental influences and heredity. In Guangdong (Canton) in Southern China, it accounts for 18% of all cancers and has an
incidence of 25 cases per 100,000, 25 times higher than the rest of the world (Wang 2013). It is also quite common in Taiwan. The
regional differences may be due to the Southeast Asian diet of salted vegetables, fish and meat. Salt preservation is inefficient,
leading to partially putrefied foods, which may accumulate significant levels of nitrosamines, a known carcinogen (Li 2016, Tan
2014).
The etiological role of EBV in the pathogenesis of nasopharyngeal carcinoma is unknown but involves attacks on networks in
different cells at multiple points. Possible mechanisms are: (a) defective immune system presentation of EBV antigens to host
immune cells based on the HLA locus at chromosome 6p, preventing an appropriate immune response, (b) clonal expansion of an
EBV infected cell, (c) multiple somatic mutations of regulators of NFκB signaling, which drive the transformation of pre-invasive
nasopharyngeal epithelial cells to cancer cells, (d) nitrosamine consumption may drive networks toward malignancy via other
mechanisms (Tsao 2014, Tsao 2017).
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Germ line variants in MST1R (Dai 2016) or MLL3 (Sasaki 2015) are associated with nasopharyngeal carcinoma. Other studies
show individuals with a first degree family history have a greater than fourfold increased risk of nasopharyngeal carcinoma but no
excess risk of other malignancies (Liu 2017), which suggests a strong genetic predisposition or efficient cultural transmission of
environmental exposures (Rottenberg 2017).
Radiation therapy is the mainstay of treatment, with chemotherapy used in advanced cases (He 2017, Chapman 2017). In a recent
study, estimated 5 year overall survival and disease free survival (DFS) rates for all patients were 87.5% and 70.1%, respectively (Li
2017). Future treatments may also incorporate EBV DNA testing (Kim 2017) or dietary plant products such as grape seed
proanthocyanidins (Yao 2016).
Cervical cancer due to HPV
Virtually all cervical cancers are associated with human papilloma virus (HPV) (Brianti 2017). As of 2012, cervical cancer was the
fourth leading cancer in women worldwide and the seventh overall, with an estimated 528,000 new cases and 266,000 deaths, 87%
of which occur in less developed regions. Mortality rates range from less than 2 per 100,000 in Western Asia, Western Europe and
Australia / New Zealand to 22.2 per 100,000 in Middle Africa and 27.6 per 100,000 in Eastern Africa (IARC: Globocan 2012,
accessed 8Dec17). In the U.S., cervical cancer is the 20th most common cause of cancer deaths, with 4,210 deaths projected in
2017 (Cancer Facts and Figures 2017).
Papillomaviruses were first identified in 1933 from rabbits as a transmissible, filterable cause of benign papilloma. In 1956, human
papillomavirus (HPV) was first identified. It causes multiple human cancers including anogenital cancer, and its discovery by Harald
zur Hausen led to his winning the 2008 Nobel Prize in Medicine (zur Hausen 1974, Dürst 1983).
Persistent HPV infection is the main cause of anogenital cancer, including cervical cancer, which is typically due to high risk HPV
types 16 and 18. Their E6 and E7 genes immortalize human keratinocytes. The E6 protein binds p53, which promotes its
ubiquitination and subsequent proteolysis, which diminishes its tumor suppressive and transcriptional properties. The E7 protein
interacts with the retinoblastoma susceptibility gene product pRb and related proteins, releasing the transcriptional activator E2F
from a complex with Rb, allowing E2F to activate genes engaged in cell cycle progression (The Nobel Prize in Physiology or
Medicine 2008: Advanced Information, accessed 26Nov17).
HPV appears to be necessary but insufficient for developing cervical carcinoma. Although 65-100% of sexually active adults have
been exposed to HPV (Pytynia 2014), most women with HPV do not develop cervical cancer (World Cancer Research Fund
International, accessed 9Nov17); other cellular, immunological, genetic, epigenetic or environmental cofactors are required
(Pedroza-Torres 2014). Cofactors include smoking, passive smoking (Roura 2014, Zeng 2012), Chlamydia trachomatis infection
(Zhu 2016), burning wood in kitchen stoves or ovens (Ferrera 2000) and tar based vaginal douching (historically, Rotkin 1967).
Although the immune system typically clears HPV, organ transplant recipients and HIV infected patients have more severe and
recalcitrant disease, higher viral loads, infections with unusual HPV genotypes and a greater propensity for HPV related
malignancies (The Nobel Prize in Physiology or Medicine 2008: Advanced Information, accessed 26Nov17). Worsening
immunodeficiency, even with only moderately decreased CD4+ cell counts, is a significant risk factor for cervical cancer (Clifford
2016). Specific HLA alleles are associated with an increased or reduced risk of cervical cancer (Hu 2014, Zhao 2013).
The HPV vaccine is safe and effective at reducing cervical cancer (Basu 2013) and has markedly reduced infection rates
(Markowitz 2016, Kahn 2016). Routine vaccination at age 11 or 12 years is recommended by the (U.S.) Advisory Committee on
Immunization Practices (Meites 2016).
Cervical cancer screening is recommended beginning at age 21 (American Cancer Society Guidelines 2016, accessed 9Nov17).
Since subclinical genital HPV infection typically clears spontaneously, antiviral therapy is not recommended to eradicate subclinical
HPV infection (Centers for Disease Control and Prevention: 2015 STD Guidelines, HPV, accessed 26Nov17). Treatment of
precancerous lesions is surgical (WHO guidelines for screening and treatment of precancerous lesions for cervical cancer
prevention 2013, accessed 26Nov17). Treatment of invasive cancer is surgery or chemoradiation, based on clinical stage (NCI-
Cervical Cancer Treatment (PDQ®)–Health Professional Version 2017, accessed 9Nov17).
Head and neck carcinoma due to HPV
Head and neck carcinoma is projected to cause 9,700 deaths in the U.S. in 2017 (oral cavity and pharynx: Siegel 2017, Table 1).
There has been a rapid rise in oropharyngeal squamous cell cancer involving the tonsil and base of the tongue in men younger than
age 50 with no history of tobacco or alcohol use (Sathish 2014, Khode 2014). Although historically tobacco and alcohol use caused
75-80% of all oral cavity cancers in the U.S. (Khode 2014), HPV prevalence in oropharyngeal cancers rose from 16.3% during
1984-1989 to 71.7% during 2000-2004, with similar increases reported in many European countries. In Sweden, 90% of oral
squamous cell carcinomas are HPV positive (Sathish 2014). The reasons for the increase are unknown. Transmission of HPV is
primarily through sexual contact and oral-genital contact can lead to oral / oropharyngeal HPV infection (Pytynia 2014). HPV can
also be transmitted by less intimate skin to skin contact. Although the increased incidence of HPV associated head and neck cancer
could be attributable to increased oral sex practices and more oral sex partners, HPV positive oral squamous cell carcinoma is
documented in patients reporting very few oral sexual partners and 8-40% of patients report never having had oral sex. In addition
the plausible reasons for the increased incidence of HPV associated oropharyngeal cancers in men, with no substantial rise among
women, are unclear (Sathish 2014).
The pathogenesis of HPV associated head and neck carcinoma appears similar to that of cervical cancer. HPV proteins E6, E7 and
E5 induce cell cycle progression of differentiated oral squamous epithelial cells, causing deregulated proliferation, loss of apoptosis,
genomic instability and transformation to cancer (Sathish 2014).
Other risk factors for oropharyngeal squamous cell carcinoma include smoking, HIV infection, more than 8-10 sexual partners and
more than four oral sexual partners (Pytynia 2014). Vaccines prevent infection with HPV16 and HPV18 but vaccination after
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development of cancer is unlikely to provide clinical benefit as expression of the capsid proteins is usually lost during transformation
(Blitzer 2014).
Cutaneous squamous cell carcinoma due to HPV
HPV may be an important factor for some cutaneous squamous cell carcinomas, particularly in the immunocompromised (Nichols
2017, Wang 2014) . More than 200 HPV types have been identified and classified into five genera, α, β, γ, µ and ν (McLaughlin-
Drubin 2015). HPV from the β genus, considered a commensal organism acquired shortly after birth, is suspected to play a role in
the development of cutaneous squamous cell carcinoma (Farzan 2013). Although the main risk factor for nonmelanoma skin cancer
is UV radiation, immunosuppressed individuals have β HPV loads 100 times higher than immunocompetent persons (Moscicki
2017). Immunosuppressive agents vary in their association with cutaneous squamous cell carcinoma - mTOR inhibitors are actually
associated with a decreased risk of developing post transplant nonmelanoma skin cancers (Jung 2016). Treatment options for post
transplant cutaneous squamous cell carcinoma include electrodessication and curettage, excision, Mohs surgery, systemic retinoid
therapy, topical therapy and radiation therapy (Chockalingam 2015).
Epidermodysplasia verruciformis is a rare genodermatosis associated with a high risk of cutaneous carcinoma (Orth 2006) and
abnormal susceptibility to cutaneous β HPV infections. Homozygous inactivating mutations in TMC6 (EVER1) and TMC8 (EVER2)
account for 75% of affected individuals; mutations in RHOH, MST1, CORO1A and IL7 cause extensive β HPV replication and an
epidermodysplasia verruciformis-like phenotype (Przybyszewska 2017).
Kaposi sarcoma due to HHV8
Kaposi sarcoma, the most common malignancy in untreated HIV patients, is caused by Kaposi sarcoma associated herpesvirus
(KSHV / HHV8) (Chang 1994, Ganem 2006). It is characterized by abnormal neoangiogenesis, inflammation and proliferation of
spindle cells, known as Kaposi sarcoma spindle cells, which have an endothelial cell origin and are phenotypically similar to
lymphatic endothelial cells but poorly differentiated (Cancian 2013). HHV8 reprograms the host endothelial cells by upregulating
lymphatic vessel endothelial receptor 1 (LYVE1), podoplanin and vascular endothelial growth factor receptor 3 (Radu 2013).
HHV8 infection alone is insufficient to cause Kaposi sarcoma; progression requires host immune dysfunction and an appropriate
local inflammatory milieu. Like other herpesviruses, HHV8 remains latent within cells and has developed a variety of mechanisms to
evade the host immune system (Radu 2013) but infection is typically associated with immunodeficiency states, including HIV
infection, iatrogenic immunodeficiency and aging (Kaplan 2013).
AIDS associated KS has declined dramatically since the introduction of combination antiretroviral therapy in 1996 but remains the
most common malignancy in HIV infected individuals and is a significant problem in sub-Saharan Africa where combination
antiretroviral therapy is unavailable. The classic form of Kaposi sarcoma is occasionally seen in older individuals from endemic
HHV8 regions (Kaplan 2013).
Merkel cell carcinoma due to Merkel cell polyoma virus
Merkel cell carcinoma is the eponym for primary cutaneous neuroendocrine carcinoma, a dermal malignancy which is typically due
to a well defined mutated form of the Merkel cell polyoma virus (Feng 2008, Moore 2014) although some cases are not viral
associated (Tothill 2015). This uncommon and aggressive tumor typically occurs in the head and neck of the elderly in actinic
damaged skin. It has an estimated disease associated mortality between 33% and 46% and is now the second most common cause
of skin cancer death in the U.S. after melanoma, with a 333% increase in deaths from 1986 to 2011, due to increased incidence
(Schadendorf 2017). It tends to recur and cause local and distant metastases; distal metastases are usually fatal (Medscape: Skin
Cancer - Merkel Cell Carcinoma, accessed 10Nov17).
The Merkel cell is found in the basal layer of the epidermis, parallel to the surface. These cells function as mechanoreceptors in skin
and cluster in areas of sensory perception, such as fingertips, tactile hair follicles and the tip of the nose (Halata 2003). The Merkel
cell virus is part of the normal viral skin flora but is usually clinically silent. Merkel cell carcinoma, similar to Kaposi sarcoma, is
sensitive to immune surveillance and occurs more frequently in AIDS and transplant recipients (Moore 2014). Increased risk for
carcinoma occurs when an individual is infected (common), loses immune surveillance against MCV proteins (uncommon) and
when the virus undergoes a precise set of mutations (rare) (Moore 2014).
Merkel cell carcinoma has two viral products, the large T and small T antigens, which have cellular functions and targets in addition
to those of other polyomavirus T antigens. The large T antigen facilitates the viral life cycle and also disables the Rb and p53
pathways. A small T domain region is required for transformation activity and also targets eukaryotic translation (Wendzicki 2015).
Surgery and radiotherapy achieve high rates of locoregional control but distant failure rates are high (Tothill 2015).
Section 2.5 Tobacco use
The American Cancer Society indicates that smoking is the world’s leading preventable cause of death; in the U.S., it causes an
estimated 480,000 annual premature deaths, including 42,000 from secondhand smoke exposure (Cancer Facts and Figures
2017, page 40). Excluding secondhand smoke, it is estimated to cause 32% of all cancer deaths. In the U.S., the Centers for
Disease Control and Prevention indicates that cigarette smoking caused 163,700 annual cancer deaths during 2005-2009
(Tobacco-Related Mortality, accessed 10Nov17). The World Health Organization Global Report - Mortality Attributable to Tobacco,
states that tobacco use is responsible for 22% of cancer deaths worldwide (WHO Report, accessed 10Nov17).
Cigarette smoking causes cancer by: (a) exposure to carcinogens and production of reactive oxygen species, (b) methylation of
CpG sites (Sayols-Baixeras 2015), (c) DNA adduct formation, (d) accumulation of permanent somatic mutations in important genes
leading to clonal outgrowth, (e) promotion of autophagy and premature aging in the host stromal microenvironment (Salem 2013)
and (f) cancer associated inflammation linked with immune suppression (the mechanisms are discussed in more detail below). Of
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note, smoking decreases the risk of endometrial cancer, possibly due to its association with a reduced body mass, decreased
estrogen levels and earlier menopause (Zhou 2008, Felix 2014).
Tobacco smoke contains more than 60 carcinogens which react synergistically with respiratory particulates to generate reactive
oxygen species, leading to oxidative stress and increased production of mediators of pulmonary inflammation (Valavanidis 2013).
Although protected by enzymatic and nonenzymatic antioxidant defenses, an imbalance of prooxidants and antioxidants in the
cellular environment can enhance reactive oxygen species production, which induces DNA damage, inhibits apoptosis and activates
protooncogenes (Valavanidis 2013). In addition, due to the numerous carcinogens present, typically acting over decades, tobacco
may created marked tumor heterogeneity by activating a myriad of different pathways at multiple sites within a tissue or organ
(Fisher 2013). Thus, a reductionist strategy based on countering a specific pathway is unlikely to be effective long term. In contrast,
targeting multiple pathways, the instability induced by these carcinogens or the reactive oxygen species imbalances may be more
effective (Crawford 2017). To date, there is no specific therapy targeting tobacco smoke itself.
Most smokers do not get tobacco associated cancer; risks vary greatly between individuals. For example, a New York study
projected ten year lung cancer risks ranging from 0.8% for a 51 year old woman who smoked one pack per day for 28 years and quit
9 years previously, compared with 15% for a 68 year old man who smoked two packs a day for 50 years and continued to smoke
(Bach 2003).
According to the U.S. Surgeon General, smoking cessation is the only proven strategy to reduce the pathogenic processes leading
to cancer because the specific impact of many tobacco carcinogens, alone or in combination, have not been identified (How
Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the
Surgeon General 2010, Chapter 5). Within 5 years of quitting, the risk of cancer of the mouth, throat, esophagus and bladder is cut
in half; within 10 years of quitting, the risk of dying from lung cancer drops by half (U.S. Centers for Disease Control and
Preventing: Smoking and Cancer, accessed 19Nov17).
We discuss below the major causes of cancer death due to tobacco by site, ordered by a declining population attributable fraction
(Siegel 2015-Table, see also The Health Consequences of Smoking - 50 Years of Progress, A Report of the Surgeon General
2014, at Table 12.1, page 652, PDF page 737). The population attributable fraction is the projected reduction in death or disease
that would occur if exposure to a risk factor were reduced to an alternative ideal exposure scenario, such as tobacco use compared
with no tobacco use (World Health Organization - Metrics: Population Attributable Fraction, accessed 25Nov17, Alberg 2013).
Lung cancer due to tobacco
Lung cancer is the leading cause of U.S. cancer death in men and women, with a projected 155,870 cancer deaths in 2017,
representing 25% of all cancer deaths (Cancer Facts and Figures 2017, page 4). For lung cancer, 80-85% of deaths are
attributable to smoking (How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable
Disease: A Report of the Surgeon General, accessed 10Nov17, Siegel 2015-Table). The lung cancer death rate has declined due
to reductions in smoking, in men by 43% since 1990 and in women by 17% since 2002, with the rate of decline increasing in recent
years. From 2010 to 2014, the rate decreased by 3.5% per year in men and by 2.0% per year in women (Cancer Facts and
Figures 2017, page 19).
Cigarette smoking is by far the most important risk factor for lung cancer (Cancer Facts and Figures 2017, page 19) and risk
increases with quantity and duration of smoking. Cigar and pipe smoking also increase the risk. Exposure to radon gas released
from soil and building materials is the second leading cause of lung cancer in the U.S. but radon exposure is synergistic with
smoking, as is asbestos exposure (Ngamwong 2015).
The pathways described above are important in lung carcinogenesis. Increased lung cancer risks due to cigarette smoking have
been ascribed to: (a) various carcinogens including cigarette tar (Meyers 2017), polycyclic aromatic hydrocarbons, N-nitrosamines,
aromatic amines, aldehydes and volatile organic compounds (Leon 2015, Hecht 2003), (b) alterations of DNA methylation
(Fasanelli 2015), (c) DNA adduct formation (Wiencke 2002), which may persist when cellular repair systems are overwhelmed or
otherwise not functioning efficiently (How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-
Attributable Disease: A Report of the Surgeon General, Chapter 5), (d) the propagation of genetic damage during clonal
outgrowth, consistent with the accumulation of multiple genetic changes observed in lung cancer progression (Alexandrov 2016,
How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the
Surgeon General, Chapter 5, see Figure 5.1), (e) induction of premature aging and mitochondrial dysfunction in stromal
fibroblasts, which actively promote anabolic tumor growth (Salem 2013), (f) suppression of the immune system by multiple
mechanisms, including by modulating the tumor microenvironment (Lee 2012, Rodriguez-Vita 2010) through tumor cells co-opting
signaling molecules of the innate immune system (Valavanidis 2013).
Numerous germ line changes are associated with lung cancer risk, affecting CRP, GPC5 (Zhang 2015, Liu 2014) and NFKB1 genes
(Shiels 2012), as well as cytochrome P450 2A6 (CYP2A6) activity (Park 2017) and DNA methylation levels (Levine 2015).
Treatment is surgery, chemoradiation therapy and targeted therapy. It is based on histologic subtype (most commonly small cell
carcinoma, squamous cell carcinoma or adenocarcinoma) and results of molecular testing (NCCN Clinical Practice Guidelines in
Oncology: Ettinger 2017). Five year survival varies by histology: 21% for nonsmall cell lung cancer versus 7% for small cell lung
cancer; it also varies by stage: 55% if localized (16% of cases), 27% for regional disease and 4% for disseminated disease (55% of
cases, Miller 2016).
Laryngeal cancer due to tobacco
Smoking is strongly associated with laryngeal cancer, with a population attributable fraction of 76.6% (Siegel 2015-Table) and an
odds ratio of 21.7 for those with 60+ pack years of smoking compared with never smokers (Lubin 2010; see also Wyss 2013: odds
ratio of 8.3, Franceschi 1990: odds ratio of 4.6). Alcohol consumption and smoking synergistically increase the risk by several
mechanisms (How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A
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Report of the Surgeon General, Chapter 5). First, alcohol inhibits the metabolism and clearance of NDMA, a nitrosamine and
carcinogen in tobacco smoke, through competitive inhibition of the liver enzyme P450 2E1 (Swann 1984). Second, for some
nitrosamines, alcohol induces the production of P450, which may increase metabolic activation of nitrosamines (McCoy 1979).
Third, alcohol abuse is associated with deficiencies in folate, zinc and vitamin A, which can exacerbate the effects of smoking (How
Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the
Surgeon General, Chapter 5). Finally, in the mouth, alcohol acts as a solvent, increasing absorption of tobacco carcinogens
(Squier 1986).
Mechanisms of tobacco induced carcinogenesis identified in the larynx include DNA adduct formation (Szyfter 1996, Flamini 1998)
and frequent mutations in TP53 with patterns resembling lung cancer in smokers (Pfeifer 2002).
Polymorphism in GSTM1 are related to the risk of laryngeal cancer (Zhang 2017).
Treatment is surgery and chemoradiation therapy and varies by stage (Laryngeal Cancer Treatment (PDQ®), accessed 25Nov17).
Overall relative 5 year survival is 61%, varying from 76% for local disease, 45% for regional disease and 35% for distant disease
(Cancer Facts and Figures 2017, page 21).
Esophageal squamous cell carcinoma due to tobacco
For esophageal cancer in the U.S. in 2011, 50.7% of 14,404 or 7,307 deaths were attributed to tobacco use (Siegel 2015-Table),
with total esophageal cancer deaths projected to increase to 15,690 in 2017 (Cancer Facts and Figures 2017, page 4). This
disease is 3 - 4 times more common among men than women. Smoking is strongly associated with squamous cell carcinoma and
adenocarcinoma, the major subtypes. Squamous cell carcinoma is the most common type of esophageal cancer worldwide (Zhang
2013) but in the U.S., adenocarcinoma is more common in whites. Esophageal cancer makes up about 1% of all cancers diagnosed
in the U.S. but it is much more common in Iran, northern China, India and southern Africa, where squamous cell carcinoma
predominates.
The major risk factors for esophageal carcinoma are tobacco smoking and alcohol drinking, which act synergistically (Yaegashi
2014). Dietary carcinogens and low consumption of fruit and vegetables may be important risk factors in certain areas (Yang 2016).
As indicated in section 1.7, gastroesophageal reflux is the major cause of esophageal adenocarcinoma (Yang 2016).
Possible mechanisms of tobacco related carcinogenesis in the esophagus include: (a) ingestion of tobacco condensates provides
direct contact of tobacco specific nitrosamines and other tobacco carcinogens with the esophageal mucosa (Zhang 2013), (b)
tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons and aromatic amines, which are converted by cytochrome
P450 related enzymes into DNA reactive metabolites (Ohash 2015), (c) tobacco smoke upregulates cyclooxygenase 2 (Gong
2016), which promotes the progression from esophagitis to dysplasia to carcinoma (Huang 2011), and (d) tobacco promotes chronic
inflammation associated genomic instability (Lin 2016).
Genetic polymorphism associated with tobacco related esophageal carcinogenesis involve the CYP (Bartsch 2000), ADH1B and
ALDH2 genes (Cui 2009, Zhang 2013).
The overall 5 year survival for all subtypes is 20% (American Cancer Society: Key Statistics for Esophageal Cancer, accessed
19Nov17). Early stage disease, with negligible risk of nodal metastases, can be cured by endoscopic resection of tumor,
radiofrequency ablation or photodynamic therapy; surgical resection or chemoradiotherapy are required for more advanced disease
(Ohashi 2015). Targeted therapy using EGFR inhibitors has shown early promising results (Saumel 2017). Nutrition management is
often required, not as specific antitumor treatment but as supportive care (Mak 2017).
Oral cavity and pharyngeal cancer due to tobacco
Smoking is strongly associated with cancers of the oral cavity and pharynx, with a population attributable fraction of 47.0%; smoking
caused 4,032 deaths due to oral cavity and pharynx cancer in the U.S. in 2011 (Siegel 2015-Table). There is also an increased risk
due to cigar and pipe smoking (Wyss 2013, Franceschi 1990), and a markedly increased risk with smoking and alcohol use
(Ferreira 2013).
Cigarette smoke mediates oral carcinogenesis primarily via reactive free radicals and volatile aldehydes (Nagler 2016, Choudhari
2014); in addition increased production of matrix metalloproteinases may be important (Allam 2011).
Stage I/II cancers of the lip and oral cavity are highly curable by surgery or radiation therapy. Stage III/IV disease typically receive
both surgery and radiation therapy and clinical trials are recommended to prevent local recurrence and distant metastases. Small
tumors have high cure rates; even moderately advanced tumors without nodal spread have cure rates up to 65%, which varies by
site (Lip and Oral Cavity Cancer Treatment (PDQ®), accessed 25Nov17). Second primaries are common but isotretinoin may
reduce their incidence (Kadakia 2017).
Bladder cancer due to tobacco
Smoking is the most well established risk factor for bladder cancer (Cancer Facts and Figures 2017, page 27), accounting for
44.8% of bladder cancer related deaths in 2011 (Siegel 2015-Table). There is a linearly increasing risk of bladder cancer with
increasing duration of smoking, ranging from an odds ratio of 1.96 after 20 years of smoking to 5.57 after 60 years (Brennan 2000).
Smoking cessation for 10 or more years reduces the risk (Rink 2013), but not completely (Mir 2013). Recent changes in cigarette
composition may have increased the risk (Freedman 2011).
The increased risk of bladder cancer in smokers is attributable to aromatic amines in tobacco smoke, which cause DNA adduction
and mutagenicity (Besaratinia 2013). Cigarette smoke may also promote epithelial-mesenchymal transition (Sun 2017).
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Other cofactors for bladder carcinogenesis include diet and occupational factors (Al-Zalaban 2016), prostatitis, syphilis and
hormone replacement therapy (Mir 2013), pelvic radiation, cyclophosphamide and birth defects. There is no association with HPV or
polyoma virus (Polese 2012).
Some authors believe bladder cancer may be due to chronic inflammation associated with calculi (Chung 2013, Vermeulen 2015),
prior urinary tract infections (Kantor 1984, Shih 2014), chronic indwelling urinary catheters (Ho 2015) or urinary tuberculosis (Lien
2013) although many studies have reported no association (González 1991, Jhamb 2007, Kjaer 1989). The discrepancy has been
explained by possible recall and selection biases, as well as a greater detection of bladder cancer during workup of bladder
infections or calculi (Chang 2010). There may be a multiplicative interaction of urinary tract infections with smoking (La Vecchia
1991), which may distort the apparent effect of minor contributors to the disease.
Nonmuscle invasive bladder cancer (stages Ta, Tis and T1) is treated with transurethral resection of the bladder tumor, followed by
intravesical chemotherapy, with followup that may include intravesical bCG or other chemotherapy. Standard curative treatment for
muscle invasive bladder cancer is either neoadjuvant multiagent cisplatin based chemotherapy followed by radical cystectomy and
urinary diversion or radiation therapy with concomitant chemotherapy (Bladder Cancer Treatment (PDQ®), accessed 9Dec17).
The 5 year relative survival by stage is: stage 0 - 98%, stage I - 88%, stage II - 63%, stage III - 46%, stage IV - 15% (American
Cancer Society > Survival Rates for Bladder Cancer, accessed 25Nov17).
Liver and intrahepatic bile duct cancer due to tobacco
Tobacco use causes 23.6% of U.S. deaths due to liver and intrahepatic bile duct cancer, estimated at 5,060 deaths in 2011 (Siegel
2015-Table). Several constituents of tobacco smoke are known liver carcinogens in humans and experimental animals (Lee 2009),
including 4-aminobiphenyl and polycyclic aromatic hydrocarbons (Wang 1998, Chen 2002).
The 5 year relative survival is: localized to liver (stage I, II, IIIA, IIIB) - 31%, regional (stage IIIC, IVA) - 11%, distant (stage IVB) - 3%
(American Cancer Society > Survival Rates for Liver Cancer, accessed 25Nov17). Patients with early stage disease may be
cured by liver transplantation, surgical resection or radiofrequency ablation; other patients receive palliative or supportive treatment
(Adult Primary Liver Cancer Treatment (PDQ®), accessed 25Nov17).
Cervical cancer due to tobacco
Tobacco use causes 22.2% of U.S. deaths due to cervical cancer, or 862 deaths in the U.S. in 2011 (Siegel 2015-Table). Smokers
have an excess risk of cervical squamous cell carcinoma that persists after controlling for the strong effect of HPV, the most
important risk factor for cervical cancer, and for other potential cofactors (Fonseca-Moutinho 2011).
Cervical mucus of smokers contains measurable amounts of nicotine, other cigarette constituents and their metabolites, such as
aromatic polycyclic hydrocarbons and aromatic amines (Fonseca-Moutinho 2011), which may cause DNA adduct formation
(Simons 1993). In addition benzo[a]pyrene, a major carcinogen in cigarette smoke, is detected in the cervical mucus and may
interact with HPV to enhance viral persistence and promote carcinogenesis (Alam 2008).
Cervical cancer risk in smokers may be modified by genetic variants in activated T helper cytokine genes (Hardikar 2015) and other
immune response genes (Mehta 2017). Cervical neoplasia is also associated with HLA haplotype (Leo 2017).
During treatment, women with cervical carcinoma frequently do not quit smoking or decrease tobacco consumption (Waggoner
2010) although providing counseling (Chang 2017), educational materials and staff training can be helpful (duPont 2016).
Stomach cancer due to tobacco
Tobacco use causes 19.6% of U.S. deaths due to gastric carcinoma or an estimated 2,131 deaths in 2011 (Siegel 2015-Table).
Worldwide, it is estimated to cause 11% of gastric carcinoma cases or 80,000 cases annually (Trédaniel 1997). The risk of stomach
cancer among smokers varies from 1.59 to 1.98 in men and 1.11 to 1.78 in women (Trédaniel 1997, Nomura 2012) with
consistency across five ethnic groups, and evidence of a dose response effect in both sexes.
This increased risk may be mediated by polycyclic aromatic hydrocarbons or their metabolite 1-OHPG (Liao 2014).
Smoking may be synergistic with H. pylori bacterial load and virulence factors to increase the risk of intestinal metaplasia and gastric
cancer (Santibáñez 2015).
Smoking cessation reduces the risk but it remains significantly increased up to 14 years after cessation (Koizumi 2004). For
patients undergoing gastric cancer surgery, preoperative smoking cessation can reduce postoperative complications (Jung 2015).
Renal cell carcinoma due to tobacco
Tobacco use causes 16.8% of U.S. deaths due to renal cell carcinoma, estimated at 2,253 deaths in 2011 (Siegel 2015-Table).
This increased risk applies to clear cell and papillary renal cell carcinoma but not chromophobe renal cell carcinoma, suggesting that
these subtypes have distinct carcinogenic mechanisms (Patel 2015).
Metabolism of tobacco carcinogens in renal cell carcinoma include: (a) creation of highly reactive metabolites that damage DNA,
such as N-nitrosamines (Kabaria 2016), (b) inducement of chromosome 3p aberrations, the most frequently identified genetic
alterations in renal cell carcinoma, by benzo[α]pyrene diol epoxide, a major constituent of cigarette smoke (Kabaria 2016) and (c)
nicotine induced tumor growth (Heeschen 2001).
Acute myeloid leukemia in adults, due to tobacco
Tobacco use causes 14.6% of U.S. deaths due to acute myeloid leukemia in adults, estimated at 1,317 deaths in 2011 (Siegel
2015-Table). A recent meta-analysis concluded that the relative risk was increased regardless of sex and geographical region, with
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oxygen species and inflammation or other cell mediated mechanisms (Agency for Toxic Substances and Disease Registry:
Asbestos Toxicity How Does Asbestos Induce Pathogenic Changes?, accessed 10Nov17).
Mesothelioma due to asbestos
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer caused by asbestos exposure. Its frequency is dramatically
higher in asbestos polluted areas, as exemplified by the epidemic in Casale Monferrato, Italy, caused by an asbestos cement factory
(1907-1986). In this area, the average annual MPM incidence in 2009-2013 was 51.2 cases per 100K among men and 20.2 among
women, 10 times higher than the national average (Betti 2017). Many with no known exposure likely had unrecognized exposure
(Musk 2017). A Swedish asbestos ban in 1982 did not reduce mesothelioma incidence through 2009 (Plato 2016). In the U.S., with
up to 3,000 annual deaths due to mesothelioma, the rate of asbestos associated mesothelioma is increasing among women due to
better investigation into their histories of asbestos exposure, which shows bystander, incidental or take home exposures (Lemen
2016).
Asbestos induces mesothelioma by directly interfering with mitotic spindle formation, by inducing chronic inflammation and the
production of cytokines and through generation of reactive oxygen species by activated macrophages. Reactive oxygen species are
also generated by the iron contained in asbestos fibers (Betti 2017).
Germ line variants in several genes may increase susceptibility to pleural mesothelioma in the presence of asbestos exposure (Betti
2017).
Recommended treatment, based on extent of disease, includes radical surgery (extrapulmonary pneumonectomy or radical
pleurectomy with decortication), with or without chemotherapy and radiation. However median survival typically does not exceed 2
years (NIH > NCI > Malignant Mesothelioma Treatment (PDQ®), accessed 25Nov17, Verma 2017).
Bladder cancer due to aromatic amines or other occupational toxin exposure
Approximately 7% of bladder cancer cases in men are associated with occupational exposure (Lukas 2017). The most notable risk
factor is exposure to aromatic amines (2-naphthylamine, 4-aminobiphenyl and benzidine) and 4,4’-methylenebis (2-chloroaniline)
found in the chemical, dye, leather, aluminum and rubber industries as well as in hair dyes, paints, fungicides, cigarette smoke,
plastics, metals and motor vehicle exhaust (Letašiová 2012, Cancer Facts and Figures 2017, page 27, Medscape, Bladder
Cancer, accessed 10Nov17).
Exposure to arsenic in drinking water at concentrations higher than 300 µg/l is strongly associated with bladder cancer. There may
also be an effect from other sources of arsenic exposure such as air, food, occupational hazards and tobacco (Letašiová 2012).
The pathophysiology of aromatic amines in the genesis of bladder cancer is not fully understood although aromatic amines are
involved in DNA adduction and mutagenicity (Besaratinia 2013).
Mechanisms of arsenic induced bladder carcinogenesis include: (a) arsenic interferes with DNA damage repair and chromosomal
structure, leading to genomic instability, (b) arsenic places a high demand on the cellular methyl pool, leading to global
hypomethylation and hypermethylation of specific gene promoters, which deregulates oncogenic and tumor suppressive genes, (c)
arsenic causes aberrant expression of noncoding RNAs and disrupts signaling pathways (Sage 2017), (d) arsenic inhibits indirectly
sulfhydryl containing enzymes and interferes with cellular metabolism such as cytotoxicity, genotoxicity and inhibition of enzymes
with antioxidant function (Letašiová 2012).
Bladder cancer risk is also associated with polymorphisms in the GSTM1 and UGT1A genes (Lukas 2017).
Section 2.7 Alcohol
The America Society of Clinical Oncology recently stated:
“The importance of alcohol drinking as a contributing factor to the overall cancer burden is often underappreciated. In fact, alcohol
drinking is an established risk factor for several malignancies. As a potentially modifiable risk factor for cancer, addressing high-risk
alcohol use is one strategy to reduce the burden of cancer. For example, in 2012, 5.5% of all new cancer occurrences and 5.8% of
all cancer deaths worldwide were estimated to be attributable to alcohol.
1
In the U.S., it has been estimated that 3.5% of all cancer
deaths are attributable to drinking alcohol.
2
Alcohol is causally associated with oropharyngeal and larynx cancer, esophageal cancer,
hepatocellular carcinoma, breast cancer, and colon cancer.
3
Even modest use of alcohol may increase cancer risk but the greatest
risks are observed with heavy, long-term use.” LoConte 2017
Based on 2009 data, in the U.S., 3.5% of total cancer deaths are alcohol related, totaling 19,500 cancer deaths (NIH > NCI >
Alcohol and Cancer Risk, accessed 12Nov17, Nelson 2013). The IARC has classified alcohol consumption as carcinogenic (IARC
Monograph, Volume 44, 1988, IARC monographs 100E, 2012), citing "sufficient evidence" for cancers of the oral cavity, pharynx,
larynx, esophagus and liver. A 2010 update added cancers of the colorectum and female breast (IARC Monographs on the
Evaluation of Carcinogenic Risks to Humans, Volume 96, Alcohol Consumption and Ethyl Carbamate 2010, Table of Risks
by Site). Similarly, the National Toxicology Program of the U.S. Department of Health and Human Services lists consumption of
alcoholic beverages as a known human carcinogen (14th Report on Carcinogens 2016, file is 26 MB in zip form). The more
alcohol a person drinks, particularly regularly over time, the higher the risk of developing an alcohol associated cancer. No level of
alcohol consumption is considered safe with respect to cancer risk; any reduction in consumption will reduce cancer risk (Grundy
2016, World Cancer Report 2014, page 103).
The mechanisms of action between alcohol and cancer are: (a) metabolization to acetaldehyde, which damages DNA and proteins,
(b) generating reactive oxygen species which can damage DNA, proteins and lipids, (c) impairing the ability to break down and
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absorb vitamins A, B complex, C, D, E and carotenoids, (d) increasing blood levels of estrogen, and (e) alcoholic beverages may
contain nitrosamines, asbestos fibers, phenols and hydrocarbons (NIH > NCI > Alcohol and Cancer Risk, accessed 10Nov17).
The risk of head and neck cancers decreases after cessation of drinking (World Cancer Report 2014, page 97) but the relationship
at other sites may be more complex (for example, individuals may stop drinking due to cancer related symptom (LoConte 2017)
Head and neck cancer (oral cavity, pharynx, larynx) due to alcohol
Alcohol consumption is a major risk factor for head and neck cancer, particularly in the oral cavity (excluding the lips), pharynx and
larynx (Baan 2007). The relative risk of cancers of the oral cavity and pharynx from alcohol consumption is 3.2 to 9.2 for more than
60 g/day (>4 drinks/day) when adjusted for tobacco smoking and other potential confounders (Goldstein 2010); another study
showed a 2-3 times increased risk from those who consume 50+ grams of alcohol per day (3.5+ drinks per day) (Baan 2007).
The risk of these cancers is substantially higher among those who also use tobacco (Hashibe 2009, NIH > NCI > Alcohol,
accessed 10Nov17, Maasland 2014). For French patients, the population attributable risks for oral cavity cancer was 0.3% for
alcohol alone, 12.7% for tobacco alone and 69.9% for their joint consumption (Radoï 2015).