Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_53_библиотеки_им_акад_М_И_Перельмана
.pdf
with high-HDI are 12.8 and 8.5, respectively, and for males and females in countries
with low-HDI, these values are 5.7 and 3.8, respectively (Bray et al. 2018).
The world regions with the highest reported incidence of CRC include Australia
and New Zealand with ASR incidence rates (ASRi) of 41.7 per 100,000 for males,
32.1 per 100,000 for females and overall ASRi of 36.7 and overall ASR mortality
rate (ASRm) of 11.1 per 100,000 of population. The lowest incidence of CRC has
been reported from South-Central Asia with an ASRi of 6.1 per 100,000 for males,
3.8 per 100,000 for females and overall ASRi of 4.9 and overall ASRm of 3.6 per
100,000 of population (Ferlay et al. 2018b, Bray et al. 2018). The world regions with
highest reported incidence of colon cancer include Southern Europe, Australia-New
Zealand, and Northern Europe and the world regions with highest reported incidence
of rectal cancer include Eastern Europe, Australia-New Zealand, and Eastern Asia.
North America is also among the world regions with highest reported incidence of
colon and rectal cancers. Based on country and gender, the highest incidence of CRC
among males has been reported from Hungary and among females from Norway,
with an ASRi of 70.6 and 39.3 per 100,000, respectively. Hungary also has world’s
highest reported CRC related mortality rates with ASRm of 31.2 per 100,000 for
males and 14.8 per 100,000 for females. Further, CRC represents the most com-
monly diagnosed cancer among males in Slovakia, South Korea, Japan, Saudi
Arabia, UAE, Qatar, Kuwait, Oman, Bahrain, and Yemen whereas in South-Central
Asia and all African regions especially Northern, Eastern, Middle and Western
Africa, lowest CRC incidence has been reported among both males and females
(Ferlay et al. 2018b). In Saudi Arabia, UAE, and Oman, CRC is the most common
cancer and foremost cause of cancer-related mortality among males whereas in
Japan, Algeria, Portugal, Belarus, and Sp ain, CRC is the foremost cause of cancer-
related mortality among females (Bray et al. 2018).
The trends in incidence and mortality associated with CRC and the trends in
relationship between these two inter-related epidemiological parameters exhibit a
highly dynamic variation across different world regions. Both the colorectal cancer
incidence and mortality have shown a significant increase in medium-HDI countries
like China, Russia, Philippines, Brazil, and Baltic republics (Latvia, Estonia and
Lithuania) where significant developmental progress is taking place. There has been
a significant increase in CRC incidence but considerable decrease in CRC mortality
in high-HDI countries like Denmark, United Kingdom (UK), Singapore, and
Canada. The decrease in CRC mortality in these nations is largely due to improved
diagnosis and treatment. The countries like France, Japan, Iceland, and most impor-
tantly the United States (US), which represent the nations with highest-HDI, have
shown a significant decrease in both the incidence and mortality rates of colorectal
cancer. The decrease in incidence and mortality rates is largely due to improved and
timely diagnosis and prevention (through increased screening among individuals
aged 50 years or above), improved treatment, in particular, appropriate surgical
interventions, and in some countries including the US, due to extensive usage of
non-steroidal anti-inflammatory drugs (NSAIDs) (Arnold et al. 2017; Edwards et al.
2010). In US, with a significant decrease in incidence and mortality of CRC in
individuals aged 50 years or above, a considerable increase in CRC incidence among
5 Colorectal Cancer and Genetic Polymorphism in Key Regulatory Low... 125
https://t.me/medicina_free
individuals with age less than 50 years (aged 20– 49 years) has been reported over the
past few decades. This is exemplified by an almost constant annual increase of 1.8%
in incidence since the year 1992 and an increase in ASRi from 9.3 per 100,000 in the
year 1975 to 13.7 per 100,000 in the year 2015. The mechanistic interpretation of
such an increase is still awaited. Australia is another country where a similar CRC
incidence trend is observed (Edwards et al. 2010; Young et al. 2015).
5.1.1.3 Survival
When compared with incidence rates, which have shown an overall worldwide
increase, a considerable relative decrease in mort ality rates has been observed. The
decreased mortality rates have been attributed to improved diagnosis and treatment.
The development of secondary prophylactic strategies or methods has enabled the
early detection of the disease and contributed significantly to overall increased
survival. These methods, which may be non-invasive or invasive include fecal occult
blood testing (FOBT) [guaiac-based FOBT (gFOBT) and fecal immunochemical test
(iFOBT/FIT)] and endoscopic procedures [colonoscopy (CS), flexible
sigmoidoscopy (FS), double contrast barium enema (DCBE)], and computed tomo-
graphic (CT) colonography [CTC, virtual colonoscopy (VC)] (Edwards et al. 2010).
Although these strategies have resulted in overall increase in incidence rates due to
increased disease detection or diagnosis, the early disease detection and preventive
measures, in particular, the surgical excision of precancerous polyps, a procedure
known as polypectomy, have helped in preventing the advancement of the disease to
cancerous stage. All this has led to a significant overall decrease in CRC related
mortality (Arnold et al. 2017; Benson et al. 2008; Ouyang et al. 2005).
As with CRC incidence and mortality, survival rate also exhibits a considerable
variation with geographical location, economic status and with race and ethnicity.
Economic status, race, and ethnicity have been associated with variation in survival
rate within a same geographical location. The important factors that determine the
survival rates include availability of and access to trained physicians and surgeons,
modern diagnostic procedures, and latest drug-based therapies. The overall 5-year
and 10-year CRC relative survival rates have increased significantly over the last few
decades and a considerable variation in these rates has been observed across different
world regions or countries.
The US, which represents the nations with the highest HDI, has shown a signifi-
cant increase in overall 5-year and 10-year CRC survival rates. In the US, overall
5-year survival rates for stage I colon and rectal cancer are 92% and 88%, respec-
tively. The 5-year survival rates are 87% and 81% for stage IIA colon and rectal
cancers, respectively, and 65% and 50% for stage IIB colon and recta l cancers,
respectively. These rates are 90% and 83% for stage IIIA colon and rectal cancers,
respectively, and 72% for stage IIIB of both these cancers. The 5-year survival rates
for stage IIIC colon and rectal cancers are 53% and 58%, respectively. The 5-year
survival rates for stage IV, or metastatic colon and rectal cancers are 12% and 13%,
respectively (SEER 2016). Within the US, a relatively decreased overall survival rate
across all stages of colorectal cancer has been observed among st Native Americans,
African Americans, and deprived social class. This has been largely attributed to
126 M. Z. Banday et al.
https://t.me/medicina_free
their economic status, which often manifests as non-availability or less access to
healthy diet and requisite healthcare facilities including prophylactic strategies and
post diagnosis care (Rawla et al. 2018). Based on the data collected between 2009
and 2015, the overall 5-year relative survival rates for colon and rectal cancers have
been estimated to be 63% and 67%, respectively, and 64% for CRC in the US, a
highest-HDI nation (Howlader et al. 2019). The 5-year relative survival rate is
almost 40% for high-HDI nations, even less for medium-HDI countries and overall
5-year relative survival rate worldwide has been estimated to be about 20% (Torre
et al. 2016; American Cancer Society 2020).
5.1.1.4 Risk Modulation Factors
Globally, overall lifetime risk of colorectal cancer development is 4.4% for males
and 4.1% for females. The risk depends on the absence or presence of risk modula-
tion factors, which may be genetic or environmental, non-modifiable or modifiable
and may incre ase or decrease the probability of CRC development. The
non-modifiable or unchangeable risk modulation factors include age, gender, race,
and ethnicity, personal or family history of colonic or rectal polyps, personal or
family history of colorectal cancer, inherited disorders, inflammatory bowel disease
(IBD), cystic fibrosis, cholecystectomy, androgen deprivation therapy, abdominal
radiation, diabetes, and insulin resistance. The modifiable or changeable risk modu-
lation factors include obesity and sedentary lifestyle, diet, smoking, alcohol, and
medications (Rawla et al. 2019; Sameer 2013a, b).
Non-Modifiable or Unchangeable Risk Modulation Factors
The risk of CRC development increases with age, with sharp increase observed past
the age of 50 years and individuals with age greater than 50 years account for 90% of
the reported cases of CRC. Further, CRC incidence rate in individuals with age
greater than 65 years has been reported to be as high as 12 times the CRC incidence
rate in individuals with age below 45 years (Arnold et al. 2015; American Cancer
Society 2020). The risk of CRC development is generally higher in males in
comparison with females (Purim et al. 2013). An overall 1.5 times more CRC
incidence has been reported in males in comparison with females, irrespective of
age and geographical location (Bray et al. 2018). The exact reason behind this
gender based difference in CRC incidence is still unknown though hormonal
differences and possible differences in exposure levels to cancer promoting factors
between the two sexes may partly explain this relationship. However, in comparison
with males, females are at a higher risk of developing cancer on the right side of the
colon which is highly aggressive, fatal, and associated with higher mortality rate in
comparison to cancer on the left side of the colon (Kim et al. 2015). With regard to
race and ethnicity, higher CRC inci dence and lower 5-year and 10-year relative
survival rates have been reported among Native Americans and African Americans
in comparison with white Americans and Hispanic Americans, which among them
have a comparable CRC incidence and CRC related mortality rates (Lansdorp-
Vogelaar et al. 2012).
5 Colorectal Cancer and Genetic Polymorphism in Key Regulatory Low... 127
https://t.me/medicina_free
The risk of CRC development increases significantly with family history of
colorectal cancer. Colorectal cancer diagnosed at the age of 50 years or more in a
first-degree family relation increases the risk for CRC by two times. The risk of CRC
development is three times if CRC is diagnosed in a first-degree family relation at the
age of 50 years or less. CRC in two or more family members increases the risk of this
cancer further. Overall, the family history of colorectal cancer increases the CRC risk
by two to four times. There is an increased risk also if the disease is present in a
second-degree family relation or beyond. It has been reported that almost 15 – 20% of
all CRC cases arise due to the presence of this disease in the family (Kuipers et al.
2015; De Rosa et al. 2015). There are a number of inherited disorders, which
increase the risk of colorectal cancer development. Colorectal cancer, which arises
due to inherited disorders, is known as hereditary colorectal cancer. About 5–10% of
all the cases of CRC result from inherited disorders. Lynch syndrome is the most
common inherited disorder associated with CRC with 2–4% of all CRC cases
attributed to it. The probability of CRC development in individuals with Lynch
syndrome and age 50 years or less is 20% and it is 50% in individuals with Lynch
syndrome and age 51–70 years (Bonadona et al. 2011).
Another inherited disorder, familial adenomatous polyposis (FAP) has been
associated with about 1% of all CRC cases and there is almost 100% probability
of CRC development in individuals with this disorder even before they attain the age
of 40 years (American Cancer Society 2020). Besides these two, other inherited
disorders have been associated with increased risk of CRC development. The
inflammatory bowel disease (IBD) is characterized by persistent and long-term
colonic inflammation and mainly results from two autoimmune disorders or patho-
genic conditions, ulcerative colitis (UC), and Crohn’s disease (CD). Both disorders
have been associated with an increased CRC risk and 1–2% of all CRC cases have
been attributed to these two conditions. The relative CRC risk associated with
ulcerative colitis is more in comparison with Crohn’s disease. It has been estimated
that about 2%, 8%, and 18% of individuals with ulcerative colitis develop CRC at
10 years, 20 years, and 30 years of disease duration, respectively (Lakatos and
Lakatos 2008). For Crohn’s disease, 3% and 8% of individuals develop CRC at
10 years and 30 years of disease duration, respectively (Canavan et al. 2006). Cystic
fibrosis has been associated with ten times increased risk of colorectal cancer
development (Yamada et al. 2018). Cholecystectomy has been associated with an
increased risk of colon cancer, in particular, the cancers of right-sided and proximal
colon (Lagergren et al. 2001). A meta-analysis study has shown that cholecystec-
tomy increases the risk of CRC by 22% (Zhang et al. 2017). Androgen deprivation
therapy (ADT) or androgen suppression therapy is the most important treatment
procedure for androgen-responsive prostate cancer. Androgens or male sex
hormones, mainly testosterone and dihydrotestosterone (DHT) promote the growth
and progression of various prostate diseases including prostate cancer (Eder et al.
2001). Androgen deprivation therapy is used to bring down the levels of androgens
in the body to prevent them from promoting prostate carcinogenesis. ADT based on
surgical castration (orchiectomy) and gonadotropin-releasing hormone (GnRH)
agonists has been associated with increased risk of colorectal cancer. Orchiectomy
128 M. Z. Banday et al.
https://t.me/medicina_free
and gonadotropin-releasing hormone (GnRH) agonists have been reported to
increase the risk of CRC by 37% and 31%, respectively (Gillessen et al. 2010).
Radiation therapy used for the treatment of childhood abdominal cancers and
adult cancers, in particular, prostate cancer has also been associated with an
increased risk o f colorectal cancer development. A radiation dose at 40 Gy has
been associated with 5–10 times increased risk of developing secondary solid
cancers including secondary CRC. Cancer therapy based on alkylating agents has
been associated with eight to nine times increased risk of secondary CRC develop-
ment (Berrington de Gonzalez et al. 2013; Nottage et al. 2012; Desautels et al. 2016).
Diabetes has been associated with an increased risk of CRC independent of various
shared risk factors including obesity and low physical activity (sedentary lifestyle).
Various studies have reported 18–27% increased CRC risk due to diabetes (Guraya
2015; Jiang et al. 2011; Pang et al. 2018). Figure 5.2 provides a graphical represen-
tation of non-modifiable or unchangeable risk modulation factors for CRC
development.
Modifiable or Changeable Risk Modulation Factors
Obesity and sedentary lifestyle have been associated with an increased risk of
colorectal cancer development. Obesity in general and abdominal obesity in partic-
ular have been reported to increase the risk of colon cancer in males by 50% and
females by 20% and obesity related increase in risk of rectal cancer development has
been reported to be 20% in males and 10% in females. An increase in weight by 5 kg
Fig. 5.2 Non-modifiable or unchangeable risk modulation factors for CRC development
5 Colorectal Cancer and Genetic Polymorphism in Key Regulatory Low... 129
https://t.me/medicina_free
has been reported to increase the risk of CRC by 3% (Karahalios et al. 2016).
Increase in BMI by one unit has been associated with 2–3% increased risk of CRC
(World Cancer Research Fund 2011). Sedentary lifestyle has been reported to
increase the risk of colorectal cancer development by 50% and in contrast, regular
physical activity has been reported to decrease the risk of colorectal cancer develop-
ment by 25%. Sedentary lifestyle is an important causative factor for obesity and
obesity has also been associated with an increased CRC risk but the obesity related
risk is independent of CRC risk due to sedentary lifestyle but both these risk factors
may act in a cumulative manner to increase the CRC risk. Obesity and sedentary
lifestyle have also been associated with decreased overall survival in CRC (Robsahm
et al. 2013).
Diet is an important CRC risk modulation factor, which can play a protective role
against CRC or promote colorectal carcinogenesis. Diet, which consists of fresh
fruits and vegetables, whole grains, milk and supply enough or recommended
quantities of fiber, calcium, vitamins including vitamin D has been associated with
a decreased risk of colorectal cancer development (Song et al. 2015). In contrast, the
diet, which consists of red and processed meat, has been associated with an increased
risk of colorectal cancer development (Song et al. 2015). Consumption of red meat
and processed meat has been reported to increase the risk of CRC development by
12% and 15%, respectively (Zhao et al. 2017). Digestion of high temperature cooked
red meat and processed meat promotes the formation of N-nitroso compounds,
heterocyclic amines, polycyclic hydrocarbons, genotoxic and cytotoxic aldehydes,
all of which are categorized as potentially carcinogenic substances (Bastide et al.
2011; Santarelli et al. 2008).
Alcohol consumption and smoking have also been associated with an increased
risk of colorectal cancer development. Alcohol metabolism produces acetaldehyde, a
potential carcinogen that may increase the risk of CRC. Moderate alcohol consump-
tion and excessive alcohol consumption have been reported to increase the risk of
CRC development by 20% and 50%, respectively (Fedirko et al. 2011).
Tobacco smoking is a well-characterized colorectal cancer risk factor. Long-term
smoking has been reported to increase the CRC incidence by up to 10.8% and CRC
related mortality by up to 12% (Liang et al. 2009; Zisman et al. 2006). Long-term
exposure to potent carcinogenic agents such as nicotine, NNN (N-
0
-nitrosonornicotine), NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) and
other nitrosamines in tobacco and tobacco smoke and their metabolites promotes
formation and growth of adenomatous polyps and their tumorigenic progression into
metastatic CRC (Liang et al. 2009; Zisman et al. 2006; Botteri et al. 2008). Several
medications have been associated with a decreased risk of colorectal cancer. Long-
term and continued use of low-dose non-steroidal anti-inflammatory drugs
(NSAIDs) such a s aspirin has been reported to decrease the risk of CRC. NSAIDs
decrease gastrointestinal tract (GIT) inflammation and directly or indirectly inhibit
various pro-tumorigenic mediators including cyclooxygenase-2 (COX-2) and
prostaglandins [prostaglandin E2 (PGE2) and others] and modulate various tumor
promoting processes including cell proliferation, angiogenesis, and apoptosis. Use
of NSAIDs such as aspirin in CRC has also been associated with low aggressiveness
130 M. Z. Banday et al.
https://t.me/medicina_free
of cancer and increased overal l survival (Rothwell et al. 2010; Algra and Rothwell
2012; Wang and DuBois 2013). However , long-term and continued use of NSAIDs
has been associated with increased risk of GIT bleeding and cardi ovascular disease
and general use of NSAIDs for CRC prevention has not been recommended
(Rothwell et al. 2010). Statins such as atorvastatin have also been reported to
decrease CRC risk (Bardou et al. 2010; Liu et al. 2014).
Long-term and continued use of oral bisphosphonates (BPs), characterized by
anti-resorptive properties and used in the treatment and management of osteoporosis
and other high bone turnover diseases including metastatic diseases of bones
have been reported to decrease the risk of CRC by 13% (Thosani et al. 2013).
Continued use of angiotensin-converting enzyme (ACE) inhibitors (ACE-I) for
treatment of hypertension, for a period of 1 year has been reported to decrease the
CRC risk by 16% and continued use for a period of 5 years has been reported to
decrease the CRC risk by 25%. No further decrease in CRC risk has been reported
beyond 5-year period (Makar et al. 2014). The modifiable risk modulation factors
largely explain the differences in CRC incidence with socioeconomic status and
geographical location (Doubeni et al. 2012). Figure 5.3 provides a graphical repre-
sentation of modifiable or changeable risk modulation factors for CRC development.
5.1.2 Classification and Grading
Histologically, most of the colorectal tumors (almost 95%) are adenomas (benign
form) or adenocarcinomas (malignant form), which originate from the intestinal
mucosa, more specifically, epithelium derived intestinal glands (Hamilton et al.
2010). Carcinoid tumors derived from gastrointestinal neuroendocrine cells, gastro-
intestinal stromal tumors derived from interstitial cell of Cajal (ICC) and lymphomas
are other types of colorectal cancer, which occur but rarely (O’Brien et al. 2004;
Zauber et al. 2002; Fleming et al. 2012). The cancers of cecum and ascending colon
Fig. 5.3 Modifiable or changeable risk modulation factors for CRC development
5 Colorectal Cancer and Genetic Polymorphism in Key Regulatory Low... 131
https://t.me/medicina_free
(right-sided colon cancer) mostly grow outwards from the epithelial surface into the
bowel wall (exophytic growth) whereas the cancers of descending colon and sig-
moid colon (left-sided colon cancer) show circumferential growth and may lead to
bowel obstruction. More than 95% of the tumor in a well-differentiated adenocarci-
noma involves glandular epithelium, in moderately differentiated adenocarcinoma,
glandular epithelium accounts for 50–95% of the tumor and in poorly differentiated
adenocarcinoma <50% of tumor involves glandular epithelium. From a diagnostic
perspective, moderately differentiated adenocarcinoma constitutes almost 70% of all
the clinically diagnosed colorectal tumors. The well-differentiated adenocarcinoma
and poorly differentiated adenocarcinoma constitute about 10% and 20% of all the
clinically diagnosed colorectal tumors, respectively (Fleming et al. 2012; Hamilton
et al. 2010).
Like other cancers, colorectal tumors can be categorized into different stages,
each representing the pathological progression of the disease. This categorization
into various stages can be made using any of the several systems for CRC staging, in
particular, the TNM system, the Dukes system, and the Astler-Coller system. Of the
various systems used for CRC staging, the TNM system developed by the American
Joint Committee on Cancer (AJCC) is the continually updated and the most accurate
staging system, which allows comprehensive and distinct elucidation of the primary
cancers and provides almost conclusive description of cancer progression (Akkoca
et al. 2014; Brierley et al. 2017).
The TNM system consists of three different parameters or characteristics, ‘T’,
‘N’, and ‘M’. The ‘T’ of TNM system delineates the degree of primary tumor growth
into the wall of intestine and surrounding tissues or organs; ‘N’ delineates the
expanse of tumors into regional (adjacent) lymph nodes, and ‘ M’ details the spread
of CRC to other tissues or body organs (metastasis). CRC metastasizes mostly into
the liver, which is succeeded by the lungs. The ‘T’, ‘N’, and ‘M’ are assigned
numbers from zero to four and these numbers denote the increasing progression or
degree of disease. The number ‘x’ instead of ‘zero to four’ is used to denote the
absence of specific description (null description). The letters ‘T’, ‘ N’ , and ‘M’ each
with a specific allowed number assigned are combined together and different
combinations are possible based on the different numbers assigned to each of the
letters (Akkoca et al. 2014; Brierley et al. 2017).
The descriptions or details provided by each of the three letter combinations with
different numbers assigned to each of letters are used for tumor staging. Various
tumor stages can be described ranging from least advanced to most advanced. The
tumor stages are assigned Roman numerals I, II, III and IV and identifi
ed accord-
ingly starting from stage I through stage II and stage III to stage IV. Stage I and stage
IV represent the least advanced and the most advanced stages respectively. The
stages II, III and IV can be divided into sub stages, which are represented by
assigning letters ‘a’, ‘b’ or ‘c’ (‘A’, ‘B’ or ‘C’) to the stage name (Akkoca et al.
2014; Brierley et al. 2017). The comparison between and the general characteristics
of the TNM system, the Dukes system and the Astler-Coller system are given in
Table 5.1.
132 M. Z. Banday et al.
https://t.me/medicina_free
Table 5.1 Comparison between and the general characteristics of the TNM system, the Dukes
system, and the Astler-Coller system
AJCC/TNM
Full
dukes
Astler-
Coller Description
Stage
0
Tis, N0,
M0
A A Initial stage carcinoma (carcinoma in situ); tumor
invasion limited to mucosa, not beyond inner muscle
layer or muscularis mucosa (tis); lymph node not
involved (N0); no distant metastasis (M0)
Stage
I
T1, N0,
M0
A B1 Tumor invasion into submucosa (T1); lymph node not
involved (N0); no distant metastasis (M0)
T2, N0,
M0
B2 Tumor invasion into muscularis propria (T2); lymph
node not involved (N0); no distant metastasis (M0)
Stage
IIA
T3, N0,
M0
B B2 Tumor invasion into subserosa (T3); lymph node not
involved (N0); no distant metastasis (M0)
Stage
IIB
T4a, N0,
M0
Tumor invasion into serosa (visceral peritoneum/the
outermost lining of the intestines) (T4a); lymph node
not involved (N0); no distant metastasis (M0)
Stage
IIC
T4b, N0,
M0
Tumor growth across colon/rectal wall and
attachment to or invasion into nearby tissues or
organs (T4b); lymph node not involved (N0); no
distant metastasis (M0)
Stage
IIIA
T1, N1,
M0
C C1 Tumor invasion into submucosa (T1); one to three
regional lymph nodes involved (N1); no distant
metastasis (M0)
T2, N1,
M0
Tumor invasion into muscularis propria, one to three
regional lymph nodes involved (N1); no distant
metastasis (M0)
T1, N2a,
M0
Tumor invasion into submucosa (T1); four to six
nearby/ regional lymph nodes involved (N2a); no
distant metastasis (M0)
Stage
IIIB
T1, N2b,
M0
C C1 Tumor invasion into submucosa (T1); seven or more
nearby/regional lymph nodes involved (N2b); no
distant metastasis (M0)
T2, N2b,
M0
Tumor invasion into muscularis propria (T2); seven
or more nearby/regional lymph nodes involved
(N2b); no distant metastasis (M0)
T2, N2a,
M0
Tumor invasion into muscularis propria (T2); four to
six nearby/regional lymph nodes involved (N2a); no
distant metastasis (M0)
T3, N2a,
M0
C2 Tumor invasion into subserosa (T3); four to six
nearby/regional lymph nodes involved (N2a); no
distant metastasis (M0)
T3, N1,
M0
Tumor invasion into subserosa (T3); one to three
regional lymph nodes involved (N1); no distant
metastasis (M0)
T4a, N1,
M0
Tumor growth across serosa (visceral peritoneum),
the outermost lining of the intestines (T4a); one to
three regional lymph nodes involved (N1); no distant
metastasis (M0)
(continued)
5 Colorectal Cancer and Genetic Polymorphism in Key Regulatory Low... 133
https://t.me/medicina_free
5.2 Genetic Background of Colorectal Cancer
The pathogenesis of colorectal cancer is very intricate and heterogeneous and the
disease arises due to genomic instability, which in turn results from varied and
numerous genetic and epigenetic modifications, which often involve point mutations
and changes in chromosome structure and number. The genomic instability leads to
dysregulation or dysfunction of a number of signaling pathways, whi ch are involved
in maintenance, and regulation of critical cellular processes including cellular
metabolism, cell survival, cell proliferation, cell differentiation, and apoptosis.
Most of the colorectal tumors (almost 95%) are adenomas (benign form) or
adenocarcinomas (malignant form), which originate from epithelium derived intes-
tinal glands. In most cases of CRC (90–95%), the tumorigenic transformation of
epithelium into adenomas and further into adenocarcinomas occurs through a well-
characterized and sequential multi-step process, which involves specific genetic and
histological changes and is often identified as adenoma-carcinoma sequence of
colorectal carcinogenesis (Vogelstein et al. 1988; Armaghany et al. 2012).
Table 5.1 (continued)
AJCC/TNM
Full
dukes
Astler-
Coller Description
Stage
IIIC
T3, N2b,
M0
C C2 Tumor invasion into subserosa (T3); seven or more
nearby/regional lymph nodes involved (N2b); no
distant metastasis (M0)
T4, N2b,
M0
Tumor invasion into other organs/structures and/or
perforation of visceral peritoneum (T4); seven or
more nearby/regional lymph nodes involved (N2b);
no distant metastasis (M0)
T4a, N2a,
M0
Tumor growth across serosa (visceral peritoneum),
the outermost lining of the intestines (T4a); four to six
nearby/regional lymph nodes involved (N2a); no
distant metastasis (M0)
T4b, N1,
N2, M0
Tumor growth across colon/rectal wall and
attachment to or invasion into nearby tissues or
organs (T4b); one to four or more nearby/regional
lymph nodes involved (N1, N2); no distant metastasis
(M0)
Stage
IVA
AnyT,
AnyN,
M1a
D D Metastatic spread to one distant organ or set of distant
lymph nodes (M1a)
Stage
IVB
AnyT,
AnyN,
M1b
Metastatic spread to multiple distant organs or set of
distant lymph nodes or spread to distant parts of the
peritoneum (the lining of the abdominal cavity)
(M1b)
134 M. Z. Banday et al.
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана