Module 2.2: Solid Tumours and Blood Cancers Flashcards
Indicator of Gastrointestinal Cancer
Iron deficiency anemia
Testing for GI Cancer
Preformed an upper endoscopy to visualize the esophagus, stomach, and parts of the small intestine,
and a lower endoscopy (colonoscopy) to visualize the colon (large intestine) and the rectum
Upper Endoscopy: by inserting a long
flexible tube with a small camera on the end into the mouth, down the esophagus and into the
stomach and the first part of the small intestine.
Colonoscopy: A test that physicians use to visualize the lower digestive tract, by inserting a long flexible
tube with a small camera on the end into the anus, and up the rectum and large intestine.
Aaliyah’s Colonscopy
Mass was found, suggesting colorectal cancer. Extracted a biopsy for further testing
Development of Colorectal Cancer
Hyper-Proliferation
A cell has incurred one or more oncogenic mutations and begins to hyper-proliferate. These cells grow and divide at a faster than normal rate.
Adenomatous Polyp
When the rapidly dividing mass of cells projects into the intestinal lumen it is known as an adenoma. Adenomas are often referred to as colonic polyps
Precancerous Polyp
Precancerous polyps can be removed before they become malignant. It may take 7-10 years for these growths to progress into the next stage, a malignant Adenocarcinoma!
Adenocarcinoma
Over time, a polyp can become invasive and develop into an adenocarcinoma which is the most common type of colorectal cancer. This transition is when the cells invade into the adjacent tissue layers.
Advanced Cancer
If polyps go undetected, they will continue to grow and further invade into deeper tissue layers. Once this occurs, the cancer may enter the bloodstream and metastasize to other parts of the body. The presence and degree of invasion of a cancer are important components of staging
Screening for Colorectal Cancer
done on patients that have an elevated risk due to two major
contributing factors: age and family history of colorectal cancer
fecal immunochemical test (F I T) is a great screening tool because it is a safe and painless at-home cancer screening test. The F I T examines stool for tiny amounts of blood, which could be caused by
colorectal cancer or precancerous polyps
Factors Restricting Colon Screenings
- Fear that the test is difficult or painful. Many people are unaware of the less invasive
screening tools available, opposed to colonoscopies. - No family history of colorectal cancer leads people to believe that they aren’t at risk and don’t have to be screened.
- Misconception that only those with symptoms need to be screened.
- Concern over the cost of the test and complexity of scheduling a test.
Aaliyah’s Story: Imaging of Metastasis
Biopsy confirmed invasive cancer. staging computed tomography (C T)
scan of her abdomen and chest was performed. no evidence of metastasis
Aaliyah’s Story: Tumour Removal
a right hemicolectomy (remove part of the large intestine. Once the colon is partially removed, the remaining ends are joined back together) was done. This type of surgery removes the cancer and the surrounding lymph nodes
that drain the area where the tumour is located
Histology
Pathologists use histology to look for changes to normal tissue structure, and use this information to determine the extent of tumour progression.
Histology slides are created by cutting and staining thin sections of a specimen, then viewing under a microscope. In the colon, four tissue layers can be clearly distinguished.
The vast majority of colorectal cancers are (adeno) carcinomas
Colorectal Cancer Characterization: Stage
Described using three classifications: T, N, and M. Staging is specific for
different cancers.
* T: Depth of tumour invasion.
* N: Spread to the lymph nodes.
* M: Metastasis of the cancer to other parts of the body.
Pathologists examine the histology slides to provide a score for T and N. This is combined with the
presence/absence of metastasis (M) for an overall stage (e.g., T2N1M0).
T: Size of the main tumour. From T0 (no tumour) to T4 (large tumour invading adjacent tissues).
N: Number of nearby lymph nodes with cancer cells. From N0 (no cancer in nodes) to N4 (cancer in multiple nodes).
M: Whether metastasis has occurred. Either M0 (no metastasis) or M1 (cancer has metastasized
Colorectal Cancer Characterization: Grade
The grade of a cancer is based on how abnormal the cells in the biopsy, or tumour, appear compared to normal cells in that tissue. A grade (G) score is given from 1 to 4; the higher the grade, the more abnormal cancer cells that are present in the sample, and the poorer the prognosis.
Normal colon epithelial cells form circular structures known as glands.
* The cells appear hollow on the inside
* Larger glands have a space in the middle
Grade 1 (Low Grade)
- Nearly all cancer cells still form glands
- Glands are less circular
- Hollow appearance of cells is lost
- Cells may grow into central space
Grade 2 (Medium Grade
Some gland formation still visible
* Additional loss of circular gland structure
* Cell shape drastically different
* Central gland space occupied by cells or debris from necrosis
Grade 3 (Medium - High Grade)
- Very little gland formation present
- Cells vary in shape and size
- Only a few cells continue to exhibit their normal hollow appearance
Grade 4 (High Grade)
- Gland structure practically nonexistent
- No trace of the original hollow cell appearance or central space
- Instead, cells have no specific structure
Aaliyah’s Story: Genetic Testing
The pathologist runs some specialized tests on Aaliyah’s tumour sample to screen for one form of inherited cancer called Lynch syndrome. Her tumour shows irregularities in expression of the M S H 2 gene, raising the possibility that she may have Lynch syndrome
Sporadic and Familial Colorectal Cancer
Sporadic
In sporadic colorectal cancer, somatic mutations spontaneously occur on both alleles of the adenomatous polyposis coli (A P C) gene.
Familial
Familial colorectal cancer is characterized by an inherited mutation. The most common include mutations to one of the mismatch repair genes, such as M S H 2.
Mismatch Repair Genes: Genes that correct mismatched nucleotides arising from errors in D N A
replication and recombination.
Familial Pathway: Lynch Syndrome
Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (H N P C C) syndrome, is the most common hereditary colorectal cancer syndrome, accounting for 2-4% of all colorectal cancers.
It is caused by a germline mutation in a D N A mismatch repair gene, such as M S H 2. Since one copy (or allele) of the gene is already mutated, it only takes one more acquired mutation in the second copy of M S H 2 to develop cancer.
Individuals with Lynch syndrome are at an increased risk of developing a number of cancer types, but most commonly colorectal cancer
Developing a Prognosis
Age and General Health: Age and overall health of the patient.
Response to Treatment: The tumour’s responsiveness to the treatment is a determinant of prognosis. For example, colorectal cancers with certain mutations are less responsive to available treatments.
Stage and Grade: Stage and grade of the cancer. For colorectal cancer diagnosed at Stage 1, there is ~90% survival, while at Stage 4, it is ~10%.
Genetics: The type of mutation causing the cancer impacts the prognosis. For example, there are specific colorectal cancers caused by a specific known gene mutation that lead to more aggressive
cancers, leading to a poorer prognosis.
Access and Compliance: Access to screening and treatment, along with treatment compliance impact
prognosis. In Ontario, 10% more of Métis women are overdue for colorectal cancer screening, suggesting delayed detection and a poorer prognosis
Jorge’s Story: Blood Work
Blood tests can provide a wide array of patient information. The two main types of data collected are concentrations of blood cells (red, white, and platelets) and clotting factors. These numbers are compared to normal values, and any abnormalities will help to diagnose the patient
Introduction to Blood Cancers
These cancers begin in the bone marrow when rapidly growing blood stem cells fail to mature into the healthy, functioning blood cells our bodies need. Instead, they divide to produce more cancer cells, and eventually crowd out the normal stem cells.
These types of changes in cell population often result in fatigue due to decreased red blood cells providing insufficient oxygen, immune issues due to a lack of different forms of white blood cells, and bleeding and clotting issues due to a loss of platelets.
Jorge displayed characteristic fatigue and his blood test result showed lower counts of critical cells, suggesting he has leukemia, a blood cancer
Hematopoietic Stem Cell
From bone marrow. Have a long lifespan of several years, unlike specializes blood cells that only live weeks to months.
Common Myeloid and Lymphoid Progenitor
Common myeloid progenitor cells and common lymphoid progenitor cells are multipotent. They have the potential to differentiate into only a subset of specialized blood cell types.
Like any progenitor cells, common myeloid progenitor cells replace specialized cells that are damaged or lost. These cells produce different immature cells called blasts, which will eventually develop
into fully differentiated specialized cell types
Specialized Myeloid Cells
Common myeloid progenitor cells differentiate into specialized myeloid cells such as red blood cells, platelets, and specific types of white blood cells.
Unlike H S Cs or common myeloid progenitor cells, these cells are highly specialized and have specific capabilities
Specialized Lymphoid Cells
Common lymphoid progenitor cells differentiate into a few specialized lymphoid cells such as T-cells, B- cells, and natural killer cells.
Unlike H S Cs or common lymphoid progenitor cells, these cells are highly specialized and have specific capabilities
Jorge’s Story: Blood Smear
Now that leukemia is suspected, another sample of Jorge’s blood was drawn and sent to a pathologist,
who performed a blood smear.
The blood smear revealed that the immature cells, or blasts, found in Jorge’s blood test are
promyelocytes. Promyelocytes are a precursor to white blood cells of myeloid lineage.
Jorge’s pathologist diagnoses him with acute myeloid leukemia (A M L)
Classical Blood Cancer Pathway
Differentiation Block
In the first step, a tumour suppressor gene that is involved in cell differentiation is lost in the H S Cs or the common progenitors. This leads to the initial accumulation of immature blood cells, or ‘blasts’.
Enhanced Proliferation
At some point, another gene is mutated in these cells; this time a proto-oncogene that produces growth signals. The result is a major increase in proliferation.
When both these mutations occur, malignant blasts crowd out normal H S Cs and produce the symptoms associated with disease progression
Types of Leukemia
Leukemias can be classified into four main types. Each type is identified by two factors:
* Proliferation speed, which can be acute or chronic
* Cell of origin, which can be myeloid or lymphoid
Acute lymphocytic leukemia (A L L)
Chronic lymphocytic leukemia (C L L)
Acute myeloid leukemia (A M L)
Chronic myelogenous leukemia (C M L)
Acute vs. Chronic Leukemia
Acute Leukemia (A M L, A L L)
* Characterized by proliferation of poorly differentiated cells
* Usually progresses rapidly
* Immediate treatment is usually required
Immature cells with more open nuclear chromatin.
Chronic Leukemia (C M L, C L L)
* Characterized by proliferation of well-differentiated cells
* Usually progresses slowly
* May be monitored for some time before treatment is initiated
Mature cells with more clumped nuclear chromatin
Myeloid Leukemia
In myeloid or myelogenous leukemias, one of the myeloid progenitors becomes malignant. When the
progenitors allow the formation of mature cells (but in a skewed fashion) and grow slowly, this is known as chronic myeloid leukemia (CML).
When progenitors to myeloid cells grow rapidly and partially or fully lose the ability to form mature cells, this is known as acute myeloid leukemia (AML). These tend to be less differentiated blasts than
in CML.
Lymphotcytic Leukemia
If the leukemia is lymphocytic, the cancer arises from a lymphoid cell origin.
In acute lymphocytic leukemia (ALL), malignant undifferentiated blasts grow quickly. It is frequently
a common progenitor of all or most lymphocytes that becomes malignant.
Chronic lymphocytic leukemia (CLL) is a slow growing and more differentiated malignancy. It is
normally from a more differentiated malignant blast cell leading to a specialized lymphoid cell.
Prognostic Factor for Leukemia
Age
Patients over 65-years old have the highest mortality. In contrast, childhood leukemia (diagnosed at 1-
15 years old) have a survival rate of about 90%.
Weight
People with a normal body-mass index (B M I) at diagnosis or during treatment have significantly higher survival rates than those who are underweight or obese.
Previous Blood Disorders
A medical history of anemia, hemophilia, or other blood disorders tend to have a less favourable prognosis.
Genetics
Some specific mutations can cut leukemia survival odds by half, while others can raise them to near
100%
AML - Related Genes
Differentiation Block
Loss-of-Function Mutations
* A M L1-E T O
* C B F ꞵ-S M M H C
* P M L-R A R ɑ
Enhanced Proliferation
Gain-of-Function Mutations
* F L T3
* c-K I T
* N-R A S, K-R A S
* B C R-A B L
* T E L-P D G F ꞵ R
Jorge’s Story: Genetic Testing
Jorge is under 65-years old, has a normal B M I, and no history of blood disorders. Genetic testing on Jorge reveals that he has a mutation known as P M L-R A R A translocation. In this scenario, the discovery of the P M L –R A R A translocation improves Jorge’s prognosis
AML and Chromosomal Translocation
Occasionally, chromosomes may break and be fused together incorrectly in an event known as a
translocation.
Sometimes the break occurs between two gene sequences. Fusion results in a hybrid sequence thatcodes for a fusion protein. Fusion proteins have the potential of being oncogenic.
One such hybrid sequence is named P M L-R A R A, which occurs during a fusion of chromosomes 15 and 17 at the sites of the P M L and R A R A genes
PML-RARA Oncogene and Leukemia Therapy
Normal R A R A
The normal R A R A gene codes for the R A R-α protein. Under normal conditions, when healthy H S Cs receive a signal to produce more myeloid cells, R A R-α is temporarily inactivated to allow differentiation to take place.
P M L-R A R A Fusion
When a P M L-R A R A fusion takes place, R A R-α no longer responds to differentiation signals, leading to an accumulation of immature blasts.
A T R A Treatment:
The effects of P M L-R A R A on white blood cell differentiation can be effectively reversed by treatment with A T R A. A T R A treatment specifically acts on blast cells, causing them to mature into normally-
functioning specialized myeloid cells
Cancer Genetics and Biomarker
Gene expression is a type of biomarker
Types of biomarkers:
1. Small Chemical Products
2. Enzymes
3. D N A
4. R N A
5. Cancer Cells
6. Protein
Biomarker: A measurable indicator of some state or condition in the body. These are often measured in blood, urine, or tissue samples.
Diagnostic, Prognostic and Predictive Biomarkers
Diagnostic Biomarker
The finding of a diagnostic biomarker detects or confirms the presence of a disease.
Prognostic Biomarker
A prognostic biomarker indicates the likelihood of disease progression or recurrence.
Predictive Biomarker
The finding of a predictive biomarker can predict the response to a particular treatment.
Well: Cancer Screening in Healthy Individuals
One of the biggest improvements to patient outcomes is the use of routine cancer screening for at-risk
populations who are otherwise healthy.
Common screening tools are:
* Pap smears for cervical cancer
* Mammograms for breast cancer
* Digital rectal exams for prostate cancer
* F I Ts and colonoscopies for colorectal cancer
Treatment: Living with Cancer
Types of treatment options include:
* Surgery
* Radiation
* Chemotherapy
* Immunotherapy
