Neoplasia IV Flashcards
1
Q
carcinoma in situ invade beyond basement membrane. True/False
A
False.
All layers of the epithelium show features of neoplasia.
It does not invade beyond the basement membrane, therefore, any access to lymphatics or blood vessels
2
Q
carcinoma in situ can metastasize. T/F
A
False.
– No metastatic potential at this stage but if not removed is “capable” of metastasis
– Cancers are curable at this stage
3
Q
Why carcinoma in situ is called malignant if it does not metastasize?
A
They have potential to metastasize but are only physically limited not biologically limited
4
Q
what is defined by a neoplastic change in epithelium which shows some of the microscopic features of malignancy but does not involve the full thickness of the epithelium, can progress to cancer
A
dysplasia
5
Q
the architectural organization is preserved in dysplasia.True/False.
A
False.
disordered growth- loss of cellular uniformity and architectural organization
6
Q
dysplasia necessarily will progress into malignancy. True/False
A
False.
Dysplasia doesn’t equate malignancy and dysplastic cells don’t necessarily progress to cancer
7
Q
dysplasia is irreversible. True/False
A
False.
Removal of inciting stimulus from dysplastic epithelium can result in reversal to complete normalcy. When dysplastic changes are marked and involve the entire thickness of an epithelium –lesion considered pre-invasive neoplasm – carcinoma in situ.
8
Q
when dysplastic changes are called precancerous?
A
. When dysplastic changes are marked and involve the entire thickness of an epithelium — lesion considered pre-invasive neoplasm — carcinoma in situ.
9
Q
grade the dysplasia
A
– MILD
– MODERATE
– SEVERE
10
Q
what is the term used for dysplasia in cytological preparations (abnormal nucleus) since there is no architecture?
A
DYSKARYOSIS
11
Q
why dysplasia of cervix is called intraepithelial neoplasia?
A
In the cervix, the term intraepithelial neoplasia has been introduced to highlight the fact that dysplasia is neoplastic. If not treated always will progress to neoplasia, Detected on Pap smear.
12
Q
describe cervical intraepithelial neoplasia (CIN) 1,2 and 3
A
o CIN1- mild dysplasia which shows disorderly maturation limited to the basal and parabasal layers
Upper 2/3 stratified
Basal 1/3 high nucleo-cytoplasmic ratio + pleomorphic ratio
o CIN2- moderate dysplasia
Superficial stratification
Cellular abnormalities extending up into basal 2/3
o CIN3- sever dysplasia + carcinoma in situ
atypical cells through the entire thickness of epithelium (carcinoma in situ)
may have 1 or 2 layers of stratified squamous epithelium (remainder: immature, large nuclei, mitoses)
13
Q
CIN 3 is the same as carcinoma in situ.True/False
A
True.
Involve entire layer of epithelium
14
Q
CIN 1 vs 2
A
Confined to the basal 1/3 of the epithelium vs confined to the basal 2/3 of the epithelium
15
Q
what type of HPV is associated with CIN?
A
oncogenic types 16/18.
6/8 cause condyloma
16
Q
SIL vs CIN
A
Both terms are used to describe changes in the cervix. However, they are used in different situations. “Squamous intraepithelial lesion (SIL) is used to describe Pap test results. “Squamous” refers to the type of cells that make up the tissue that covers the cervix. SIL is not a diagnosis of precancer or cancer. The Pap test is a screening test. It cannot tell exactly how severe the changes are in cervical cells. A cervical biopsy is needed to find out whether precancer or cancer actually is present.
Cervical intraepithelial lesion (CIN) is used to report cervical biopsy results. CIN describes the actual changes in cervical cells. CIN is graded as 1, 2, or 3. CIN 1 is used for mild (low-grade) changes in the cells that usually go away on their own without treatment. CIN 2 is used for moderate changes. CIN 3 is used for more severe (high-grade) changes. Moderate and high-grade changes can progress to cancer. For this reason, they may be described as “precancer
17
Q
LSIL vs HSIL?
A
Low-grade SIL- 80% associated with a high risk of HPV
High-grade SIL – 100% associated with a high risk of HPV
differentiated by cytology
18
Q
what is actinic keratosis
A
dysplastic lesion of skin squamous cells
19
Q
what is the reason for screening for cancers?
A
to catch dysplasia (precancerous stage) before it becomes carcinoma or before clinical symptoms arise. The efficacy of screening requires a decrease in cancer-specific mortality.
Common screening methods:
• Pap smear
• Mammography
• PSA and digital rectal exam (PSA is not useful now, mainly used to assess treatment response**)
• Hemoccult test and colonoscopy
20
Q
what are the hematological effects of cancers?
A
1) anemia
2) hypercoagulable state-thrombosis (DVT/PE)
3) polycythemia
21
Q
what is the mechanism of anemia due to malignancy?
A
1)Iron deficiency anaemia (commonest)
– Blood loss
2)Megaloblastic anaemia
– Cytotoxic drugs interfering with DNA synthesis
3)Hypoplastic anaemia
– Marrow infiltration by tumour
– or chemotherapy destruction of haemopoietic cells
– or radiotherapy destruction of haemopoietic cells
4)Haemolytic anaemia
– Immune-mediated - the destruction of RBC’s
5) more importantly: AOCD (anaemia of chronic disease). Long-standing inflammatory state leads to increased production of hepcidin which interferes iron usage from storage
22
Q
why megaloblastic anemia is seen with cancer?
A
some cytotoxic drugs interfering with DNA synthesis, the cell grows but does not divide-so megaloblasts
23
Q
why malignancy increases the risk of clotting?
A
-Tumour activates
Clotting factors
Platelets
Endothelial cells
-Tumour inhibits
Fibrinolysis
24
Q
what is the Trousseau sign?
A
The Trousseau sign of malignancy or Trousseau’s syndrome is a medical sign involving episodes of vessel inflammation due to blood clots (thrombophlebitis) which are recurrent or appearing in different locations over time (thrombophlebitis migrans or migratory thrombophlebitis). Commonly seen with pancreatic cancer.
25
what is the mechanism or polycythemia due to cancer
some cancer (eg Renal cell carcinoma) produce erythropoietin which triggers RBC production
26
define ectopic hormone
A hormone is ectopic if it is produced by cells which do not normally produce that hormone
27
list some hormonal effects of malignancies
1. Cushing’s Syndrome (ACTH)
2. Excess ADH-SIADH: syndrome of inappropriate ADH production: hypoosmolar serum, hyperosmolar urine
3. Gynaecomastia - Oestrogen
4. Hypercalcemia- Squamous cell carcinoma lung
5. Insulin XSS- Insulinomas of the pancreas
28
what is PTHrp
parathyroid hormone-related peptide produced by lung SCC leads to severe hypercalcemia (dehydration, QT prolongation---arrhythmia)
hypercalcemia can also occur due to bone osteolytic metastasis
29
list some paraneoplastic syndromes
1) Peripheral Neuropathy
2) Myopathy
3) Dermatomyositis (common with ovarian carcinoma)
4) Cerebellar Degeneration (small cell cancer)
5) P.U.O (Pyrexia of Unknown Origin)
6) Night sweats
30
what is the probable explanation of paraneoplastic syndromes?
* The most likely cause is an immune or cytokine-mediated response.
* E.g. anti cerebellar antibodies have been secreted by some tumors.
31
melanoma arise from what cells?
melanocytes (in basal layer of epidermis)
32
what is the ABCD of melanoma?
* A- asymmetry
* B – border irregular/bleeding
* C – Colour
* D – Diameter
* E- Elevation/Evolution
33
melanoma can occur in the eye.True/False
True.
| There are melanocytes in the retina
34
what is the most important risk factor for melanoma?
Sunlight (sun-exposed areas in which lightly pigmented are at more danger) – severe sunburns early in life a risk factor
35
what gene mutations predispose to melanoma?
10-15% are familial mutations (increase RAS and PI3K/AKT associated with sporadic melanomas. BRAF mutations occur in 40-50% of melanomas)
36
prognosis of melanoma depends on?
the thickness of the skin involved.
> 2mm -very poor prognosis (<0.76mm (98% cure).
Clarke's level of invasion assesses level into different parts of the dermis.
37
schwannoma is a type of sarcoma. True False
True.
| Malignant neoplasm arising from Schwann cells which cover nerve cells protecting them from losing action potential
38
what is the significance of Herpes Virus 8?
leads to Kaposi sarcoma in AIDS patients (purple nodules on the skin, in the GI tract)
39
what factors predispose to sarcoma development?
```
– Radiotherapy < 1% post-therapy. Mean latency 10 years
– Chemicals
– Herbicides
– Pesticides
– Asbestos
– Genetic
```
40
what is the Li Fraumeni syndrome
cancers arising in different organs due to germline mutation of the P53 tumor suppressor gene. Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer. This syndrome is also known as the sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome.
41
name 2 genetic causes of sarcomas.
– Li Fraumeni Syndrome - P53 germline DEFECT
| – Von Recklinghausen disease 3% - neurofibrosarcomas (neurofibromatosis 1).
42
chemotherapy is the most important way to treat sarcomas. True/False.
```
False. Weakly chemosensitive.
– Wide local excision
– Radiotherapy
– +/- chemotherapy
– Only a limited role for chemotherapy
– Targeted Tx Imatinib for GIST
```
43
mutations in genes RAS and PI3K/AKT are associated with which cancer?
sporadic melanomas
44
sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome, what is this?
Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer.
Due to germline mutation of the P53 tumor suppressor gene
45
what are neuroendocrine tumors?
Neoplasms with endocrine function and neural features
| Tumors showing differentiation of neural cells and endocrine cells
46
name 2 highly and low aggressive neuroendocrine tumors
* highly aggressive and lethal (Small cell carcinoma)
| * low aggression (carcinoid tumor)
47
what is chromogranin?
tumor marker detected by immunohistochemistry, present in neuroendocrine tumors
48
other tumor markers:
1) vimentin
2) desmin
3) cytokeratin
4) neurofilaments
5) synaptophysin
6) S-100
7) TRAP
8) GFAP
1) mesenchymal cells (macrophage, fibroblast, endothelial cell-osteosarcoma, chondrosarcoma, liposarcoma, etc
2) smooth and skeletal muscle-rhabdomyosarcoma, leiomyosarcoma
3) epithelial cells-SCC, BCC
4) neurons-neuroblastoma, neuroendocrine tumors
5) neuroendocrine tumors
6) neural crest cells-schwannoma, melanoma, Langerhans cell histiocytosis
7) Hairy Cell leukemia
8) neuroglia-glioblastoma, astrocytoma
49
list few benign neuroendocrine tumors
* Insulinoma
| * Parathyroid Adenoma
50
list few malignant neuroendocrine tumors
* Carcinoid tumor
* Small cell ca lung
* Pancreatic islet cell neoplasms (some only, 10%)
* Parathyroid carcinoma
* Phaeochromocytoma
* Medullary carcinoma thyroid
51
papillary thyroid carcinoma is a neuroendocrine tumor. True/False
False.
| Medullary thyroid carcinoma is a neuroendocrine tumor
52
name neuroendocrine tumor that causes episodic headaches, tremor, sweating, and high blood pressure
phaeochromocytoma
53
carcinoid tumors are low or high-grade neuroendocrine tumors?
low (well-differentiated)
54
what tumor markers contain carcinoid tumors?
chromogranin and synaptophysin
55
what is the most common site of carcinoid tumor
appendix (but rarely metastasize so does not cause carcinoid syndrome, to cause carcinoid syndrome tumor must metastasize to the liver so the biological products will bypass liver detoxifying ability)
56
what are the sites of carcinoid tumor?
* Appendix (appendiceal carcinoids are found at tip, less than 2cm, usually benign)
* Ileum
* Bronchus
* Anywhere
* All are capable of metastasis but may not do so for many years. They are less aggressive than the usual carcinoma.
57
carcinoid tumor can cause acute appendicitis. True/False
True
| If located on appendix
58
what is the most common presentation of bronchial carcinoid?
hemoptysis. Can block the bronchus leading to atelectasis and recurrent pneumonia
59
what is carcinoid syndrome?
These tumors may secrete a variety of neuroendocrine and paraendocrine substances, in many cases without any clinical functional effects. BUT ileal carcinoids tend to produce peptides (5-HT) which are normally destroyed in the lung and liver. When metastatic deposits are present in the liver,
they may enter the general circulation and produce carcinoid syndrome.
– Carcinoid syndrome develops due to the effects of serotonin
– Serotonin regulates intestinal movement and also causes bronchospasm
– Serotonin is detoxified in the liver and to a lesser extent in the lung.
– Syndrome develops when the liver is bypassed or when the ability of the liver to detoxify is overwhelmed by tumor
Carcinoid Syndrome Effects of Serotonin
– Facial flushing (due to vasodilation)
– Diarrhea (due to hypertrophy of intestinal muscle and fibrosis and obstructive symptoms like diarrhea)
– Bronchospasm
– Pulmonary stenosis
Why pulmonary stenosis and not mitral stenosis? Fibrin formation deposits on valves on the right side of the heart so fibrosis leads to stenosis of the pulmonary valve and tricuspid valve.
60
which carcinoids commonly produce carcinoid syndrome?
ileal, which will metastasize to the liver
61
which substance is responsible for carcinoid syndrome?
serotonin
62
what are the effects of serotonin?
Facial flushing (due to vasodilation)
– Diarrhea (due to hypertrophy of intestinal muscle and fibrosis and obstructive symptoms like diarrhea)
– Bronchospasm
– Pulmonary stenosis
63
what are multiple endocrine neoplasms? (MEN)
• Clustering of more than 1 neuroendocrine neoplasm in the one patient
• Autosomal dominant inheritance
• Types 1 and 2(A and B)
MEN1
- due to the MEN1 gene on chromosome 11 -menin protein
- eg. Parathyroid adenoma
```
MEN2 due to mutations activating RET oncogene (neural growth factor receptor) on chromosome 10 (point mutation)
MEN 2A
- eg. Parathyroid adenoma
MEN2B
- eg. mucosal neuroma
```
• Why is it important to know this?
Because they occur as a cluster (so need to be aware that their organs need to be checked). Family screening may pick up tumors at an early age as well.
64
what tumors are seen with MEN1?
parathyroid hyperplasia--hyperparathyroidism
gastrinoma
pituitary adenoma
3 P's: parathyroid, pancreas, pituitary
65
describe MEN 2A and 2B
Medullary thyroid carcinoma and pheochromocytoma in both
| parathyroid adenoma in 2A and mucosal neuromas in 2B
66
MEN 1 vs MEN 2
due to suppression of tumor suppressor gene vs activation of RET protooncogene
67
what is menin?
Menin is a tumor suppressor gene deactivated in MEN1
68
how carcinoid tumor is diagnosed biochemically?
Increased urinary 5 HIAA’s (5-Hydroxyindoleacetic acid)
| –These are a breakdown product of serotonin.
69
in what organs germ cell tumors arise?
1. Testis
2. Ovary
3. Thymus
4. Pineal
5. Retroperitoneum
70
name tumor that arises from all 3 layers: endoderm/mesoderm/ectoderm
germ cell tumors (so can contain tissues derived from all 3 layers )
71
list common germ cell tumors?
* Seminoma (Testis) / Dysgerminoma (Ovary)
* Teratoma
* Choriocarcinoma
* Yolk sac Tumour
* Embryonal Carcinoma
* Mixed Tumours
72
what is the most common testicular tumor?
seminoma
– 50% of testicular tumors
– All are malignant
– Age 20-40 (rare before puberty) – seminoma spreads via lymphatics
– Have a characteristic lymphocytic response and host response
– Usually do not need chemotherapy unless late-stage
73
seminoma present most commonly at what age?
20-40
74
what is the treatment of seminoma
orchiectomy (no chemotherapy)
75
what is the common site of metastasization of germ cell tumors?
lungs
76
teratomas in testis vs ovary
mostly malignant vs benign
77
origin of teratoma?
Originates from totipotent germ cells capable of differentiating into derivatives of ectoderm, endoderm, and mesoderm, so frequently contain hair, teeth and other tissues
78
what does it mean totipotent germ cell?
capable of differentiating into derivatives of ectoderm, endoderm, and mesoderm
79
malignant tumor derived from the trophoblast is called?
choriocarcinoma. The trophoblast is composed of cytotrophoblast and syncytiotrophoblast
80
choriocarcinoma usually arises after?
hydatidiform mole
81
what is the most important feature of choriocarcinoma?
is aggressive and cause early lung metastases
82
what hormone is secreted by choriocarcinoma?
beta-HCG which is normally secreted by the syncytiotrophoblast, used to monitor disease and treatment
83
Yolk sac tumors produce what tumor marker?
Alpha-fetoprotein
84
what is the best treatment option for germ cell tumors?
chemotherapy
85
describe embryonic tumors
- Occur in children
- Aggressive tumours
- Consist of one embryonal-like cell
- Neuroblastoma - neural tissue
- Nephroblastoma - kidney
- Retinoblastoma - retina
- Medullablastoma - cerebellum
86
list few borderline tumors
* This categorization is most commonly ascribed to ovarian serous and mucinous tumors.
* Examples- Kaposi sarcoma and hemangioendothelioma (borderline vascular tumors)
87
why the incidence of cancers increases at old age?
* Carcinogens have sufficient time to cause multiple genetic alterations.
* Immunosuppression - elderly people have mild immunosuppression.
* Less lymphoid tissue (regresses and atrophies the older you get)
88
why do cancers occur in childhood?
•Often found an inherited loss of one allele on an important gene
– e.g. retinoblastoma
•Subsequent acquired loss of the second allele of retinoblastoma.
89
what is hamartoma?
A benign mass composed of mature cells that are native to the tissue of origin but have abnormal tissue organization. Has a low potential to undergo malignant transformation.
example: capillary angioma
90
hamartoma is present at birth.true/False
True.
| Enlargement continues until physiological growth ceases (reach adulthood)
91
what is tumor marker?
– The term is used for the antigen or antibody which is specific to a tumor.
– These are either antigen-specific to certain cell types that are recognized by antibodies.
92
what is the role of tumor markers?
– They can be used in the diagnosis, follow up and screening of tumors.
– Useful in determining therapeutic responses or tumor recurrence
93
list a few examples of tumor markers
– HCG
• Choriocarcinoma
– AFP - Alpha-fetoprotein
• Hepatocellular carcinoma
• Yolk sac tumor
– Prostatic specific antigen (not used for screening)
• Prostatic carcinoma
94
AF is seen in what tumors?
Hepatocellular carcinoma
| Yolk sac tumor
95
Where Are Tumour Markers Detected?
Blood/Serum
Urine
Tissue section
96
list tumor markers commonly used on tissue sections on histopathology
```
– Carcinoma-Cytokeratin
– Sarcoma-Vimentin (found in mesenchyme)
– Lymphoma- CD45
– Melanoma-S100 P or Melan A
– Prostate-PSA
– Thyroid-Thyroglobulin
– Yolk Sac tumor-AFP
– Choriocarcinoma-HCG
```
97
how tumor markers on tissue sections are detected?
– An antibody detects the antigen on the cell by a process called immunohistochemistry
– A colored dye (usually brown dye) is attached to an antibody.
– The antibody is poured on to the tissue
– If the antibody finds its antigen, it binds to it and cannot be washed off
– After washing the section, the antibody, which is bound to the antigen, is recognized by its attached dye
98
tumor markers are used for the diagnosis of both primary tumor and metastasis.True/False
True
e.g. a node which contains a tumor which reacts with thyroglobulin can be definitively diagnosed as a metastasis from thyroid carcinoma
99
what is a magic bullet?
Magic bullet: Or, sometimes, silver bullet. The perfect drug to cure a disease with no danger of side effects
100
what is the cell cycle?
a sequence of events that take place to enable DNA replication and cell division.
The cell cycle is first divided into two phases: interphase and mitosis.
Interphase is further divided into the G1 (gap 1), S (synthesis), and G2 (gap 2) phases, which prepare the cell for division.
Billions of cells are replaced in the body every day in a carefully controlled manner through the influence of factors on the cell cycle. These include proteins with different functions e.g. growth factors, growth factor receptors, enzymes, and signal transducers. Such cell replacement is essential to replace cells lost every day through natural wastage and injury
101
controlled vs uncontrolled cell proliferation?
```
-Controlled
Hyperplasia and Hypoplasia
- Uncontrolled
Neoplasia
Benign
Malignant
```
102
what is the clinical significance of the cell cycle?
Neoplasms occur when cell cycle is not normally controlled
103
list 3 types of cell (based on cell proliferation)
```
• Labile (rapid turnover)
o e.g. skin, GIT
• Stable (low turnover)
o Liver
• Permanent (no turnover)
o Neurons and cardiac muscles and skeletal muscles
```
104
liver cells are stable or permanent?
stable
| In some situations, they can proliferate
105
name few permanent cells
Neurons and cardiac muscles and skeletal muscles
| – This explains the relentless loss of cerebral function in Alzheimer’s disease.
106
what is a stem cell?
Stem cells are cells capable of self-renewal and differentiation into specialized cells.
Cell division
-Symmetric division: self-replication → both daughter cells possess the stem cell properties.
-Asymmetric division: differentiation → one stem cell is a copy of the mother stem cell and the other daughter cell is a precursor cell with differentiated properties.
Characteristics
Totipotent (omnipotent): the ability of a cell to differentiate into all cell types
Pluripotent: the ability of a cell to differentiate into nearly all cell types
Multipotent: the ability of a cell to differentiate into more than one cell type, but not all cell types
Classification
Embryonic stem cells (ESCs)
Origin: from the inner cell mass in the blastocyte stage
Degree of differentiation: pluripotent cells that can only develop into embryonic cells, but not trophoblastic cells
Adult stem cells
Origin: differentiated tissue with high potency (e.g., bone marrow)
Degree of differentiation: pluripotent cells that provide a supply of cells for regenerative tissue
107
what is the role of telomere?
The distal end of a chromosome that contains a non-coding, repetitive base sequence (TTAAGGG in humans). A chromosome is shortened with every successive cycle of DNA replication because the enzymes that replicate DNA cannot proceed all the way to the end of a DNA sequence. The presence of expendable, non-coding telomeres at the end of a chromosome ensures that important genetic information is not lost with every cycle of cell division.
–When the telomere runs out, cell replication is no longer possible.
108
list phases of the cell cycle
- G0 = resting phase
- G1 - M = cells becoming altered in preparation for cell division i.e. mitosis
- M - Cell division (mitosis)
Interphase
Definition: The interval between cell divisions in which the cell prepares for the next division. The duration of interphase varies and contains three phases (excluding the G0 phase):
G1 phase : synthesis of RNA, proteins, and cell organelles
Occurs after mitosis
There is one chromatid present per chromosome
The cell grows during this phase
Nucleotide excision repair takes place.
G1 checkpoint before entering S phase
S phase
DNA replication → results in two sister chromatids per chromosome
Synthesis of proteins required for DNA packaging (especially histones)
Most mismatch repair takes place during the S phase.
Once the S phase is initiated, the cell cycle must be completed.
G2 phase :
Further synthesis of proteins required for mitosis
Repair of DNA replication errors
G2 checkpoint before entering mitosis
G0 phase (Resting phase)
Resting period of a cell after exiting the cell cycle.
Cell is differentiated and has a specific respective function but is no longer undergoing cell division.
Only proliferating cells pass through the cell cycle. Most mature tissue cells are in the G0 phase.
Certain cell types can enter the G1 phase from the G0 phase if stimulated
Mitosis
Definition: the process of cell division from the distribution of DNA to budding of the cellular body
Duration: ∼1 h
Mitotic index: the ratio of the number of cells undergoing mitosis to the total number of cells in the given population (e.g., per 1,000 cells or per microscopic area in the specimen)
Phases of mitosis
--Prophase
Chromosome condensation begins
Centrosome separation
--Centrosome
Point of origin of the mitotic spindle
Composed of two centrioles and a surrounding matrix, from which the microtubules can emerge
Formation of the mitotic spindle begins
--Prometaphase
Degradation of the nuclear membrane into small vesicles and intercellular vesicle storage
Completion of the mitotic spindle
--Metaphase
Maximal condensation of the chromosomes, which are aligned in the equatorial plane of the cell
--Anaphase
Separation of sister chromatids due to cohesion dissolution at the centromere by the enzyme separase
The cell becomes elongated.
--Telophase
Decondensation of the chromosomes
Disintegration of the mitotic spindle
Formation of a new nuclear membrane
Cell bodies divide at the equatorial plane
Ribosomal RNA (rRNA) synthesis begins
few things from me to better understand cell cycle**
109
what is a mitotic index
the ratio of the number of cells undergoing mitosis to the total number of cells in the given population (e.g., per 1,000 cells or per microscopic area in the specimen)
• A high mitotic rate is seen in especially aggressive tumours.
• A high mitotic index is seen in tumours that progress rapidly through the cell cycle.
The apoptotic index is a reflection of the loss of tumor cells by apoptosis
110
what are the factors that control cell proliferation?
```
• Signaling from cell membrane → nucleus
• Growth factors
– (k-ras)
• Growth factor receptors
– (c-erbB-2)
• Signal transducers
– (k-ras)
– e.g. protein kinases
– G Proteins
• Transcription factors
– (c-myc)
```
111
what is PDGFB?
Platelet-derived growth factor, overexpressed in astrocytomas
112
what is ERBB2
epidermal growth factor receptor, amplified in breast carcinomas (Her2)
113
what is RET?
neural growth factor receptor, point mutation in MEN 2A and 2B, medullary thyroid cancer
114
what is kIT
stem cell growth factor receptor, point mutation in gastrointestinal stromal tumor
115
what is RAS?
GTP-binding protein (signal transudcer), point mutation in carcinomas/ melanoma
116
what is ABL
Tyrosine kinase (signal transducer), translocation with BCR in CML t(9;22)
117
what are C-MYC, L-MYC, and N-MYC?
transcription factors, C-MYC is translocated (8;14) in Burkit Lymphoma, L-MYC and N-MYC are amplified small cell lung cancer and neuroblastoma
118
what is CCND1 (cyclin D1)
cyclin, translocated (11;14) in mantle cell lymphoma
119
what is CDK4?
cyclin-dependent kinase, amplified in melanoma
120
what is hyperplasia?
increase in organ or tissue size due to increase cell number,
121
hyperplasia is controlled or uncontrolled?
controlled
| – Increased cell proliferation due to increased controlled proliferation, in response to a stimulus
122
what type of cells can undergo hyperplasia?
– It can only occur in labile or stable cells as permanent cells cannot divide e.g.left ventricle.
123
list few clinically significant hyperplasia examples
- Breast(Physiological)
- Endometrium(Physiological)
- Thyrotoxicosis(Due to increased TSH)
- Lymphadenopathy(Viral infection)
- Marrow hyperplasia(After blood loss)
- Skin in wound(Healing)
124
how heart increase in size if myocardial cells cannot undergo hyperplasia
due to hypertrophy (increase in individual cell size not a number)
125
how permanent cells increase their workload?
by hypertrophy, eg cardiac hypertrophy in response to long-standing hypertension, bodybuilding, If one limb is in a plaster other limb hypertrophies.
126
reduction in the size of organ or tissue is called?
ATROPHY
- Thymus in adults
- Breasts after pregnancy
- Salivary gland in duct obstruction.
127
Failure of the organ to reach expected size is called?
hypoplasia (underdevelopment of an organ, with a decreased number of cells)
lung hypoplasia of the fetus
128
Failure of an organ to develop is called?
Agenesis (complete absence of an organ and its associated primordium)
e.g. renal agenesis
129
what is metaplasia?
- Abnormality of cellular differentiation.
| - Change from 1 adult type of epithelium to another adult type.
130
what is Barret esophagus?
- e.g. Barrett's esophagus (acid reflux); squamous metaplasia of lung due to smoking(lung is usually pseudostratified squamous epithelium).
- Barrett's esophagus is the finding of gastric type epithelium rather than squamous epithelium in the esophagus.
131
is metaplasia protective?
Yes
-Metaplasia is a protective mechanism
e.g. in reflux oesophagitis (Barrett’s esophagus)
squamous epithelium changes to gastric epithelium to withstand the acid environment due to the reflux of acid contents into the oesophagus.
132
does metaplasia have malignant potential?
YES!
It had been previously thought that metaplasia is not neoplastic but we now find that similar genetic changes occur both in metaplasia and neoplasia.
This suggests that metaplasia is a neoplastic process in some instances, eg Barret metaplasia can transform in adenocarcinoma
133
what are the events causing cancer?
- Environmental factors
- Inherited genetic factors (Seed & Soil!!!!)
- Role of the immune system
- 100 times incidence of carcinoma of the skin in renal transplant recipients who have been immunosuppressed
134
does immunosuppression increase the risk of cancer?
Yes
| 100 times incidence of carcinoma of the skin in renal transplant recipients who have been immunosuppressed
135
give examples of evidence that inherited factors cause cancer
1. Familial Adenomatous polyposis coli → colonic carcinoma
2. Retinoblastomas occur in families
3. Breast carcinoma (5%) have an FH
4. Melanoma (2% FH)
5. Medullary carcinoma of the thyroid (30% of cases have FH)
136
what are BRCA 1 and 2?
An autosomal-dominant inherited gene mutation (BRCA1 or BRCA2) of a tumor suppressor gene that codes for a DNA repair protein. Associated with an increased risk of breast cancer (∼ 70%) and ovarian cancer as well as, to a lesser extent, colon, pancreas, stomach and prostate cancer. BRCA is an abbreviation for BReast CAncer.
- 60% lifetime risk of breast cancer
- 40% lifetime risk of ovarian cancer
- Probably 100 different mutations involved so it is difficult to screen for them all.
137
list a few environmental carcinogens?
- Chemicals
- Radiation (UV & Ionizing)
- Hormones
- Viruses
- Chronic Inflammation
- Parasites and other organisms
80% of cancers are caused by environmental factors
138
how chemical carcinogens cause cancer?
```
1)Genotoxic (initiator)
– Interfere with DNA binding
– Impede DNA repair
2)Non genotoxic (promoter)
– Non genotoxic chemical carcinogens act as promoters eg. Hormones, oestrogens
```
139
list genotoxic vs nongenotixic chemical carcinogens
1) genotoxic:
- Polycyclic hydrocarbons (lung)
- Nickel& chromate (nose)
- Aniline dye (bladder)
- Alkylating agents (leukemia)
2) Hormones e.g. estrogen
140
aniline dyes cause what cancer
bladder cancer
141
nickel cause what type of cancer
nose (head and neck)
142
what cancer is caused by polycyclic hydrocarbons?
lung
143
alkylating agents?
leukemias
144
what cancers are caused by UV radiation?
– Squamous cell carcinoma of skin
– Basal cell carcinoma of skin
– Malignant melanoma of skin
145
what are the sources of ionizing radiation?
– HIROSHIMA
– CHERNOBYL
– Therapeutic radiotherapy
– Diagnostic Radiotherapy
146
ionizing radiation causes what cancers?
– Cause leukemias and sarcomas
147
the risk of what cancers are increased due to exposure to asbestosis?
1. Mesothelioma
2. Lung cancer
(SCC of lung>mesothelioma)
148
list a few examples of hormones causing cancer
- Breast carcinoma -e.g. HRT
- Endometrial carcinoma - e.g. Tamoxifen (it is an antagonist of estrogen receptor in the breast, but agonist in endometrium!!!!!)
- Prostatic carcinoma - Androgens
149
risk of what cancers increased due to EBV?
- Nasopharyngeal carcinoma
| - Some of Hodgkin’s Disease
150
list a few viruses that cause cancer
```
•Epstein Barr
-Nasopharyngeal carcinoma
-Burkitt’s lymphoma
-Some Hodgkin’s Disease
•HPV (some types)
-Cervical carcinoma and anal carcinoma
•Hepatitis B&C Viruses
-Hepatocellular carcinoma
•Herpes-type 8-Kaposi’s sarcoma
•HPV 16 oropharyngeal carcinoma
```
151
schistosomiasis can cause what cancer?
bladder cancer
152
what cancer can be caused by parasite Clonorchis Sinensis
cholangiocarcinoma
153
what bacteria is oncogenic?
helicobacter Pylori
| Carcinoma and lymphoma of stomach (MALToma)
154
what genes can be altered to cause cancer?
- Proto-oncogenes
- Tumor suppressor genes
- Repair genes
- Anti Apoptotic genes
- Methylation of genes hyper or hypomethylation affect DNA function
155
what is proto-oncogene?
Genes that encode proteins that are important in normal cell division and cell differentiation. Cause cancer when activated!!! Examples include:
Protein kinases, e.g., protein kinase B (PKB)
PKB activates and inhibits various substrates and therefore suppresses, e.g., apoptosis, and activates translation and, indirectly, cell division.
PKB is activated by phosphatidylinositide 3-kinase (PI3K).
Ligand-directed transcription factors (intracellular hormone receptors)
GTP-binding proteins
G protein-coupled receptors
Small G-proteins such as Ras
Tyrosine kinase receptors
Growth factors and cytokines
156
what is the tumor suppressor gene?
A gene that normally controls and suppresses cell proliferation. Loss of function or inactivation leads to an increased risk of developing cancer. Both alleles need to be mutated in order for complete loss of function of the gene.
157
list few proto-oncogenes
- Growth factors (C-sis)
- Growth factor receptors (c-erbB-2)-breast cancer
- Signal transducers (c-ras)-colorectal cancer
- Nuclear regulation (c-myc)-Burkitt lymphoma
- Mitochondrial (Bcl-2)-Follicular lymphoma
158
what genetic changes are the reasons of proto-oncogene activation?
```
-Mutation
•e.g. radiation
-Amplification
-Translocation
•e.g. EB virus
-Insertional Mutagenesis
•e.g. viral insertion
-Methylation
```
159
why genetic changes occur to activate proto-oncogenes?
1) Environmental agents – carcinogens
2) Inherited susceptibility to mutation or amplification.
3) *These genetic changes are caused by environmental agents often at the site of a proto-oncogene or of a promoter.
4) e.g. EB Virus
160
viruses can cause activation of proto-oncogenes.
| True/False
True, eg EBV, HHV-8, HPV
161
c-myc oncogene is activated by?
EBV virus causing translocation, result in Burkitt lymphoma
162
how tumor-suppressor genes are affected?
```
• Alteration by:
- Deletion (usually)
- Mutation
• Translocation by:
- Environmental agents.
```
163
give examples of tumor suppressor genes
* P53 (wild type and mutant type)
* APC
* Retinoblastoma
164
what is P53
p53 protein
Causes cell apoptosis (by activating proapoptotic gene such as BAX) and cell cycle arrest at the G1 phase (by activating p21)
Inhibits entry in the S phase via inhibition of pRb phosphorylation
Mutated in Most human cancers, LiFraumeni syndrome
165
what is the guardian of the genome
P53
• It detects DNA damage and stops cell progressing through the cell cycle to give cell repair enzymes time to repair before they divide.
• Therefore, they maintain the integrity of the DNA of the cell.
UV causes mutation in p53 which causes skin cancer.
• P53 is mutated in 50% of carcinomas
• Mutated P53 does not act as a guardian of the genome and does not act as a tumour suppressor gene.
166
what is Adenomatous Polyposis Coli gene (APC)
APC is a protein that prevents unregulated cell proliferation by inhibiting β-catenin synthesis
167
the risk of what tumor is increased due to loss of APC gene
Lost in colon cancer, mainly familial, but also some sporadic.
Also lost in some gastric cancers.
168
what is the retinoblastoma gene and its product?
Retinoblastoma protein (Rb protein): causes cell cycle arrest at the G1 phase by inhibiting E2F transcription factor
- Function is deleted in retinoblastoma which is an aggressive tumor of the eye in neonates or infants.
- Replacement of the Rb gene to cultured cells from a retinoblastoma tumor causes the cells to become non- neoplastic.
- can also cause osteosarcoma
169
what is mismatch repair gene?
A collection of genes that encode proteins that recognize and excise mismatched nucleotides in newly synthesized DNA strands. Essential for the maintenance of genomic stability. Examples include MLH1 and MSH2.
170
mismatch repair is defective in?
in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome).
171
what are the antiapoptotic genes?
-These genes impair the process of apoptosis, therefore giving a survival advantage to tumor cells.
172
what is BCL 2
An antiapoptotic protein that inhibits the intrinsic pathway of apoptosis by blocking the release of cytochrome C and maintaining the impermeability of the mitochondrial membrane. Translocation t(14,18) can lead to overexpression of Bcl-2, which results in inhibition of apoptosis. Alterations in Bcl-2 are associated with follicular lymphomas and diffuse large B cell lymphoma.
173
t(14;18) translocation cause
follicular lymphoma
174
germline vs somatic gene abnormalities
--Germline mutation (gametic mutation): mutations in the cells from which egg or sperm cells develop. These mutations can, therefore, be passed on to offspring
--Somatic mutation: acquired mutations that are present only in certain somatic cells
Primarily affect only one allele of a gene
Do not occur in the germline and therefore cannot be passed on to offspring via the ovum or sperm
Almost all malignancies are preceded by a somatic mutation
175
Li-Fraumeni syndrome is due to germline or somatic mutation?
germline
| An inherited germline loss of one allele and subsequent loss of the second allele is associated with some cancers
176
renal transplant patients have increased risk of what cancer?
SCC of the skin due to immunosuppression
177
immunosuppressed patients have an increased risk of what cancers?
* Renal transplant patients on immunosuppression have X 100 incidence of skin carcinoma.
* Have a higher incidence of malignancies especially lymphomas
* Older patients also have an increased risk of malignancy which may be partly due to immunosuppression.
178
how tumor cells evade the immune system
* Tolerance
* Local immune suppression
* Dysfunction in T cell signaling
* Activating endogenous immune checkpoints (that terminate immune responses)
179
what is epigenetics?
Epigenetics focuses on the heritable chemical modifications of DNA and histone proteins caused by environmental factors. Through these modifications, gene activity can be regulated, i.e., genes can be switched on or off. In contrast to genetic studies, epigenetics is not concerned with the information encoded in the DNA sequence itself.
The epigenetic regulation of genes is all about whether or not genes are transcribed. Classical genetics, on the other hand, is concerned with the presence or absence of a gene. Gene expression or repression is determined by chemical modifications of bases (methylation) and histone proteins (various covalent modifications), which are carried out by specialized enzymes.
180
what is the role of immunotherapy in the treatment of cancers?
• Up-regulate or down-regulate immune response
181
give examples of cancer immunotherapy?
Vaccination (BCG for in situ bladder ca- as it will lead to stimulation of the immune response and overcoming the cancer cells)
- Immune checkpoint pathway inhibitors
- PD1 and CTLA-4 (immune checkpoint inhibitors) dampen down the immune response.
- Anti-CTLA-4 and anti-PD1 switch on the immune response against the tumour.
182
what is CTLA 4?
A protein receptor involved in the regulation of T cell activation. Its expression is upregulated by T cell receptor activation and pro-inflammatory cytokines (e.g., IL-12, IFN-γ). Anti-CTLA-4 antibodies (e.g., ipilimumab) are immune checkpoint inhibitors used in anticancer therapy.
183
what is PD-1?
• PD1 is a cell surface receptor expressed on T cells and some B cells
• Functions as an immune checkpoint which regulates (causes) immunosuppression, thus inducing tolerance to the neoplasm, by preventing activation of T cells against the tumor antigens
• It downregulates the immune response against the tumor.
anti-PD-1 antibody drug, nivolumab for non-small-cell lung cancer, melanoma, and renal-cell cancer
184
what is the frozen tissue section?
he frozen section procedure is a pathological laboratory procedure to perform rapid microscopic analysis of a specimen. It is used most often in oncological surgery
The principal use of the frozen section procedure is the examination of tissue while surgery is taking place
• Margins of excision assessment (does the surgeon need to cut out more tumor/tissue
• An intra-operative diagnosis that will affect the extent of further surgery e.g. liver lesion is it a metastasis or benign
185
geographical epidemiology of cancer?
- Different malignancies are commoner in different parts of the world.
- Breast carcinoma - Europe & USA
- Gastric carcinoma- China & Japan
- Hepatocellular carcinoma - Middle East
- Bladder carcinoma - Egypt
- Nasopharyngeal carcinoma - Asia
- Burkitt’s lymphoma - Africa
- Cervical carcinoma - Africa
186
gastric cancer is prevalent in what countries?
China & Japan
187
hepatocellular carcinoma is prevalent in what countries?
Middle East countries
188
bladder carcinoma is prevalent in whar country?
Egypt
189
nasopharyngeal carcinoma is prevalent in?
Asia
190
Burkitt lymphoma is prevalent in?
Africa
191
cervical carcinoma is prevalent in?
Africa
192
Breast carcinoma is prevalent in?
Europe and USA
