Colorectal Cancer

Overview

Epidemiology

• 3rd most common cancer (among both men and women)
• 2nd most common cause of death due to cancer in the United States
• In the United States, incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency and mortality Mortality All deaths reported in a given population. Measures of Health Status rates have been declining.
• The majority are adenocarcinomas.
• Most colorectal cancers (CRCs) arise from polyps (adenomatous or serrated).

Risk factors

• Age ≥ 45 (94% of new CRC cases)
• Hereditary syndromes:
  • Familial adenomatous polyposis Familial Adenomatous Polyposis Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis ( FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis)
  • Hereditary non-polyposis colorectal cancer Hereditary non-polyposis colorectal cancer Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome ( HNPCC HNPCC Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome) or Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome
  • Peutz-Jeghers syndrome Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome ( PJS PJS Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome)
  • MUTYH-associated polyposis (MAP): mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the base excision repair Base excision repair DNA Repair Mechanisms gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutY homolog
  • Family history Family History Adult Health Maintenance of CRC
• Colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy pathologies:
  • Inflammatory bowel disease (IBD)
  • Large adenomatous polyps or previous CRC
• Other medical conditions:
  • Cystic Cystic Fibrocystic Change fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans
  • Abdominopelvic radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Conditions with increased insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin or insulin-like growth factor (e.g., diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, acromegaly Acromegaly A condition caused by prolonged exposure to excessive human growth hormone in adults. It is characterized by bony enlargement of the face; lower jaw (prognathism); hands; feet; head; and thorax. The most common etiology is a growth hormone-secreting pituitary adenoma. Acromegaly and Gigantism, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity)
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus bovis bacteremia Bacteremia The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. Glycopeptides
  • Renal transplantation
• Lifestyle and social factors:
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases and alcohol consumption (> 4 drinks/day)
  • Diet (increased fat, red and processed meat, low fiber)
  • Low socioeconomic status

Etiology

Colorectal polyps

• Abnormal tissue outgrowths arising from the colonic mucosa and extending into the lumen
• Most common lesions from which CRC arises
• Morphology:
  • Sessile: polyp without a stalk, with growth adjacent to the mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast
  • Pedunculated: polyp with a stalk
• 30% of the population has polyps by the age of 50.

Types of polyps:

• Inflammatory polyps (non-neoplastic)
• Hamartomatous polyps (↑ CRC risk if associated with PJS PJS Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome)
• Sessile serrated lesions:
  • Sessile serrated adenomas/polyps (SSA/ Ps PS Invasive Mechanical Ventilation)
  • Traditional serrated adenomas (TSAs)
  • Hyperplastic Hyperplastic Colon Polyps polyps (histologically similar to SSA; non-neoplastic)
• Adenomatous polyps:
  • Tubular (> 80%)
  • Villous adenomas (majority are sessile)
  • Tubulovillous 

High-risk polyps:

• Polyps > 1 cm in size
• Adenomas with villous features (CRC risk > 3 times that of tubular adenomas) or high-grade dysplasia
• Serrated polyps/adenomas

Cancer development

Most polyps are benign Benign Fibroadenoma. Malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology is affected by a series of mutations and environmental factors.

Mutations:

• Germline mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations:
  • Occurs before fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week
  • Can be transmitted (from parent to offspring)
  • Found in the common inherited syndromes (e.g., FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis, Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome), which account for < 10% of CRCs
• Somatic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations:
  • Spontaneous mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in sperm/ovum or zygote Zygote The fertilized ovum resulting from the fusion of a male and a female gamete. Fertilization and First Week
  • Parent does not have the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, but future offspring can inherit.
  • Found in sporadic Sporadic Selective IgA Deficiency CRCs (> 70%)

APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis ( adenomatous polyposis coli Adenomatous polyposis coli A polyposis syndrome due to an autosomal dominant mutation of the APC genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:

• Most CRCs begin with adenomatous polyposis coli Adenomatous polyposis coli A polyposis syndrome due to an autosomal dominant mutation of the APC genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis ( APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics inactivation (either by germline or somatic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations).
• CRCs take 10–15 years to develop but can advance in a shorter time under certain conditions.
• APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis protein, encoded by APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, promotes β-catenin degradation.
• Without APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis protein:
  • β-catenin activates T cell factor (Tcf)–dependent transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of specific target genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
  • These genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure include MYC and cyclin D1 Cyclin D1 Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin D1 is the result of bcl-1 rearrangement, a t(11; 14) translocation, and is implicated in various neoplasms. Non-Hodgkin Lymphomas ( oncogenes Oncogenes Genes whose gain-of-function alterations lead to neoplastic cell transformation. They include, for example, genes for activators or stimulators of cell proliferation such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of ‘v-‘ before oncogene symbols indicates oncogenes captured and transmitted by retroviruses; the prefix ‘c-‘ before the gene symbol of an oncogene indicates it is the cellular homolog (proto-oncogenes) of a v-oncogene. Carcinogenesis), which promote proliferation.
• APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis mutations: the initiating event for adenoma formation, but multiple genetic hits are required for CRC progression

Pathophysiology

APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis

Adenomatous polyposis coli Adenomatous polyposis coli A polyposis syndrome due to an autosomal dominant mutation of the APC genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis is an initial gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.

• Most adenomas and CRCs begin with APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics inactivation (either by germline or somatic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations).
• After the initiating event, CRCs take 10–15 years to develop (shorter time in certain conditions).
• APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis protein, encoded by APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, promotes β-catenin degradation.
• Without APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis protein:
  • β-catenin (of the WnT pathway) activates Tcf–dependent transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of specific target genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
  • These genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure include MYC and cyclin D1 Cyclin D1 Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin D1 is the result of bcl-1 rearrangement, a t(11; 14) translocation, and is implicated in various neoplasms. Non-Hodgkin Lymphomas ( oncogenes Oncogenes Genes whose gain-of-function alterations lead to neoplastic cell transformation. They include, for example, genes for activators or stimulators of cell proliferation such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of ‘v-‘ before oncogene symbols indicates oncogenes captured and transmitted by retroviruses; the prefix ‘c-‘ before the gene symbol of an oncogene indicates it is the cellular homolog (proto-oncogenes) of a v-oncogene. Carcinogenesis), which promote proliferation.

Molecular mechanisms of tumorigenesis

Multiple genetic hits are required for CRC progression.

Accumulation of mutations and molecular events:

Accumulation of mutations and molecular events (e.g., genetic alteration, DNA methylation DNA methylation Addition of methyl groups to DNA. DNA methyltransferases (DNA methylases) perform this reaction using s-adenosylmethionine as the methyl group donor. Epigenetic Regulation, overexpression) contributes to carcinogenesis Carcinogenesis The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years. Carcinogenesis.

• Chromosomal instability (CIN):
  • Structural chromosomal aberrations chromosomal aberrations Abnormal number or structure of chromosomes. Chromosome aberrations may result in chromosome disorders. Chromosome Testing (deletions or loss of heterozygosity)
  • Results in either promotion of oncogenes Oncogenes Genes whose gain-of-function alterations lead to neoplastic cell transformation. They include, for example, genes for activators or stimulators of cell proliferation such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of ‘v-‘ before oncogene symbols indicates oncogenes captured and transmitted by retroviruses; the prefix ‘c-‘ before the gene symbol of an oncogene indicates it is the cellular homolog (proto-oncogenes) of a v-oncogene. Carcinogenesis or reduction of tumor Tumor Inflammation suppressor genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure (TSGs)
  • Seen in genetic alterations of APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis
  • Other genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure: DCC, TP53/p53, and SMAD4 ( tumor Tumor Inflammation suppressor genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure) or KRAS (a proto-oncogene)
  • 85% of CRCs develop through this mechanism.
• Microsatellite instability (MSI):
  • Also called mutator phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics/ mismatch repair Mismatch repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome pathway
  • Microsatellites: repeated, abnormal, short sequences of nucleotide bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance caused by mismatch repair Mismatch repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome deficiency
  • Cause: germline mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure MLH1, MSH2, or PMS2 leading to dysfunctional DNA mismatch repair DNA Mismatch Repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. DNA Repair Mechanisms ( MMR MMR A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome) enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Microsatellite accumulation: found in MSI-high (MSI-H) tumors
  • Biologic hallmark of Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome
  • Seen in up to 15% of sporadic Sporadic Selective IgA Deficiency CRCs
• CpG island methylator phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics (CIMP+) pathway:
  • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure hypo- or hypermethylation can change gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expression.
  • High methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids of CpG islands ( cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids followed by a guanine Guanine Nucleic Acids base, linked by phosphodiester bond Phosphodiester bond DNA Types and Structure) occurs in TSG.
  • Methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids inactivates TSG, leading to tumor Tumor Inflammation progression.
  •  Found in CIMP+ tumors

Cyclooxygenase Cyclooxygenase Nonsteroidal Antiinflammatory Drugs (NSAIDs) (COX)-2 overexpression: 

• COX-2: overexpressed in 43% of adenomas and 86% of carcinomas
• COX-2 inhibition reduces the number of intestinal polyps.

Morphologic mechanisms of tumorigenesis

Adenoma-carcinoma sequence:

• Sequence followed by most CRCs
• Progression: early adenoma (tubular or tubulovillous) → advanced adenoma (villous) → adenocarcinoma
• Adenomatous polyps:
  • Develop with disrupted epithelial renewal
  • Replacement of surface cell lining becomes dysplastic as the adenomas increase in size.
• APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations common
• Associated molecular pathway(s): CIN

Serrated polyp pathway:

• Serrated polyps: also have malignant potential 
• Seen in 10%–20% of cases
• Progression: sessile serrated polyp Sessile serrated polyp Colon Polyps/adenoma → adenocarcinoma
• BRAF oncogene activation with KRAS mutations noted
• Associated molecular pathway/s:
  • CIMP (major mechanism that drives the serrated pathway toward CRC)
  • MSI

Clinical Presentation

General clinical findings

• Often asymptomatic, with CRC detected on screening Screening Preoperative Care colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening
• Symptomatic:
  • Systemic features: weakness, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
  • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types in an elderly patient indicates colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy cancer until proven otherwise.
  • Dependent on location

Right-sided carcinomas

• Obstructive symptoms are not common:
  • Stool in the area ( ileocecal valve Ileocecal valve The valve, at the junction of the cecum with the colon, that guards the opening where the ileum enters the large intestine. Small Intestine: Anatomy to ascending colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy) is still liquid.
  • Lumen is larger (than left side).
• Lesions can grow, ulcerate, and lead to occult blood loss:
  • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types: fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, angina, palpitations Palpitations Ebstein’s Anomaly
  • Melena Melena The black, tarry, foul-smelling feces that contain degraded blood. Gastrointestinal Bleeding 

Left-sided carcinomas

• From the transverse to the descending colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy, stool becomes formed.
• Thus, cancerous lesions can impede passage of stool, causing:
  • Abdominal cramping Abdominal cramping Norovirus or colicky pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Changes in bowel habits ( constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation alternating with loose stools)
  • Blood-streaked stools or hematochezia Hematochezia Gastrointestinal Bleeding
  • Decreased stool caliber due to obstruction

Rectal cancers

• Palpable ulcerating mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast on rectal exam
• Tenesmus 
• Rectal bleeding
• Obstruction

Metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis

• CRCs metastasize by direct extension Extension Examination of the Upper Limbs or via hematogenous Hematogenous Hepatocellular Carcinoma (HCC) and Liver Metastases and lymphatic route. 
• Sites of metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis:
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy (1st site for intestinal tumors): abdominal distention Abdominal distention Megacolon, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites, hepatomegaly
  • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy (1st site for distal rectal tumors): cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea (may be from pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion), hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis

Diagnosis

Colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening

• Diagnostic test of choice
• Visualization of lesion(s) and tissue sampling ( biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma or lesion removal) can be performed.
• Screening Screening Preoperative Care colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening:
  • Asymptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • For the population with average risk: performed at age 45 years and above
  • Screening Screening Preoperative Care at a younger age depends on conditions and risks.
• Diagnostic colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening:
  • Performed in symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Indicated for those with abnormal imaging studies
• Findings:
  • Polyps 
  • Carcinoma:
    • Bulky exophytic Exophytic Retinoblastoma masses
    • Annular Annular Dermatologic Examination constricting lesions

Computed tomography (CT) colonography

• Virtual colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening 
• Requires mechanical preparation
• Can be used in incomplete colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening (e.g., obstruction, tortuous colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy) or as an initial diagnostic test
• Colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening remains the gold standard.
• Limitations Limitations Conflict of Interest:
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should be able to pass flatus.
  • Cannot perform biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma or lesion removal

PILLCam 2

• Colon capsule endoscopy Colon capsule endoscopy A direct visualization test in which the patient swallows a capsule with wireless video cameras. Images are taken as the capsule goes through the intestine. Colorectal Cancer Screening: Patient swallows a capsule-sized endoscope.
• Considered in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with incomplete colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship should have no obstruction.

Further imaging studies

• Air contrast barium enema Barium enema X-ray examination of lower gastrointestinal tract. Imaging is done while a barium compound (e.g., barium sulfate) fills the large intestine via the rectum as a contrast material. Diarrhea may show apple core lesion.
• CT scan:
  • For preoperative staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis
  • Detects associated complications (e.g., obstruction, perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis, fistula Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal Fistula)
  • Detects metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
• Pelvic magnetic resonance imaging (MRI) or transrectal endoscopic ultrasonography (US):
  • For rectal cancers 
  • For assessment of cancer depth through the rectal wall and perirectal lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes

Laboratory tests

• Carcinoembryonic antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination ( CEA CEA A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the response to colon cancer treatment. Serum Tumor Markers):
  • Tumor Tumor Inflammation marker for CRC; obtained with proven CRC
  • Not used for screening Screening Preoperative Care or diagnostic test
  • Prognostic value: preoperative CEA CEA A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the response to colon cancer treatment. Serum Tumor Markers > 5 ng/mL has worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
  • Non-normalization of values after surgery: indicative of persistent disease
• Complete blood count (CBC): may show anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
• Metabolic panel:
  • May show additional metabolic abnormalities
  • Elevated alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma: most common liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy abnormality associated with liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis

Staging

After establishing the diagnosis of CRC, staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis the disease is needed for appropriate management.

TNM ( tumor Tumor Inflammation, node, metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis) staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis system: 

• Determines disease extent
• Findings based on:
  • Preoperative examination (e.g., ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites, lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes)
  • Imaging results:
    • CT scan (chest/abdomen/ pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy)
    • MRI (identifies more metastatic hepatic lesions)
    • Transrectal endoscopic US (for rectal cancer)
  • Endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD) (with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma) and lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

Prevention

• Adults (50–59 years of age):
  • United States Preventive Services Taskforce: daily low-dose aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) for primary prevention of CRC
  • Individuals should have:
    • No bleeding risk 
    • At least 10 years of life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids
    • ≥ 10% of 10-year CVD risk
• Individuals with average risk:
  • Screening Screening Preoperative Care is initiated at 45 years of age
  • Options for screening Screening Preoperative Care:
    • Annual high-sensitivity guaiac-based fecal occult blood test High-sensitivity guaiac-based fecal occult blood test Stool-based test – Identifies hemoglobin in stool Colorectal Cancer Screening ( HSgFOBT HSgFOBT Stool-based test – Identifies hemoglobin in stool Colorectal Cancer Screening)
    • Annual fecal immunochemical test Fecal immunochemical test Stool-based test – Measures hemoglobin in the stool Colorectal Cancer Screening (FIT)
    • sDNA-FIT test every 3 years
    • Flexible sigmoidoscopy Sigmoidoscopy Endoscopic examination, therapy or surgery of the sigmoid flexure. Colorectal Cancer Screening every 5 years (limited to distal part of the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy)
    • Colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening every 10 years
    • CT colonography CT colonography A non-invasive imaging method that uses computed tomographic data combined with specialized imaging software to examine the colon. Colorectal Cancer Screening every 5 years
  • A positive screening Screening Preoperative Care stool-based test, CT colonography CT colonography A non-invasive imaging method that uses computed tomographic data combined with specialized imaging software to examine the colon. Colorectal Cancer Screening, or sigmoidoscopy Sigmoidoscopy Endoscopic examination, therapy or surgery of the sigmoid flexure. Colorectal Cancer Screening warrants a colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening. 
  • Screening Screening Preoperative Care generally not recommended after age 75
• Individuals with a family history Family History Adult Health Maintenance of CRC/advanced adenoma/advanced serrated lesion:
  • Colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening at age 40 or 10 years earlier than the age of diagnosis of the 1st-degree relative (whichever comes first)
  • Repeat every 5 years

Management

General principles

• Resection of primary cancer:
  • Treatment of choice for almost all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with resectable lesions
  • Can be laparoscopic or open surgery
• Regional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node dissection (at least 12 lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes) is performed with resection ( aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS in determining additional adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy).
• Chemotherapy Chemotherapy Osteosarcoma:
  • Adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination chemotherapy Chemotherapy Osteosarcoma: given depending on stage of colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy carcinoma
  • Neoadjuvant chemotherapy Neoadjuvant Chemotherapy Osteosarcoma and/or radiotherapy: given for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with rectal carcinoma ( T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones or higher, node-positive cancers) 
  • Chemotherapy Chemotherapy Osteosarcoma regimens:
    • FOLFOX ( 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy/ 5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy + folinic acid/leucovorin + oxaliplatin Oxaliplatin An organoplatinum complex in which the platinum atom is complexed with 1, 2-diaminocyclohexane, and with an oxalate ligand which is displaced to yield active oxaliplatin derivatives. These derivatives form inter- and intra-strand DNA crosslinks that inhibit DNA replication and transcription. Oxaliplatin is an antineoplastic agent that is often administered with fluorouracil and folinic acid in the treatment of metastatic colorectal neoplasms. Alkylating Agents and Platinum) regimen
    • FOLFIRI ( 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy + folinic acid + irinotecan Irinotecan A semisynthetic camptothecin derivative that inhibits DNA topoisomerase I to prevent nucleic acid synthesis during s phase. It is used as an antineoplastic agent for the treatment of colorectal neoplasms and pancreatic neoplasms. Microtubule and Topoisomerase Inhibitors)
    • CAPOX/XELOX: oral capecitabine Capecitabine A deoxycytidine derivative and fluorouracil prodrug that is used as an antineoplastic antimetabolite in the treatment of colon cancer; breast cancer and gastric cancer. Antimetabolite Chemotherapy (Xeloda) used with oxaliplatin Oxaliplatin An organoplatinum complex in which the platinum atom is complexed with 1, 2-diaminocyclohexane, and with an oxalate ligand which is displaced to yield active oxaliplatin derivatives. These derivatives form inter- and intra-strand DNA crosslinks that inhibit DNA replication and transcription. Oxaliplatin is an antineoplastic agent that is often administered with fluorouracil and folinic acid in the treatment of metastatic colorectal neoplasms. Alkylating Agents and Platinum

The stage of CRC and molecular biology (in the case of targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy) dictate the roles of surgical and pharmacologic treatments.

Carcinoma in a polyp

• Endoscopic removal or polypectomy
• When invasive cancer is suspected, tattooing is done (for localization if an invasive lesion is found or if additional therapy/surgery is needed).
• Factors indicating high risk for residual cancer or nodal metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis (consider radical surgery):
  • Poorly differentiated histology
  • Cancer at stalk margin
  • Lymphovascular invasion
  • T2 lesion
  • Invasive carcinoma in a sessile polyp

Colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy cancer stage I–III

• Wide resection of the lesion with regional lymphadenectomy is performed.
• Surgical options:
  • Right hemicolectomy: lesion(s) in the cecum Cecum The blind sac or outpouching area of the large intestine that is below the entrance of the small intestine. It has a worm-like extension, the vermiform appendix. Colon, Cecum, and Appendix: Anatomy and right colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy (can be extended to include transverse colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy)
  • Left hemicolectomy: lesion(s) in the splenic flexure Splenic flexure Small Intestine: Anatomy and left colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy (can be extended to include transverse colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy)
  • Sigmoid Sigmoid A segment of the colon between the rectum and the descending colon. Volvulus colectomy: sigmoid colon Sigmoid colon A segment of the colon between the rectum and the descending colon. Colon, Cecum, and Appendix: Anatomy 
  • Total abdominal colectomy:
    • Synchronous colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy cancers
    • FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis
    • HNPCC HNPCC Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome
• Multivisceral resection with negative margins of the involved structure is recommended in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who have an invasion of the contiguous organs or adhesions with adjacent structures.
• Chemotherapy Chemotherapy Osteosarcoma options:
  • Stage I: no adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy
  • Stage II: controversial; those at high risk of recurrence may benefit from adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy
  • Stage III (node-positive disease):
    • Significant benefit from adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy
    • MSI-H tumors: do not benefit from 5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy based chemotherapy Chemotherapy Osteosarcoma

Metastatic disease or stage IV

• The majority do not have a resectable (curable) disease.
• Chemotherapy Chemotherapy Osteosarcoma: standard treatment and can slow tumor Tumor Inflammation progression
• Isolated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy/lung lesions: Metastatic lesions confined to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy or lung can be resected.
• The addition of biologic agents Biologic Agents Immunosuppressants/ targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy improves survival in suitable patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
• Unresectable metastatic disease:
  • Address the associated complication(s) (obstruction, perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis).
  • Local ablative techniques (cryosurgery, radiofrequency coagulation, embolization Embolization A method of hemostasis utilizing various agents such as gelfoam, silastic, metal, glass, or plastic pellets, autologous clot, fat, and muscle as emboli. It has been used in the treatment of spinal cord and intracranial arteriovenous malformations, renal arteriovenous fistulas, gastrointestinal bleeding, epistaxis, hypersplenism, certain highly vascular tumors, traumatic rupture of blood vessels, and control of operative hemorrhage. Gastrointestinal Bleeding, hepatic intra-arterial chemotherapy Chemotherapy Osteosarcoma) or radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma

Rectal cancer

• Preoperative (neoadjuvant) chemotherapy Chemotherapy Osteosarcoma and/or radiotherapy:
  • In T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones or greater tumors
  • Recommended in all node-positive tumors
• Operative approach post-chemotherapy depends on:
  • Level of the tumor Tumor Inflammation above the anal verge
  • Size and depth of penetration Penetration X-rays
  • Patient’s overall clinical status
• For minimally invasive, small (less than 3 cm), well-differentiated T1 rectal tumors: transanal excision
• Most stage II–III:
  • Low anterior resection (LAR):
    • Sphincter-preserving surgery
    • Moderately or well-differentiated tumors within 2 cm of the anal sphincter 
    • Poorly differentiated tumors within 5 cm of the anal sphincter
  • Abdominoperineal resection (APR):
    • Total rectal excision with a permanent colostomy
    • Moderately or well-differentiated tumors < 2 cm from the anal sphincter
    • Poorly differentiated tumors < 5 cm from the anal sphincter
• Unresectable rectal cancer: palliative treatment with a diverting colostomy

Role of targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy

• Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics profiling of tumor Tumor Inflammation tissue: performed to find specific molecular abnormalities and determine treatment options 
• Used with chemotherapy Chemotherapy Osteosarcoma or on its own when cancer has progressed on chemotherapy Chemotherapy Osteosarcoma
  • Anti-VEGF (vascular epidermal growth factor):
    • Bevacizumab Bevacizumab An anti-vegf humanized murine monoclonal antibody. It inhibits vegf receptors and helps to prevent pathologic angiogenesis. Targeted and Other Nontraditional Antineoplastic Therapy (added to 1st-line chemotherapy Chemotherapy Osteosarcoma)
    • Ramucirumab (2nd-line treatment) 
    • VEGF trap or aflibercept (2nd-line treatment) 
  • Anti-EGFR (epidermal growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors) (added to chemotherapy Chemotherapy Osteosarcoma in stage IV tumors with specific mutations): cetuximab Cetuximab A chimeric monoclonal antibody that functions as an antineoplastic agent through its binding to the epidermal growth factor receptor, where it prevents the binding and signaling action of cell growth and survival factors. Targeted and Other Nontraditional Antineoplastic Therapy, panitumumab Panitumumab Recombinant human monoclonal antibody that binds to and inhibits the function of the epidermal growth factor receptor. It is used in the treatment of egfr-expressing metastatic colorectal cancer that expresses wild-type RAS gene. Targeted and Other Nontraditional Antineoplastic Therapy 
  • BRAF inhibitor (for metastatic CRC that progressed with prior chemotherapy Chemotherapy Osteosarcoma): encorafenib
  • Immune checkpoint inhibitors Immune Checkpoint Inhibitors Drugs that block negative regulator immune checkpoint proteins (e.g., PD-1 receptor and CTLA-4 antigen) thereby increasing suppressed immune activation in immunotherapies. Cancer Immunotherapy (for MSI-H or deficient mismatch repair Mismatch repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome (dMMR) CRC): pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC), nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma
  • Multi-targeted kinase inhibitor (for metastatic, refractory CRC after progression on standard regimens): regorafenib
  • Trifluridine/tipiracil (refractory CRC after progression on standard regimens) 

Follow-up

Carcinoembryonic antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination:

• Monitored for 5 years after the completion of treatment (every 6 months). 
• Serial values after surgery/treatment:
  • Elevation of CEA CEA A glycoprotein that is secreted into the luminal surface of the epithelia in the gastrointestinal tract. It is found in the feces and pancreaticobiliary secretions and is used to monitor the response to colon cancer treatment. Serum Tumor Markers should be retested.
  • When confirmed, testing may include CT scan, positron emission tomography ( PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging), and/or colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening looking for disease recurrence.

Colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening:

• Within a few months after surgical resection, then 1 year after surgery
• Every 3–5 years thereafter

Imaging:

• Annual CT scan (chest and abdomen) for at least 3 years
• Annual CT scan ( pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy) for rectal cancer if pelvic radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma was not given

Familial Colon Cancer Syndromes

Familial adenomatous polyposis Familial Adenomatous Polyposis Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis

• Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
• Occurs due to a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the APC APC A polyposis syndrome due to an autosomal dominant mutation of the apc genes on chromosome 5. The syndrome is characterized by the development of hundreds of adenomatous polyps in the colon and rectum of affected individuals by early adulthood. Familial Adenomatous Polyposis gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
• Hundreds of colorectal adenomas develop (seen in colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening) by age 15 years.
• Risk of CRC: 100%, often detected by age 40 years
• Screening Screening Preoperative Care for cancer: colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening starting at 10–15 years of age
• Treatment: prophylactic colectomy (proctocolectomy or total colectomy), usually by age 20
• Indications for colectomy in FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis:
  • Elective
  • Suspected CRC
  • Presence of colonic dysplasia or neoplasia 
  • Significant increase in polyp number during screening Screening Preoperative Care

Hereditary non-polyposis colorectal cancer Hereditary non-polyposis colorectal cancer Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome/ Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome

• Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
• Occurs due to mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of 1 of the DNA mismatch repair DNA Mismatch Repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. DNA Repair Mechanisms genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure (MSH2, MSH6, MLH1) resulting in MSI, or the EPCAM EPCAM A cell adhesion molecule that is expressed on the membranes of nearly all epithelial cells, especially at the junctions between intestinal epithelial cells and intraepithelial lymphocytes. It also is expressed on the surface of adenocarcinoma and epithelial tumor cells. It may function in the mucosa through homophilic interactions to provide a barrier against infection. It also regulates the proliferation and differentiation of embryonic stem cells. Lynch syndrome gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
• Risks of CRC: 75%
• At-risk individuals who meet the Amsterdam II criteria Amsterdam II criteria Lynch syndrome (“3-2-1 rule”):
  • 3 or more relatives with CRC, 1 of whom must be a first-degree relative of the other 2
  • Involvement of 2 or more generations
  • At least 1 cancer must have been diagnosed < 50 years of age.
  • FAP FAP Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps in the colon. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. Familial Adenomatous Polyposis has been excluded.
  • Tumors verified by pathologic examination
• Confirmatory test: DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure sequencing
• CRC screening Screening Preoperative Care: annual screening Screening Preoperative Care colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening at 20–25 years of age
• Management:
  • Surveillance Surveillance Developmental Milestones and Normal Growth generally preferred
  • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) (may reduce risk of CRC)
  • Surgery if surveillance Surveillance Developmental Milestones and Normal Growth not feasible/confirmed mutations/when advanced adenoma/CRC found

Peutz-Jeghers syndrome Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome

• Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
• STK11 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
• Development of hamartomas of the small and large intestines
• Associated with hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi of the mouth, hands, and feet
• Risk of developing CRC: 40%
• Malignancies:
  • Gastrointestinal (GI) malignancies ( stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy, small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy, and colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy) develop in 40%–60% of cases.
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer in 30%–50% of cases
  • Nonintestinal organs ( gonads Gonads The gamete-producing glands, ovary or testis. Hormones: Overview and Types, pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy)

Differential Diagnosis

• IBD: also presents with changes in bowel habits, abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, but colonoscopy Colonoscopy Endoscopic examination, therapy or surgery of the luminal surface of the colon. Colorectal Cancer Screening findings and extraintestinal manifestations of IBD help differentiate this disease from CRC. Fecal calprotectin Calprotectin Irritable Bowel Syndrome is a highly sensitive test for intestinal inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation that can be used to distinguish IBD.
• Hemorrhoids Hemorrhoids Hemorrhoids are normal vascular cushions in the anal canal composed of dilated vascular tissue, smooth muscle, and connective tissue. They do not cause issues unless they are enlarged, inflamed, thrombosed, or prolapsed. Patients often present with rectal bleeding of bright red blood, or they may have pain, perianal pruritus, or a palpable mass. Hemorrhoids: also presents with blood per rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal: Anatomy and changes in bowel habits. Hemorrhoids Hemorrhoids Hemorrhoids are normal vascular cushions in the anal canal composed of dilated vascular tissue, smooth muscle, and connective tissue. They do not cause issues unless they are enlarged, inflamed, thrombosed, or prolapsed. Patients often present with rectal bleeding of bright red blood, or they may have pain, perianal pruritus, or a palpable mass. Hemorrhoids may cause rectal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and can be identified on physical exam or anoscopic exam. Bleeding per rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal: Anatomy in a patient > 50 years of age with hemorrhoids Hemorrhoids Hemorrhoids are normal vascular cushions in the anal canal composed of dilated vascular tissue, smooth muscle, and connective tissue. They do not cause issues unless they are enlarged, inflamed, thrombosed, or prolapsed. Patients often present with rectal bleeding of bright red blood, or they may have pain, perianal pruritus, or a palpable mass. Hemorrhoids still needs to be investigated for CRC.
• Diverticular disease Diverticular disease Diverticula are protrusions of the bowel wall occurring most commonly in the colon. The condition of having diverticula (called diverticulosis) is mostly asymptomatic. These diverticula can become symptomatic, however, when associated with diseases. Diverticulitis is the inflammation of diverticula, often presenting with lower abdominal pain and changes in bowel habits. Diverticular Disease: diverticulosis Diverticulosis A pathological condition characterized by the presence of a number of colonic diverticula in the colon. Its pathogenesis is multifactorial, including colon aging, motor dysfunction, increases in intraluminal pressure, and lack of dietary fibers. Diverticular Disease is the presence of sac-like protrusions in the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy. Complications include diverticular bleeding and diverticulitis Diverticulitis Inflammation of a diverticulum or diverticula. Diverticular Disease, which also present with blood per rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal: Anatomy and changes in bowel habits. Colonoscopic findings differentiate diverticular disease Diverticular disease Diverticula are protrusions of the bowel wall occurring most commonly in the colon. The condition of having diverticula (called diverticulosis) is mostly asymptomatic. These diverticula can become symptomatic, however, when associated with diseases. Diverticulitis is the inflammation of diverticula, often presenting with lower abdominal pain and changes in bowel habits. Diverticular Disease from CRC.
• Small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors: also present with blood in stool and obstructive symptoms. To differentiate these neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors from CRC, upper and lower endoscopy Endoscopy Procedures of applying endoscopes for disease diagnosis and treatment. Endoscopy involves passing an optical instrument through a small incision in the skin i.e., percutaneous; or through a natural orifice and along natural body pathways such as the digestive tract; and/or through an incision in the wall of a tubular structure or organ, i.e. Transluminal, to examine or perform surgery on the interior parts of the body. Gastroesophageal Reflux Disease (GERD) may be required.
• Neuroendocrine tumors Neuroendocrine tumors Tumors whose cells possess secretory granules and originate from the neuroectoderm, i.e., the cells of the ectoblast or epiblast that program the neuroendocrine system. Common properties across most neuroendocrine tumors include ectopic hormone production (often via apud cells), the presence of tumor-associated antigens, and isozyme composition. Gastrinoma: affect the right colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy in the majority of cases. These lesions have characteristic symptoms of carcinoid syndrome Carcinoid syndrome A symptom complex associated with carcinoid tumor and characterized by attacks of severe flushing of the skin, diarrheal watery stools, bronchoconstriction, sudden drops in blood pressure, edema, and ascites. The carcinoid tumors are usually located in the gastrointestinal tract and metastasize to the liver. Symptoms are caused by tumor secretion of serotonin, prostaglandins, and other biologically active substances. Cardiac manifestations constitute carcinoid heart disease. Carcinoid Tumors and Syndrome ( diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, flushing, and wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing).