Neoplasia

Tuesday, August 18, 2015 9:10 PM

1. Define the following

Neoplasia - Neoplasia is cell growth that is monoclonal (arise from single cell),
unregulated, and irreversible.
- Contrast to hyperplasia (ex hyperplasia of uterus during childbirth) which
is polyclonal and is regulated.
Desmoplasia - Process by which tumor becomes firm (it is because neoplastic cells induce
fibroblasts within the stroma to form abundant collagen)
Carcinoma - (aka high-grade dysplasia) - when dysplastic changes involve entire
in site thickness of epithelium (earliest form of epithelial malignancy)

2. What are two ways to determining monoclonality?

- G6PD or androgen receptor isoforms,
- Ig light chain phenotype for lymphomas.

3. How is monoclanity determined from G6PD?

- G6PD is a protein with multiple isoforms which is encoded in X-chromosome. Lets say a
female has isoforms A and B in her 2 x chromosomes. Due to random silencing of X-
chromosomes, her A:B protein ratio in hyperplasia or normal condition will be 1:1. If the
ratio is different from 1:1, it strongly suggests monoclonality.

4. How is monoclonality determined from Ig light chain phenotype?

- The ratio of K to Lambda light chain is 3:1. If the ratio is different than this, it suggests
monoclonality

6. What are differences between benign and malignant neoplasm?

Benign neoplasia Malignant neoplasia
Remain localized and do not Invade locally and have potential to metastasize (don't
metastasize have to be already metastasized)
Slow-growing Rapid growing
Distinct Infiltrative
Mobile Fixed to surrounding tissue

7. Name the lineage of following benign and malignant tumors:

Cell lineage Benign Malignant (cancer)
Epithelium Adenoma Adenocarcinoma
Papilloma Papillary carcinoma
Mesenchyme Lipoma Liposarcoma
Angioma Angiosarcoma
Chondroma Chondrosarcoma
Osteoma Osteosarcoma
Lymphocyte doesn't exist Lymphoma
Melanocyte Nevus (mole) Melanoma (not melanosarcoma)

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 Adenoma = tumor that makes glands
Papilloma = tumor that makes papillary finger like structures

8. What are leading cause of death in adults in children? (HY)

Adults Children
1. Cardiovascular disease 1. Accidents
2. Cancer 2. Cancer
3. Cerebrovascular disease 3. Congenital defects

9. What are leading cancers by incidence and death toll in male and females?
Cancer by incidence Male 1. Prostrate 2. Lung 3. Colorectal
Female 1. Breast 2. Lung 3. Colorectal
Cancer by death tolls Male 1. Lung 2. Prostrate 3. Colorectal
Female 1. Lung 2. Breast 3. Colorectal
- Table excludes squamous cell and basal cell carcinoma of skin - very common and
malignant but rarely metastasize. Detected early and easily treatable.
- Lung cancer doesn't have easy screening test like others. It's usually detected late.

10. What are some properties of neoplasia?

- Approximately 30 divisions before earliest symptoms arise (2^30 cells)
- Subsequent divisions results in increased mutations
- Cancers that don't produce symptoms till late (ex-ovarian, pancreatic, lung cancer- because
lots of space to expand) will have accumulated tons of mutations and hence poor prognosis

11. What area goals of cancer screening?

- Catch dysplasia before it becomes carcinoma (dysplasia is reversible)
- Detect carcinoma before clinical symptoms
Tests Detection
Pap smear - Cervical intraepithelial neoplasia
Mammography - Breast cancer
- Ductal carcinoma in-situ
PSA (prostrate specific - Prostrate cancer (usually grow on rectal side and doesn't
antigen) and DRE (digital produce urinary syndrome until late; BPH grows centrally
rectal exam) and produce urinary syndrome)
Hemoccult test and - Colorectal cancer
colonoscopy - Detect blood in stool (hemoccult test)

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Carcinogenesis 1
Sunday, October 25, 2015 8:38 PM

1. What do carcinogens do? What are examples?

- They damage DNA. Ex - chemicals, viruses, radiation.

2. What are cancer associations of the following chemicals? (HY)

Chemicals Cancer Remarks
Aflatoxins - Hepatocellular carcinoma (most common cancer - Derived from Aspergillus
in some African countries) flavus;
- Usually contaminates
stored grains
Alkylating - Leukemia - Found in chemotherapy
agents - Lymphoma drugs
Alcohol - Squamous cell carcinoma (SCC)of oropharynx and
upper esophagus(another risk is tobacco)
- Pancreatic carinoma (EtOH causes chronic
pancreatiis that incrases risk of cancer)
- Hepatocellular carcinoma
Arsenic - SCC of skin (women used to apply Arsenic to be
fair-skinned) - test Arsenic poisoning from
fingernail and hair follicles
- Lung cancer (Arsenic present in cigarettes)
- Angiosarcoma of liver
Asbestos - Lung cancer (far more likely) and mesothelioma
Cigarette - SCC of oropharynx and esophagus - MOST COMMON
- Lung cancer CARCINOGENIC
- Kidney and bladder cancer (urithelial carcinoma - WORLDWIDE
cells that line urinary tubes; most IMP risk factor: - Polycyclic hydrocarbons
cigerrate - toxins from smoking in urine irritate main carcinogen
the cells)
Nitrosamine - Stomach carcinoma (intestinal type) (other - Found in smoked food;
stomach carcinoma is diffuse type but responsible for high
nitrosamine not associated) stomach cancer in Japan
Napthylaine - Urothelial carcinoma of bladder - Derived from cigarette
smoke (excreted by
urine)
Vinyl chloride - Angiosarcoma of liver - Occupational exposure
(used to make PVC pipes)
Nickel, - Lung cancers - Occupational exposure
chromium,
beryllium, or
silica
- 1 Billion people smoke worldwide

3. What are ongogenic association of the following viruses?

Virus Cancer type
EBV - Nasopharyngeal carcinoma (Classic pt - Chinese male, African person) -

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 EBV - Nasopharyngeal carcinoma (Classic pt - Chinese male, African person) -
metastasizes early; classic presentation is neck mass
- Burkitt lymphoma (Classic pt - African kids)
- CNS lymphoma in AIDS
HHV-8 - Kaposi sarcoma (tumor of endothelial cell) (Classic pt - 1. older Eastern
european males - take tumor out; 2. AIDS pt - treat HIV; 3. transplant pt -
reduce immunosuppression)
HBV and HCV - Hepatocellular carcinoma
HTLV-1 - Adult T-cell lukemia/lymphoma
HPV (type 16, - SCC of anogenital area (vagina, vulva, cervix, anus)
18, 31, 33) - Adenocarcinoma of cervix

4. What are cancer association of ionizing and non-ioninzing radiation?

Radiation type Cancer types MOA
Ionizing (nuclear - AML - Generation of hydroxyl free radical
reactor, - CML
radiotherapy) - Papillary thyroid carcinoma
(Cherbonyl kids have lots of
papillary cancer)
Nonionizing (UBV - Basal cell carcinoma of skin - DNA damage (formation of too much
from sun most - SCC of skin pyrimidine dimers to be excised by
common) - Melanoma of skin restriction endonuclease)
- In xeroderma pigmentosum, restriction endonuclease is bad and pt has high risk of BCC, SCC and
melanoma of skin

5. What is most common cause of ionizing radiation in USA?

- Radon (formed by decay of uranium) - present in soil and accumulates in closed space (basement)
2nd most common cause of lung cancer in USA

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Carcinogenesis 2
1. What are three systems to be disturbed in carcinogenesis? (HY)
- Proto-oncogene
- Tumor suppressor genes
- Regulator of apoptosis

Protooncogenes
2. What are protooncogenes and how can they cause cancer?
- Proto-oncogenes are essential for regular cell growth and differentiation
- Mutation produces oncogenes that leads to unregulated cell growth

3. What are examples of protooncogenes?

- Growth factors and their receptors
- Signal transducers
- Nuclear regulators (transcription factors)
- Cell cycle regulators (move cell division stuff around in cell)

- Normally, binding of growth factors to its receptor induces signal transduction. In

nucleus, cell cycle regulators are activated that induce cycling of cells through G1 - S -
G2 - M stages of cell division

4. What cancer are the following protooncogenes associated with and what's their
function and mechanism of causing cancer?
Cancer Function of MOA of cancer
protooncogene
Growth factor
PDGFB - Astrocytoma - Platelet derived Overexpression,
growth factor autocine loop
Growth factor
receptors
ERBB2 - Subset of breast Epidermal growth Amplification
(HER2/neu) cancer factor receptor
RET - MEN2A, MEN2B Neural growth factor Point mutation
- Sporadic MTC receptor
KIT - Gastrointestinal Stem cell growth Point mutation
stromal tumor factor receptor
Signal
Transducers
RAS gene family - Carcinoma GTP-binding protein Point mutation
- Melanoma
- Lymphoma
- (Found in ~70% of
all cancers)
ABL - CML Tyrosine kinase Translocation - t(9,22)
- Some ALL with BCR
Nuclear
regulators
C-MYC - Burkitt lymphoma Transcription factor T (8,14) involving IgH

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C-MYC - Burkitt lymphoma Transcription factor T (8,14) involving IgH
(heavy chain)
N-MYC - Neuroblastoma Transcription factor Amplification
L-MYC - Lung carcinoma Transcription factor Amplification
(small cell)
Cell-cycle
regulators
CCND1 (cyclin Mantle cell Cyclin T(11, 14) involving IgH
D1) carcinoma
CDK4 Melanoma Cyclin dependent Melanoma
kinase

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Carcinogenesis 3 (clinical characters)
Monday, October 26, 2015 7:00 AM

1. Differentiate benign and malignant neoplasia.

Benign neoplasia Malignant neoplasia
Remain localized and do not Invade locally and have potential to metastasize (don't
metastasize have to be already metastasized)
Slow-growing (years) Rapid growing (weeks/months)
Distinct (well localized, ex - can isolate Infiltrative (can't distinguish from surrounding breast
by breast exam) tissue in physical exam)
Mobile (ex - you can grab a breast Fixed to surrounding tissue
tumor and move it around)
- Classification of benign vs malignant requires biopsy

2. What are histologic differences of benign and malignant tumor?

Benign neoplasia (well-differentiated) Malignant tumor (poor differentiation)
- Organized growth - Disoganized growth (doesn't look like tissue it's
growing in)
- Uniform nuclei - Nuclear pleomorphism with hyperchromasia (very
dark blue)
- Low nuclear to cytoplasm ratio (more - High nuclear to cytoplasm ratio (less cytoplasm, big
cytoplasm) nuclei)
- Minimum mitotic activity - High mitotic activity
- Lack of invasion - Invasion
- No metastatic potential

Fig: Follicular thyroid adenoma (left) - note organized cell growth with colloid in between cells,
uniform nuclei with lots of cytoplasm, minimum mitotic activity. Anaplastic thryoid carcinoma
(right) - disorganized growth (cells look nothing like thyroid), large nuclei:cytoplasm ratio, nuclear
pleomorphism, mitotic figure (very dark nuclei cell).

3. What's the absolute distinguishing feature between benign and malignant tumors?

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 3. What's the absolute distinguishing feature between benign and malignant tumors?
- Potential to metastasize (benign tumors never metastasize, malignant tumors can metastasize)

3.5 What are some ways of identifying cell types in tumor?

- Immunohistochemistry
- Serum tumor markers

4. What is intermediate filament? How is immunohistochemistry of intermediate filament helpful in

grouping cancer? (HY)
- Intermediate filament are a type of cytoskeletal protein; different intermediate filament are
present in different cell types. -
- Immunohistochemistry of intermediate filament helps in identifying cell types in tumor.
Cell type Intermediate filament present
Epithelium Keratin
Mesenchyme (connective tissue) VImentin
Muscle Desmin
Neuroglia GFAP
Neurons Neurofilament

5. What immunohistochemical molecules help identify cancer of following cell types?

Cell type Immunohistochemistry
molecule
Prostrate PSA (prostrate surface antigen)
Breast epithelium ER (estrogen receptor)
Thyroid follicular cells Thyroglobulin
Neuroendocrine cells (small cell cancer of lung and carcinoid Chromogranin (HY)
tumor)
Melanoma S-100
- Well differentiated neuroendocrine tumor = carcinoid tumor. Poorly differentiated neuroendocrine
tumor = small cell cancer.

6. What are serum tumor markers and what's their utility?

- They are proteins released by tumors.
- Useful for
Screening (ex- high PSA) - still need biopsy for diagnosis
monitoring response to treatment (ex- PSA should drop after prostrate cancer surgery)
recurrence of tumor (ex - same pt returns 2 year later with bone pain; check for PSA to see if
it's prostrate cancer again)

7. What does tumor grading of well differentiated and poorly differentiated mean?
- Well differentiated - tumor resembles parent tissue - good prognosis
- Poorly differentiated - tumor doesn't resemble parent tissue - poor prognosis
- Look at cellular architecture and nuclear morphology to classify differentiation

8. What's staging of cancer? What's its value?

- Staging of cancer is based on size and spread
- It's no. 1 prognostic factor (more important than grade)
- Determined after final resection of tumor

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9. What's TNM staging of cancer?
- T = tumor size and depth (size important for solid organ tumor, and depth important for tubular
organs like colon)
- N = spread to regional lymph nodes (2nd most important prognostic factor)
- M = metastasis (no. 1 prognostic factor)

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Tumor progression
Monday, October 26, 2015 7:48 AM

1. What are the steps in invasion and spread of tumor?

- Downregulation of e-kedherin (e-kedherin is an adhesion molecules that keeps epithelial cells
attached to each other)
- Tumor cells attach to laminin in basement membrane
- Tumor cells produce collagenase that destroys collagen 4 in basement mebrane. This helps tumor
pass through basement membrane
- Tumor cells bind to fibronectin in extracellular membrane and spread locally. It can now pass to
blood vessel or lymphatics.

2. How do metastatic cancer spread?

- Lymphatic spread is characteristic of carcinomas and less common for sarcoma.
- Hematogenous spread is characteristic of sarcoma and some carcinoma - usually follows venous
drainage and seeds at first capillary bed encountered
- Seeding of body cavities - most common is peritoneum (ex - by ovarian carcinoma (omental
caking)) but may also occur in the pleural or pericardial cavities, the subarachnoid space, and the
joint spaces

Fig: omental caking by ovarian carcinoma

3. What are carcinomas that spread hematogenously?

- Renal cell carcinoma - renal vein
- Hepatocellular carcinoma - hepatic vein
- Follicular thyroid carcinoma
- Choriocarcinoma (placental cancer - of trophoblast cells - function of placenta is to invade blood
vessels)

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