Neoplasia Flashcards
1
Q
What is meant by benign and malignant neoplasms?
A
Benign- limited or no capacity to invade adjacent structures or metastasize
Malignant- high probability of invasion and metastasis
2
Q
What 5 factors allow us to differentiate between benign and malignant tumors?
A
- Demarcation of surrounding tissue
- Induration
- Rate of growth
- Degree of differentiation
- Distance spread (metastases)
3
Q
What is meant by demarcation?
Describe the demarcation of benign and malignant tumors.
A
Essentially it is how defined the borders of the tumor are and how movable it is on palpation.
Benign:
1. sharp, distinct margins
2. freely movable on palpation
Malignant:
1. ill-defined margins (jagged or stellate)
2. fixed to surrounding tissue
4
Q
What about benign tumor growth allows it to be clearly demarcated?
A
It is slow expansible growth where it presses on the surrounding tissue but does NOT invade the surrounding tissue.
Often it is encapsulated (dense collagen made by fibroblasts in response to pressure from the adjacent mass)
5
Q
What does the presence of a capsule say about the tumor growth? Are benign or malignant tumors more likely to have a capsule?
A
Slow, expansive and NON-INVASIVE growth.
The capsule is made of collagen made by fibroblasts in response to the pressure of the surrounding tissue
6
Q
What kind of malignant cancer grows slowly enough that it appears well-circumcised and encapsulated? How can we tell it is malignant?
A
Hepatoma (hepatocellular carcinoma) grows very slowly and is encapsulated.
Malignant tumors almost always exhibit a small foci of penetration of the capsule where they have invaded into the surrounding tissue or vasculature.
7
Q
What is induration?
A
The firmness of the tumor on palpation.
Fibroblasts are recruited by the tumor to make a tumor stroma which is densely collagenous and rock hard on palpation.
8
Q
What is the process of abnormal stroma production by a tumor called?
How does it happen?
Are malignant or benign cells more likely to demonstrate this quality?
A
Desmoplasia- recruitment of fibroblasts and the production of dense collagenous stroma.
Some benign tumors can be very firm, but induration is usually a sign of invasive (malignant) cancer
9
Q
What is meant by differentiation in reference to a tumor?
What are the two ways to determine differentiation?
A
The degree to which the neoplastic cells resemble the normal tissue from which it arose.
- functionally (express and secrete factors normally secreted by that cell type)
- Morphologically (look like normal cells under a microscope)
10
Q
Are benign or malignant tumors generally more differentiated? Why?
A
Benign are usually more differentiated because they have modest genetic load with few mutations.
11
Q
What is the relationship between degree of differentiation and tumor aggressiveness in malignant tumors?
A
They are inversely proportional. The less well differentiated = the more mutations.
The more mutations = the more invasive the cancer
12
Q
What are the four major morphological changes noted in epithelial differentiation?
A
- polarity- basal and apical surfaces
- stratification of epithelial structures
- loss of ability to form glands
- cellularity- density of cells
13
Q
What is meant by polarization of epithelial cells? What would be the morphological change associated with malignant tumors?
A
It means that there are basal and apical surfaces to the epithelial cell.
Malignant tumors are lacking the polarization so there is increased stratification of epithelial structures.
14
Q
If you are looking at the histology of tissue, how would gland formation help you determine the malignancy?
A
The ability to make well-formed glands is lost in moderately differentiated tumors and there will be no glands at all in some poorly differentiated tumors
15
Q
What is meant by cellularity?
A
It is the density of cells seen in tissue as # of cells per unit area.
poorly differentiated cells will be smaller and thus there will be an increased density.
16
Q
What 5 features of nuclear morphology are indicative of tumor cells?
A
- Pleomorphism
- Hyperchromasia
- High N/C ratio
- Mitotic figures (tripolar mitoses- mickey ears)
- Prominent nucleoli
17
Q
What is pleomorphism?
What typically causes nuclear pleomorphism?
A
Greater variability in nuclear size shape and other characteristics of the cell and nuclei.
Nuclear pleomorphism is caused by variation in DNA content (aneuploidy) in tumor cells
18
Q
What is hyperchromasia?
A
Tumor nuclei stain more darkly than normal cell nuclei
19
Q
Why do tumor cells have prominent nucleoli?
A
They have increased:
- metabolic activity
- Protein turnover
- rRNA synthesis
20
Q
What are four “normal cell products” that can be tested to distinguish functional differentiation in tumor cells?
A
- Mucin in glandular cells
- Keratin in squamous cells
- Hormones in endocrine cells
- ECM in bone and cartilage cells
21
Q
What is a signet ring cell? What kind of tumor is it seen in?
A
It is a cell that produces so much mucin, the nucleus gets pushed to the side of the cell.
It is seen in adenocarcinomas specifically in the GI epithelium.
22
Q
What is anaplasia?
What four histological features are noted with it?
A
“backwards growth” describing the extreme degree of loss of differentiation that can be seen in tumors.
- lack of tissue organization
- cell and nuclear pleomorphism
- large, hyperchromatic, bizarre nuclei
- numerous mitotic figures
23
Q
What are the two techniques used to determine histogenesis of anaplastic tumors?
A
- Electron microscopy to I.D. special organelles
2. Immunohistochemistry to I.D. specific products
24
Q
Describe the rate of growth of malignant tumors.
A
They may grow rapidly for a while, then plateau due to:
Limitation of blood supply
Limitation of nutrition
Immunological factors
25
What is the relationship between rate of growth and degree of differentiation?
They are inversely related. The faster a tumor grows, the less differentiated it will be.
26
How does the rate of growth change with tumor progression? Why?
Rate of growth will increase with tumor progression because they will acquire additional mutations.
It is more difficult to treat recurrence.
27
What therapies are used for primary tumors with local interventions?
What therapies are available for metastatic or systemic spread of tumors?
Local:
1. Surgery to remove the tumor
2. Radiation to kill microscopic cells that may be missed by surgical removal
Systemic:
1. Chemotherapy + Radiation
Systemic therapy is only curative in a few select tumor types
28
Metastases is a complex process that implies heavy ___________ that are mostly ______________________.
Heavy load of genetic changes mostly present before the metastases
29
What are two types of tumors that become metastatic very early in their progression?
1. Melanoma
| 2. Small Cell carcinoma of the lung
30
What are the four routes of metastasis?
1. Direct Seeding
2. Lymphatic spread
3. Hematogenous Spread
4. Transplantation
31
What is direct seeding?
The spread within a body by detachment and subsequent implantation in a physically contiguous manner.
Ex. Ovarian tumors will seed into the peritoneal cavity
CNS tumors will seed into the spinal cord and nerve roots
32
What is lymphatic spread?
| What tumor type tends to utilize this method of metastasis?
It is when malignant cells enter the lymphatic drainage system, go to the lymph nodes and proliferate. From there they can spread more via lymphatics or enter the blood via the thoracic duct and spread hematogenously.
Carcinomas spread lymphatically.
33
What is the most likely site of lymphatic spread for:
1. Breasts
2. Lungs
3. Testis
4. Leg skin
1. Axillary lymph nodes
2. Hilar or peribronchial nodes
3. Para-aortic nodes
4. Inguinal lymph nodes (melanoma spreads this way)
34
What is hematogenous spread?
| What tumor type utilizes this method to metastasize?
It is when tumors spread via venous system. Blood-borne metastases can spread practically anywhere.
Sarcomas (mesenchymal malignant tumors) spread this way.
35
Where do the following tumors tend to metastasize?
1. intestinal tumors
2. visceral tumors
3. prostatic tumors
1. to the liver via portal system
2. lungs via systemic venous drainage
3. lower spine via vertebral plexus
36
Where do lung tumors tend to metastasize?
Adrenals
37
Where do renal cell carcinomas tend to metastasize?
Inferior Vena Cava via contiguous spread up the renal vein into IVC
38
What is a gross anatomical sign that there has been metastatic spread?
There will be multiple nodules on the organ of different sizes
39
What are the most common sites of metastasis?
1. lymph nodes
2. lungs
3. liver
4. bone
Less common:
1. brain
2. kidney
Rarely:
1. skeletal muscle
2. heart
3. GI
40
What is transplantation?
When medical procedures (surgery/biopsy/fine-needle aspirations) can give tumor cells access to a new territory.
41
What are two types of tumors that are NEVER biopsied? Why?
1. Testicular masses- because the testes is surrounded by the tunica albugenea that keeps the tumor confined. Biopsy would break this barrier allowing the tumor to seed in the scrotal sac and peritoneal cavity via inguinal canal
2. Ovaries- surgery could allow seeding into peritoneal cavity
42
What type of cancer commonly invades tissue, but almost NEVER metastasizes?
Who is this type of cancer common in?
Basal cell carcinoma invades but does not metastasize. It is common in elderly people with sun-exposed skin
43
What is an example of a benign tumor that deposits tumor at distant sites?
Benign metastasizing leiomyomatosis where uterine smooth muscle tumors seed in the peritoneum or lung
44
What is the difference between grading and staging?
| When they do not agree, which is more important for prognosis?
Grading is the level of histologic differentiation. Higher grades= less differentiation = worse prognosis/more aggressive tumor
Staging is the physical extent or spread of the disease (TNM system)
Stage is more important for prognosis
45
What are the two different grading scales for tumors?
| In what type of cancer does the grading scale NOT correlate to prognosis?
1. low, intermediate, high grade
2. Grade 1-4
Grade does not correlate to prognosis for squamous cell carcinomas of the skin or cervix
46
T=
N=
M=
```
T= size of primary tumor (t1->t4)
N= regional lymph node involvement
M= distant metastasis (M0 or M1)
```
47
TNM stages correspond to one of 5 stages. What are they and what does each mean?
Stage 0= cancer in situ (cells look like cancer but have not spread past the basement membrane)
Stage 1,2,3 = higher number is more extensive disease, greater tumor size, and spread to lymph nodes
Stage 4= spread to another organ (distant metastasis
48
What other variables besides primary tumor size, lymph node involvement and metastasis are considered in staging?
1. depth of invasion in hollow organs (colon cancer)
| 2. lab markers for tumor burden
49
Embryonic Stem Cells are ____________ whereas adult stem cells are _________________.
Which are cancer stem cells analogous to?
```
ES= totipotent and can differentiate into any cell of the body
AS= multipotent and can differentiate into various cells that make up the organ where they reside
```
Cancer stem cells are analogous to adult stem cells
50
What is an adult stem cell niche? What three things does it strike a critical balance between?
```
It is the microenvironment comprised of surrounding cells that communicate with and support the adult stem cell.
It balances:
1. stem cell renewal
2. maintenance
3. differentiation
```
51
In what type of tumor is there good evidence for the existence of cancer stem cells?
In what type of tumor is the existence highly controversial?
Established in hematopoietic malignancies, but highly controversial in solid tumors
52
What does the cancer stem cell hypothesis state?
A cancer stem cell is a rare, undifferentiated cell within a tumor that occupies a niche and can replenish itself and differentiate into a viable tumor.
If a cancer stem cell was transplanted into a suitable host (immunocompromised) it would be able to form an entire tumor.
If it failed to grow it could be because of genomic instability, mutation, partial differentiation
53
According to the cancer stem cell hypothesis, why do many tumors that shrink eventually regrow?
Conventional chemotherapy kills differentiated cells, but not cancer stem cells. The stem cells then differentiate to reform viable tumor.
54
What three signalling pathways are of interest for development of agents and drug targets for cancer stem cells?
1. Wnt
2. SHH
3. Notch
55
What are the four classes of regulatory genes that are critical targets of genetic mutation in cancer?
1. Proto-oncogenes
2. Tumor suppressor genes
3. Genes that regulate Apoptosis
4. Genes involved in DNA damage repair
56
What is meant by tumor progression?
As neoplastic cells evolve, they acquire additional mutations leading to increasingly aggressive behavior and malignant transformation
57
What are the six fundamental changes in cell physiology that dictate a malignant phenotype?
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibition signals
3. Evasion of apoptosis
4. Limitless replication (overcome senescence and mitotic catastrophe)
5. Sustained angiogenesis
6. Invade and metastasize
58
What are the three examples of "self-sufficiency" and growth signals (oncogenes) that we discussed?
1. HER2/NEU
2. ABL (BCR-ABL)
3. RAS
59
What is the difference between a proto-oncogene and an oncogene?
Proto-oncogenes are normal genes that can be mutated or produced in excess to CAUSE oncogenes
Ex. Proto-oncogene is RAS, oncogene is Ras12 the mutated version that has autonomous cell growth
60
Oncoproteins resemble _____________ normally produced from these genetic loci but are either:
1.
2.
to cause excess activity.
They resemble the wild-type protein product of the gene but are :
1. mutated
2. overexpressed
to cause excessive activity.
61
Oncogenes normally act ____________ regardless of the proto-oncogene counterpart in the cell.
dominantly
62
Normally what are the 5 steps in cell proliferation by growth factors?
1. Growth factor binds to cell surface receptor
2. Activated cell membrane receptor activates signal transduction proteins
3. Transmission from cytosol to nucleus
4. Transcription of genes to activate and induce regulatory factors
5. Entry into the cell cycle and cell division
63
What are the two ways that a growth factor receptor can cause tumorigenesis?
What is an example of a mutated growth factor receptor?
1. It can be genetically mutated in the protein sequence ITSELF to cause exuberant activity
2. Regulatory mutation or DNA amplification can cause over-expression of the growth factor receptor
An example would be HER2/NEU and other receptors in the epidermal growth factor receptor family (EGFR)
64
What are two examples of EGF receptor mutations/overexpressions that lead to autonomous growth signaling?
1. ERBB1- overexpressed in 90% of head/neck epithelial tumors
2. HER2/NEU (ERBB2) overexpressed in breast cancer
65
What causes the inflated growth rate of HER2/NEU positive tumors?
How are they treated?
They are extremely sensitive to mitogenic effects of growth factor (lime green on immunohistochemistry)
They are treated by humanized anti-HER2/NEU antibodies (Herceptin) that bind the extracellular domain of the receptor to block activation
66
What is an example of a mutation in a gene encoding components of the signaling pathway for growth factors downstream of the GF receptor?
RAS
67
How does RAS normally work?
| What happens when it is mutated?
1. RAS protein is inactive when bound to GDP.
2. A growth factor stimulates the signal transduction
3. RAS exchanges GDP for GTP and is active.
4. Active RAS stimulates signaling pathways and promotes proliferation.
5. RAS hydrolyzes GTP back to GDP to turn itself off.
The most common mutation is a point mutation that eliminates the intrinsic GTP hydrolysis activity leaving it constitutively activated
68
How are RAS mutations treated?
| What are they resistant to?
Drugs that interfere with RAS-mediated signaling are used as chemo agents.
RAS mutations are resistant to anti-tumor antibodies directed against receptors upstream of them in the growth pathway.
69
What disease is associated with an ABL mutation?
| How does this mutation occur?
ABL is a tyrosine kinase proto-oncogene associated with chronic myeloid leukemia (CML)
ABL gets fused to BCR gene due to chromosomal translocation (9 to 22 Philadelphia chromosome)
BCR-ABL has unregulated tyrosine kinase activity
70
What does ABL normally do that the BCR-ABL fusion cannot?
ABL usually enters the nucleus so BCR-ABL:
1. unregulated tyrosine kinase activity
2. abnormal cellular localization
71
How are BCR-ABL mutations treated?
They are treated with Gleevec/Imatinib which is a drug that interacts with the BCR-ABL hybrid but neither component alone. This makes treatment very specific and effective.
72
How do anti-growth signals (tumor suppressors) prevent cell proliferation?
1. direct division-capable cells into G0 (quiescence)
2. direct division-capable cells into post-mitotic differentiated state (senescence)
(1 is reversible and 2 is irreversible)
73
What are the three major tumor suppressors we discussed?
1. Retinoblastoma (RB)
2. p53
3. APC
74
What is retinoblastoma? How are the mutations acquired?
Retinoblastoma is a childhood malignancy of the retinal epithelium.
60% are sporadic and 40% are inherited in an autosomal dominant fashion
75
What is the two-hit hypothesis?
Inactivating mutations in BOTH RB genes are required for retinoblastoma tumorigenesis. (if you only have one mutation, you still have 1/2 the "brakes" on growth)
If one defective RB gene is inherited, spontaneous mutation or epigenetic silencing of the other is required for tumorigenesis.
76
Tumor suppressor genes act in a ________________ manner while oncogenes act in a _________________ manner.
Tumor suppressors are recessive (need both mutations to have tumorigenesis).
Oncogenes are dominant (one mutation is sufficient to disregulate cell growth)
77
How does RB gene regulate mitosis?
It controls G1 to S transition of the cell cyle. (The most critical checkpoint for neoplasia).
1. Early G1, RB is hypophosphorylated and active. It binds to E2F transcription factor to inhibit it
2. Under growth conditions, RB is hyperphosphorylated by CDK and turned off releasing E2F
3. E2F induces expression of cyclin E (a growth promoter) which replicates DNA
78
What are the 4 genes athat are typically mutated or amplified in most human cancers?
1. CDKN2A
2. cyclin D
3. RB
4. CDK4
79
What DNA viruses neutralize the inhibitory function of RB?
HPV and SV40
80
About 70% of all human tumors are homozygous for the loss of ________________ activity.
p53
81
What are the three ways that p53 fight off neoplastic transformation?
1. Temporary cell cycle arrest (G0 quiescence)
2. Permanent cell cycle arrest (senescence)
3. triggering apoptosis
82
What does p53 do when it senses DNA damage?
the p53 protein is released from MDM2 inhibition and becomes an activated transcription factor.
It transcribes genes that:
1. arrest the cell cycle- so the cell can repair the DNA damage
2. Induce apoptosis- if the cell is beyond repair
83
What is the syndrome when individuals inherit one p53 mutation in their germline?
Li-Fraumeni syndrome.
| They just need one more hit for tumorigenesis so they are at a 25-fold increased risk for developing a malignant tumor
84
What viruses target normal p53 activity and thus are oncogenic?
EBV and HBV
85
What is the gross clinical presentation of familial adenomatous polyposis coli?
What causes it?
Adenomatous polyps throughout the entire colon and the stomach.
Transformation of the polyps to malignancies are inevitable and usually this occurs by the 3rd decade of life
This disease is caused by the loss of the APC tumor suppressor gene allowing B-catenin to go unregulated
86
What are the functions of B-catenin in epithelial cells? If it goes unregulated, what will it cause?
B-catenin is used for cell-cell adhesion and transcriptional activation (mediated by Wnt proteins)
If it goes unregulated, it will constitutively translocate to the nucleus, transcribe genes and ultimately cause familial adenomatous polyposis coli.
87
What is the normal sequence of events for B-catenin nuclear translocation?
1. Wnt ligand binds Frizzled and LRP-family transmembrane receptors
2. Binding of Wnt releases B-catenin from APC (an inhibitory cytoplasmic protein)
(When Wnt signaling is not present, APC binds and degrades B-catenin)
3. B-catenin translocates to the nucleus to transcribe MYC and cyclin-D genes
88
How does APC disease progress?
1. Patients inherit one mutant allele. The cells still function relatively normally
2. The second APC gene is mutated or epigenetically silenced resulting in malignant change in polyps
3. Additional mutations in RAS or growth promoting genes promote progression of polyps to full-blown transformation to malignant carcinoma
89
How does BCL2 promote tumorigenesis?
| What type of cancer does it specifically play a role in?
BCL2 is anti-apoptotic by inhibiting the permeabilization of the mitochodrial outer membrane. It is on chromosome 18 and is translocated to chromosome 14 next to a gene that regulates Ig heavy chain. Since this is expressed in B cells, high levels of BCL2 are expressed in the translocation positive B cells.
BCL2 mutation is involved in follicular lymphomagenesis
90
How many doublings do most human cells have the capacity to undergo?
60-70 and then they lose the capacity and enter senescence. This process is mediated by the shortening of telomeres that will signal p53 and RB when they get too short
91
At about what size will a tumor need to promote angiogenesis to get more vascularization?
1-2mm
92
What are the critical angiogenesis molecules utilized by tumors or stromal cells to promote vascularization?
VEGF and HIF1-a
93
What four steps are required for a tumor to metastasize?
What is the rate-limiting step of metastasis?
1. Breaking of cell-to-cell contact
2. Degradation of the ECM
3. Attachment of migrating cells to new ECM components
4. migration of tumor cells to distant sites
The migration to distant sites is the rate-limiting step
94
For cells that enter the blood supply, where is the metastatic site?
The first capillary bed they encounter
| Liver for colon cancer, lung for liver cancer
95
What is organ tropism? What is an example of a cancer that demonstrates this?
It is when a tumor has a specificity for a specific tissue type.
Prostate adenocarcinoma has a tropism for bone because of SHH signaling.
96
What are three inherited mutations of genes involved in DNA repair that have a predilection for malignant tumors?
1. Hereditary nonpolyposis colon cancer syndrome
2. Xeroderma pigmentosa
3. BRCA1/BRCA2 for breast cancer
97
What are the three common types of karyotypic changes in tumors?
1. balanced translocations (BCR-ABL, BCL2)
2. deletions
3. Gene amplification (HER2/NEU)
98
Balanced translocations are extremely common, especially in _________ and _____________.
1. hematopoietic neoplasms
| 2. soft tissue sarcoma (rhabdomyosarcoma, Ewing sarcoma)
99
What are the two ways that balanced translocations cause tumorigenesis?
1. Over express proto-oncogenes by removing them from normal control and placing them under an inappropriate promoter (ex. BCL2 next to Ig heavy chain)
2. Fusion genes that combine DNA sequences, cause chimeric protein expression with enhanced novel properties (BCR-ABL)
100
What type of cancer is relatively uncommon in children? What type of cancer is relatively more frequent in childhood than adulthood?
Children have more frequent incidence of soft tissue sarcoma where adults have more frequent carcinoma
101
What is the largest group of pediatric malignancy?
Leukemias and lymphomas followed by brain tumors
102
What two types of cancer did we discuss that are common for ages 0-4?
Neuroblastomas and Wilms Tumor (kidney malignancy)
103
What two common types of cancer did we discuss for the 5-9 age group?
Neuroblastoma and Rhabdomyosarcoma
104
What are the five most common embryonal lesions that cause common pediatric tumors?
1. kidney (Wilms)
2. liver (hepatoblastoma)
3. sympathetic nervous system (neuroblastoma)
4. muscle (embryonal rhabdomyosarcoma)
5. eye (retinoblastoma)
105
What is the most common solid tumor of infancy and childhood outside of the central nervous system? When do most of these tumors arise, and where are they located?
Neuroblastomas
Most occur before the age of 2.
50% are abdominal and over half of these arise from the adrenal gland.
The rest usually are paravertebral having arisen from sympathetic ganglia
106
How do children with neuroblastoma present to the physician?
Half of the patients with neuroblastoma present with metastatic disease with bone and bone marrow involvement.
107
From what cells do neuroblastomas arise?
primitive neural crest cells destined to form the sympathetic nervous system
108
What are the gross clinical features of neuroblastoma?
Immature neuroblastoma are soft and dark reddish grey. They have white foci of calcification and sheets of neuroblastic cells found in rosettes surrounded by pink fibrillar tissue.
109
What is the name given to neuroblastoma that has mature and immature elements? What are the "mature" elements?
Mature neuroblastomas have ganglion cells and Schwann cells.
If the tumor has this as well as the neuroblastic cells it is called a ganglioneuroblastoma.
110
What is the name given to a tumor with only "mature" elements : ganglionic cells and Schwann cells? What is their gross appearance?
ganglioneuroma- shiny tan and firm gross appearance as opposed to the immature soft, reddish grey appearance
111
What 5 factors are considered to be more adverse for the outcome of a neuroblastoma?
1. Being older than one year of age (regardless of histology)
2. Metastasis beyond local lymph nodes
3. Lack of differentiation
4. NMYC amplification
5. diploid tumor
112
What is Stage IVS disease?
A neuroblastoma that is localized to liver, skin and/or bone marrow. It has a high cure rate (over80%)
113
Serum or urine levels of what metabolites would clue you in to make the initial diagnosis of neuroblastoma?
catecholamine and dopaminergic metabolites like:
1. vanillylmandelic acid (VMA)
2. homovanillic acid (HVA)
114
Wilms tumor is a tumor of what organ? What age children does it most commonly present in?
How do the children present to the physician?
It is a tumor of the kidney that presents in children between 2 and 4.
They have swollen bellies but it is usually asymptomatic and discovered accidentally (grandma or grandpa notice and tell the parents)
115
The majority of Wilms tumors are ___________ but some can be associated with what 3 genetic syndromes?
Most are sporadic but some can be associated with:
1. Beckwith-Wiedemann (imprinting or gene deletion)
2. WAGR syndrome
3. Denys-Drash syndrome
With BW it is because of imprinting or gene deletion but with the rest it is a mutation of WT1 gene which is a TF and tumor suppressor
116
Where does Wilms tumor metastasize to?
Lungs
117
Describe Wilms Tumor grossly,.
It is large, spherical and sharply circumcised.
It has a fibrous pseudocapsule.
The are soft, pale and have areas of necrosis and hemorrhage.
118
Describe Wilms tumor histologically.
They are triphasic with blastemal, epithelial and stromal components
119
What is the most common soft tissue sarcoma of childhood?
| When does it present and what three anatomical areas are most affected?
Rhabdomyosarcoma which presents in the first decade of life in skeletal muscle of :
1. head and neck (orbit, nasopharynx, sinuses)
2. GU/pelvis (prostate, bladder, vagina)
3. Extremities
120
Describe the histology of rhabdomyosarcoma.
1. pleomorphism and hyperchromatic small cells
| 2. tadpole cells with dense eosinophilic cytoplasm with striation
121
What is a botryoid rhabdomyosarcoma?
When embryonal tumor arises beneath an epithelial surface like the bladder or vagina and projects into the lumen like a grape cluster
122
What is the treatment for rhabdomyosarcomas?
combo therapy of radiation, surgery and chemo
123
What is the most lethal form of rhabdomyosarcoma?
What genetic problems causes it?
How does it present histologically?
Alveolar rhabdomyosarcoma- associated with FKHR chromosomal translocation on 13 with PAX3 (on 2) or PAX7 (on 1)
It presents with nests and sheets of malignant cells separated by thin septa
124
What stain can you use to test for rhabdomyosarcoma?
Desmin because it stains brown with muscle
125
What are the three categories of physical agents that can cause cancer?
1. chemicals
2. radiant energy
3. microbial agents
126
What is immune surveillance?
The body's immune system constantly surveys for malignant and premalignant cells to destroy.
It identifies tumor-specific antigens allowing normal cells to be distinguished from abnormal
127
What are the two classifications for chemical carcinogens?
1. Direct-acting agents that require no metabolic conversion (WEAK)
2. Indirect-acting agents that require metabolic conversion (ex. polycyclic hydrocarbons, benzo-pyrene in tobacco smoke)
128
What genetic factors dictate cancer susceptibility by indirect-acting agents?
Indirect agents need to be metabolized so genes that encode p450 monooxygenases will determine an individuals susceptibility to carcinogenesis.
p450 monooxygenases are polymorphic so there is a lot of variation in the population
129
What is an example of a chemical carcinogen that can be consumed in food?
aflatoxin B1 is produced by Aspergillus which is grown in grains/nuts.
This is thought to be the cause of hepatocellular carcinoma in the Far East and Africa
130
What are the properties of chemical carcinogens that allow them to cause cancer?
1. They have highly reactive electrophile groups that form adducts with DNA
2. They target oncogenes and tumor suppressor genes
131
How does ionizing radiation act as a carcinogen?
| What is an example of ionizing radiation?
It causes chromosomal breaks and abberations leading to genetic damage and carcinogenesis
ex. chernobyl increased risk of thyroid cancer
132
How does UV radiation act as a carcinogen?
| What is an example?
It induces pyrimidine dimer formation in DNA leading to mutation
ex. overexposure to sunlight--> melanoma
133
What are the oncogenic RNA viruses most associated with cancer?
HTLV-1 retrovirus causes T-cell leukemia endemic to the Caribbean and Japan.
It has tropism for CD4 cells
134
How does HTLV-1 cause T-cell leukemia?
| Is the process polyclonal or monoclonal?
HTLV-1 genome encodes TAX viral protein that activates cytokine genes and their receptors in T cells.
This causes the T cell to proliferate polyclonally.
Once a secondary mutation occurs, it leads to a monoclonal leukemia.
135
What are four DNA viruses that are oncogenic?
1. EBV
2. Hep C
3. Hep B
4. HPV
136
What four types of cancer are EBV implicated in?
1. Burkitt lymphoma
2. B-cell lymphoma in AIDs
3. Hodgkin lymphoma
4. nasopharyngeal carcinoma
137
How does EBV cause cancer?
It does NOT carry transforming genes but the EBV gene products contribute to oncogenesis by stimulating B cell proliferation.
It binds to CD21 complement receptor on the B cell and induces proliferation.
Proliferating B cells lead to increased risk of second mutation (like MYC gene translocation to Ig heavy chain locus)
138
How many subtypes of HPV are there that cause benign squamous papillomas?
What HPV subtypes cause low risk infections with low malignancy?
What HPV subtypes cause high risk infections that lead to squamous cell carcinoma of cervix, anogenital region or oral pharyngeal cancer?
There are 60-70 subtypes.
Low malignancy:
HPV6 and HPV11
High malignancy:
HPV16 and HPV 18
139
How does Hep B virus lead to cancer? What organ is infected?
HBV does NOT encode transforming sequence.
The effect is due to chronic inflammation, hepatocyte injury and regeneration and continued proloferation after regeneration because of DNA damage.
HBV encondes HBx transcription factor that transcribes TGFb and IGF-1 receptors
140
Describe the oncogenic nature of Hep C virus. What type of virus is it and what organ does it infect?
It is an RNA virus with reverse transcriptase that induces cirrhosis and liver damage--> liver cancer
141
What bacteria is oncogenic?
| What two cancers does it cause?
H. pylori is a G- bacteria in the mucus membrane of stomach and gastric epithelium.
1. Gastric adenocarcinoma
2. Gastric lymphoma
142
How does H. pylori cause gastric adenocarcinoma?
Infection causes persistent chronic inflammation leading to gastritis.
Chronic gastritis-> gastric atrophy-> intestinal metaplasia-> dysplasia-> adenocarcinoma
143
How does H. pylori cause gastric lymphoma?
Susceptible B cells are in the marginal zones of gastric lymphoid follicles. (MALT)
Chronic inflammation ->exuberant stimulation of B cell follicles-> accumulated DNA damage-> neoplasm
144
What is the treatment for a MALT lymphoma that is found early?
Antibiotics
145
What is the difference between a tumor specific antigen and a tumor associated antigen?
Tumor specific- only on tumor cells
| Tumor associated- on tumor cells and normal cells but the body recognizes it as being on tumors
146
What is an oncofetal antigen?
| What are two examples?
It is an antigen that is expressed normally in embryogenesis but disappears in adult tissue (but reappears in tumorigenesis).
1. CEA- carcinoembryonic antigen
2. AFP- alpha fetoprotein
147
What is CEA?
What two cancerous lesions is it expressed in?
What is this antigen most useful for?
Carcinoembryonic antigen- luminal glycoprotein involved in cell adhesion.
Pancreatic and colon cancers
Because the antigen lacks specificity for cancer, it is most useful for monitoring recurrence of carcinoma post-surgery
148
What is AFP?
| What type of canders is it seen in?
Alpha fetoprotein- a glycoprotein globulin secreted by fetal liver and yolk sac.
1. hepatocellular carcinoma
2. germ cell tumors (testicular and teratoma)
3. endodermal sinus tumors (yolk sac tumors)
149
How are some glycoproteins considered tumor antigens?
If they are aberrantly made and the chain is too long, truncated OR there is too much normal glycoprotein
150
What normal glycoprotein is overexpressed in melanoma and colon cancer?
gangliosides
151
How do mucins serve as tumor specific antigens?
| What cancers are they found in?
They are under-glycosylated and do not require MHC for T cell recognition.
Expressed in breast, ovarian, colonic, and other carcinomas
152
What are the two mucin serum markers? What type of cancer is each associated with? What are the specificity of each?
CA-125 is a serum marker for ovarian cancer
CA-19-9 is a sensitive marker for pancreatic cancer
Neither are specific
153
What are examples of oncogenes or tumor suppressor genes that can be mutated (thus creating new antigens)?
p53, RAS, CDK4
| Since they are mutated, these antigens will only be expressed on tumors and thus serve as good drug targets
154
What is an example of an antigen that is over-expressed in tumors?
HER2/NEU is overexpressed in breast cancer
| Tyrosinase is overexpressed in melanoma
155
Over-expressed antigens are targeted by _______________ as therapy.
Viral antigens are targeted by _________.
Overexpressed antigens are treated with antibodies (ex. Herceptin in HER2/NEU overexpression)
Viral antigens are presented in MHC class 1 so they are targeted by cytotoxic T cells
156
What is the dominant anti-tumor mechanism in vivo?
| What 4 cells are involved?
Cell-mediated immunity dominates.
1. Cytotoxic T cells
2. NK cells
3. Macrophages
4. Humoral mechanisms (B and plasma cells)
157
What do cytotoxic T cells appear to protect principally against?
Viral associated neoplasms like EBV-induced Burkitt lymphoma and HPV induced squamous carcinoma
158
How do NK cells kill?
| How do macrophages have antitumor effects?
NK are activated by IL-2 and then kill without sensitization. Most active against cells with low expression of MHC1
Macrophages produce ROS or secrete TNF to kill tumor cells
159
What are the 3 "escape mechanisms" for how cancer cells evade the immune system?
1. selective outgrowth of antigens (down-regulation of tumor antigens)
2. lost or reduced MHC molecules
3. spontaneous pathogen-induced or drug-induced immunosuppression
160
What are the 4 main local effects tumors have on the host?
1. destruction of normal tissue
2. ulceration through natural boundaries -->hemmorhage or necrosis
3. Tumor rupture/infarction
4. Obstruction or perforation of hollow viscera
161
What are the 3 ways tumors can destroy normal tissue locally?
1. Pressure effects
2. Direct destruction by invasive growth
3. replacement of hematopoietic marrow
162
What are 3 examples of hormones over-expressed in tumors?
1. Insulinoma of pancreas
2. ACTH over-production in pituitary tumors
3. Thyroid adenoma producing thyroxin
163
What is cancer cachexia?
| What is thought to be the cause?
Progressive loss of fat and muscle leading to wasting. (not the same as anorexia)
It is not accounted for by tumor metabolic requirements.
The cause is thought to be the overproduction of cytokines produced by the tumor or through host response to the tumor (TNF)
164
What is a paraneoplastic syndrome?
| What are two main presentations of paraneoplastic syndrome?
These are symptoms not accounted for by local or distal spread of the tumor.
1. Endocrinopathies NOT normally secreted by that tissue type (ex. ACTH pruduction in small cell lung cancer, or ADH secretion in bronchogenic carcinoma and myasthenia)
2. Vascular and hematologic derangement (ex. venous throbosis in pancreatic carcinoma)
165
What are the 4 major effects of tumors on the host?
1. Local effects
2. Cancer cachexia
3. Paraneoplastic syndrome
4. Hormonal effects
166
What are the two primary types of cytology specimens?
1. Exfoliative- like Pap Smear where cells are removed from organ or tissue
2. Fine Needle Aspiration- syringe sucks out tumor cells from organ or mass then it is smeared
167
What are the benefits of cytology for tumor diagnosis?
| What are the drawbacks?
Benefits- quick, non-invasive
| Drawbacks- limited specimen sample, no tissue architecture
168
What three antibodies have been used for immunohistochemistry? What type of cancer does each help ID?
1. PSA- prostate specific antigen for prostate cancer
2. Desmin- for muscle lineage cancers
3. HER2/NEU herceptin - for breast cancer
169
What does flow cytometry allow the identification of?
1. Clonality of B or T cell populations
2. nucleic acid content
3. classification of hematolymphoid lineage malignancies
170
What is a pro and a con of using tumor markers?
Pro- allows to monitor relapse
| Con- markers can be expressed in normal tissue and benign conditions (benign prostatic hypertrophy--> PSA expression)
171
What two molecular cancer diagnostic techniques are used to diagnose CML due to a PHL translocation (9/22)?
1. FSH
| 2. PCR for BCR-ABL fusion transcript
172
Describe the technology used in gene chip molecular profiling of tumors.
1. mRNA is extracted from two tissue- normal and tumor from same histologic tissue
2. cDNA are prepared for the mRNA and are fluorescently labeled
3. Red= cancer gene, Yellow= both, Green = normal gene
