Pathology Flashcards
Describe the HPV (the virus)
Non-enveloped double stranded DNA virus 8,000bp genome Passed through skin-to-skin contact Responsible for 99% of cervical cancers and can be considered the etiologic agent necessary for cervical cancer to develop. Most common STD.
What are the high risk types of HPV?
Types 16 and 18, account for 70% of cervical cancers Cause cervical dysplasia and cancer Adenocarcinoma has a strong association with type 18 HPV and is a more aggressive cancer with a greater recurrence rates and a higher likelihood of rapid progression or metastasizing.
What are the low risk types of HPV?
Types 6 and 11 Cause condyloma accumunatum (genital warts which can often be treated and are not usually linked with cancer)
What does HPV’s E6 protein do?
Inhibits tumor suppressor p53 resulting in the loss of cell cycle control and inhibition of apoptosis
What does HPV’s E7 protein do?
-Binds to and destabilizes tumor suppressor pRB resulting in the acceleration of DNA synthesis and cell cycle progression as well as the disruption of cell cycle control. -Alters cell metabolism and possibly causes chromosomal changes and mitotic mutations
Why is the HPV vaccine so important?
Cervical cancer is the second most common cause of cancer related death in women, creating a vaccine against HPV prevents cancer. Screening tests reduce morbidity and mortality but cannot prevent infection or precursors to cervical cancer and have trouble detecting lesions that progress quickly or are in early stages.
Describe the HPV vaccine
-Non-infectious and contain no DNA -Made up of virus like particles (VLP) -Recombinant viral capsid protein L1 assembles to this VLP that resemble native HPV particles and elicit a type specific HPV neutralizing Ab response from the patient to protect against future infection. -VLP is created by inserting the L1 gene into a yeast genome where it is transcribed and translated to create a recombinant L1 capsid protein, which then combine with four other L1 particles to create a pentamer, and 72 of these pentamers self assemble to create a non-infectious VLP.
What is the quadrivalent vaccine?
-Contains recombinant L1/VLPs for HPV types 6, 11, 16, & 18. -93-100% effective against preventing cervical precancers caused by types 16 and 18. -Also >99% effective against genital warts caused by types 6 and 11. -Vaccine is used for the prevention of cervical, vulvar, and vaginal cancers, precancers and dysplastic lesions and the prevention of genital warts
What is the bivalent vaccine?
-Contains recombinant L1/VLPs for types 16 & 18. -Vaccine is 93-100% effective against preventing cervical precancers caused by types 16 and 18. -Used for the prevention of cervical cancers, precancers and dysplastic lesions associated with types 16 and 18.
What is the vaccine schedule?
-Both quadrivalent and bivalent require 3 doses, recommended between ages 11 and 12 -2nd dose given 1-2 months after first dose -3rd dose must be separated from the second by at least 12 weeks and from the first by at least 24 weeks (6 months)
What nuclear features should you recognize in comparing tumors to their normal counterparts?
- Irregular nuclear membrane
- Irregular chromatin distribution
- Large nuclei –> increased N/C ratio
- Hyperchromasia
- Abnormal nucleoli
- Multiple nuclei
- Piling up of nuclei
- Increased mitosis
- Abnormal mitotic figures
What cytoplasmic features should you recognize in comparing tumors to their normal counterparts?
- Pleomorphism
- Anaplasia
- Hypercellularity
What 3 steps are required for a malignant transformation?
- Initiation - causes a mutation in the DNA, but does NOT cause proliferation (reversible)
- Promotion - induces cell proliferation, but is NOT mutagenic (reversible)
- Progression - irreversible genetic mutations
What is an initator? Does it cause cancer or proliferation? Is it reversible?
Initiators are compounds (chemicals, reactive electrophiles, UV radiation, etc.) that cause a non-lethal gene mutations. This may lead to hyperplasia or dysplasia, but most do not. They need to be triggered by a promoter to proliferate and become malignant. It is a reversible process.
What is a promoter? Does it cause mutations? Is it reversible?
A promoter is a compund (growth factor, hormones, bile salts, smoke, cytokines, etc.) that induces cell proliferation. It does not cause mutations. It triggers an initiated cell to proliferate. It is a reversible process.
How does Carcinogenesis start in terms of initiators and promoters? Why is the order of events important? Why is timing of events important?
First, an initiator (chemical, UV radiation, ROS from inflammation, etc.) will alter the cells DNA. Second, a promotor will cause that mutated cell to proliferate. Proliferating, mutated cells leads to cancer.
- Order of events is important - initiator then promoter; not promoter, then initiator
- Timing of events is also an important factor - the initiator and promoter need to occur within a reasonable time frame. Triggering an initiated cell 20 years later, will probably not lead to cancer.
How do chemical carcinogens cause DNA mutations? What metabolic enzyme is typically involved?
In general, the P450 enzyme reacts with many chemicals that leads to reactive, electrophilic speices (epoxides, carbonium ions). These react with DNA and RNA to cauase mutations. Some chemicals react directly with DNA.
- Direct Alkylating Agents (chemo drugs) - transfer alkyl groups to guanine residues on DNA
- Polycyclic Hydrocarbons (smoke, burned meat, etc.) - P450 Enzymes metabolize these compounds and form electrophilic epoxides that react with DNA/RNA.
- N-Nitrosamines , Aromatic Amines , Azo Dyes (smoke, cured meats, beers, etc.) - P450 Enzymes metabolize these compounds into highly reactive cabonium ions which can react with DNA.
- Alfatoxins - produced by Aspergillus Flavus. P450 Enzyme activates resulting in an expoxide that binds to guanine residues in TP53 gene.
What are the initators and promotors of cancer with regards to chronic inflammation? What is a potential treatment that would reduce the inflammation the potential cancer?
- Initiators - Reactive Oxygen Species (ROS) damages
- Promoters - Growth Factors (cytokines, PGE2, etc.)
- Treatment - COX-2 inhibitors and anti-oxidants
How do UV & ionizing radiation damage DNA? Describe the process in terms of direct and indirect damage.
What is more mutagenic, UV-A or UV-B?
- Direct - UV radiation causes pyrimadine dimers (thyamine-thyamine - aka cyclobutane dimers) that lead to a distortion of the DNA. This interferes with DNA replication which can lead to singel base substitutions of C–>T or CC–>TT. These are usally fixed by repair genes, but chronic exposure can lead to perminant mutations.
- Indirect - ROS species from inflammation (OH radicals) induce oxidative DNA adducts (8-oxo-deoxyguanosine). Chronic exposure and therefore inflammation can lead to promotion and proliferation of the mutated skin cells.
- UV-B is more mutagenic (higher energy)
What is Xeroderma Pigmentosum?
An autosomal recessive disorder that involves mutations to DNA repair genes - NER (nucelotide excision repair gene). These genes are required to protect the body against DNA damage from UV-B radiation. Causes lots of skin cancer. Chance of cancer is 2000 times more likely.
How do oncoviruses lead to cancer?
Oncoviruses integrate viral DNA into the host genome. The viral DNA is eventually transcribed to form viral proteins. Many of these viral proteins inhibit, induce, or tranlocate various proto-oncogenes or tumor suppressor genes.
For example: HPV viral proteins E7 and E6 inactivate tumor suppresor proteins p53 and rB.
How does the Human Papilloma Virus (HPV) cause cancer? What type of cancer(s) does it cause?
-
HPV
- Inactivate p53 and rB proteins
- Cause _squamous cell carcinomas _
How does the Epstein Barr Virus (EBV) cause cancer? What type of cancer(s) does it cause?
-
Epstein Barr Virus
- Causes a translocation of immunoglobulin genes t(8;14)
- Leads to Burkitt Lymophoma
How does Hepatitis B cause cancer? What type of cancers(s) does it cause?
-
Hepatitis B
- Interferes with p53 protien
- Leads to hepatocellular carcinoma
How does the Human Herpes Viruse 8 (HHV 8) cause cancer? What type of cancer(s) does it cause?
-
HHV 8
- Interferes with p53 and rB
- Causes Kaposi Sarcoma and B-cell lymphoma. Occurs in HIV infected patients
- Neoplastic endothelial cells lining blood filled cascular channels
How does the Human T-lymphotrophic Virus 1 (HTLV-1) cause cancer? What type of cancer(s) does it cause?
-
HTLV-1
- Activates IL-2 and IL-4 in T-cells which leads to proliferation
- CD4 T-cell leukemia and lymphoma
What is hyperplasia? Where is it likely to occur? Is it reversible?
Hyperplasia is the proliferation of normal cells. It occurs in tissue where cells mature and tissue stem cells can proliferate. This includes epithelial, endothelial, endometrium, breast, prostate, etc.
It is a reversible process.
What is compensatory hyperplasia?
Regrowth of tissue to compensate for a loss of tissue (ie - liver regrowth)
Is Hyperplasia a physiologic (normal) or pathologic (disease) process?
It is BOTH!
- Physiologic - wound healing, endometrial lining growth during menstral cycle, liver regeneration
- Pathologic - inflammation, prostate hyperplasia, etc.
What is hyperplasia mediated by….what causes it to occur?
Growth factors (ie - wound healing) and Horomones (ie - estrogen)
What is Metaplasia? Is it reversible?
Metaplasia is a change in the cells differentiation. One type of normal cell (typically a mesenchymal or reserve stem cell) is replaced by another type of normal type. For exampole, a stratfied squamous cell is replaced by columnar cell. This leads to an alteration in function. This is “fertile ground” for neoplastic cell formation.
It is a reversible process
What is dysplasia?
Does it penetrate the basal membrane?
How is it categorized (what are the features)?
Is dysplasia reversible?
- Dysplasia represents a disorderly cell growth and maturation that leads to architectural disorganization. Dysplasia is characterized by varying degrees of neoplastic cellular and nuclear changes such as abnormal basal appearing cells with hyperchromatic nuclei, prominent nucleoli, high N/C ratio, and increased mitoses.
- It does NOT penetrate the basal membrane
- It is categorized from low to high depending on the thickness of the epithelium being replaced by abnormal cells (Thicker=higher grade).
- Dysplasia is reversible, unless it is full thickness.
What are 4 common causes of Metaplasia in the following locations? What is the metaplastic change that occurs in each location?
- Distal Esophagus
- Airways (respiratory)
- Cervix
- Urinary Bladder
- Distal Esophagus (stratifed squamous –> Columnar) due to Acid Reflux
- Airways (pseudostratfied ciliated columnar –>stratified squamous) due to smoking
- Cervix (glandular–>stratfied squamous) due to Low pH
- Urinary Bladder (Urothelium –> stratfied squamous) due to stones or parasites
What is glandular metaplasia?
What is squamous metaplasia?
- Glandular metaplasia is when glandular cells (intestinal, goblet cells) replace other cell types, like squamous cells (Barretts Esophagus)
- Squamous Metaplasia is when squamous cells replace other cell types (columnar, transitional, etc.)
Review the following slides related to Dysplasia:
What is Carcinoma In-Situ (CIS)? Does it penetrate the basal membrane?
- Carcinoma in-situ is considered a high grade dysplasia. It is full thickness. It is a precursor to invasive carcinomas. They have high N/C ratios and clumped chromatin.
- It has not penetrated the basement membrane.
Review the following slides related to Carcinoma In-Situ (CIS):
What is another name for Excess Keratin?
Hyperkeratosis
HPV effects ________ __________, like the skin, cervix, vagina, rectum, esophagus, and upper respiatory tract.
Squamous Epithelium
What is acnthosis?
Thickened squamous epithelium
Describe Koilocytosis
Large irregular dark nucleas that lives in a cave of clear cytoplasm.
Common Warts are commonly caused by what type(s) of HPV?
Warts are commonly caused by types 6 & 11
When nuceli are located in the keratin layer of squamous cells, what is that called?
Parakeratosis
What are the 2 main types of cervical cancer caused by HPV
- Adenocarcinoma In Situ
- Squamous cell Carcinoma
In what area of the cervix is most HPV related cervial cancer found. What zone?
The transition (or transformation) zone - the zone where squmous epithelium change to endocervical epithelium (mucosal cells)
Low grade and High Grade lesions are caracterized by their CIN grade. What are those grades?
CIN = Cervial Intraepithelial Neoplasia Grade
Low Grade Lesions = CIN-1
High Grade Lesions = CIN-2 or CIN-3
Do most HPV infectios and low grade lesions progress to high grade lesoins?
No. Most will regress.
Describe the morpholigical features of CIN-1, CIN-2, & CIN-3
- CIN-1 - Good differentiation of cells in epithelium. Koilocytes are visible.
- CIN-2 - Poor Differentiation, severe dysplasia. High N/C ratios.
- CIN-3 - No differentiation. Full thickness dysplasia. Lots of mitosis. Epithelium is streaming upwards, no longer flat.
What are the current treatments for for HPV lesions based on the CIN grade? This includes CIN-1, CIN-2, and CIN-3.
- CIN-1 = No treatment
- CIN-2 = Drugs or monitor
- CIN-3 = Ablation or Excision
Is the PAP smear test more sensitive or specific?
Specific
- Sensitivity = 47%
- Specificity = 95%
Since it takes many years for the cancer to devleop, the poor sensitivity does not really matter due to the number of Pap smears that will eventually be performed over a womens life.
What system is the Pap Smear diagnosis base on?
What 4 grades or categories does it use for diagnosis?
Bethesda System
- ASCUS - Atypical Squamous Cells of Undetermined Significance
- LSIL - Low Grade Squamous Intraepithelial Lesions
- HSIL - High Grade Squamous Intraepithelial Lesions
- SqCCA - Squamous Cell Carcinoma
If a women is diagnosed with a Pap smear grade of LSIL, what are steps should be taken next?
- Colposcopy and Biopsy cervix
- If it is CIN-2 or CIN-3 –> follow treatment guidelines (ie - drugs, ablation, excision)
- It it is CIN-1, conduct HPV DNA testing
- Postive result –> Colposcopy
- Negative result –> routine screening
REMEMBER TO REVIEW THE STEPS FOR HSIL AND ACSUS
What is a Pap Smear
A Pap smear is a screening test for HPV related lesions.
What is the term for benign lesions of squamous cell origin? Malignant lesions?
Benign: papilloma or epithelioma
Malignant: squamous cell carcinoma
What is the term for benign lesions of glandular/ductular origin? Malignant lesions?
Benign: adenoma, papilloma, cystadenoma
Malignant: adenocarcinoma, papillary carcinoma, cystadenocarcinoma
What is the term for benign lesions of urothelial epithelial origin? Malignant lesions?
Benign: papilloma
Malignant: urothelial carcinoma
What is the term for benign lesions of renal epithelial origin? Malignant lesions?
Benign: adenoma
Malignant: renal cell carcinoma
What is the term for benign lesions of neuroendocrine origin? Malignant lesions?
Benign: carcinoid or adenoma
Malignant: small cell carcinoma or neuroendocrine carcinoma
What are the morphologic characteristics of a polypoid neoplasm?
Protrusion above epithelial surface (like mushroom)
Can be sessile (broad base) or pedunculated (long stalk)
What are the morphologic characteristics of a papillary neoplasm?
Fingerlike projections w/ connective tissue and vessels in center
What are the morphologic characteristics of a cystic neoplasm?
Fluid-filled cavity lined by epithelial cells
Can be unilobulated or multilobulated
Where is normal squamous epithelium found? Metaplastic squamous epithelium?
Normal: skin, oral cavity, vocal cords, vagina, cervix
Metaplastic: respiratory tract, endocervix, urothelium
What are key histologic features of squamous cell carcinoma?
Intercellular bridges:
Keratinization (whorls, pearls, dyskeratotic cells)
Staining for keratin 5/6
Where is normal glandular epithelium found? Metaplastic glandular epithelium?
Normal: endocrine and exocrine glands, resp tract, GI tract, liver, pancreas, gall bladder, kidneys, prostate, ovaries, uterus, breast
Metaplastic changes: Barrett esophagitis
What are the morphologic patterns of adenocarcinomas?
Glandular/acinar
Nests
Cords
Sheets
Trabecular
Papillary
Signet ring-like
Review the following slides related to morphology of carcinomas
What are the names for benign and malignant lesions of adipose tissue?
Benign: lipoma
Malignang: liposarcoma
What are the names for benign and malignant lesions of cartilage tissue?
Benign: chondroma
Malignant: chondrosarcoma
What are the names for benign and malignant lesions of bone?
Benign: osteoma
Malignant: osteosarcoma
What are the names for benign and malignant lesions of fibrous tissue?
Benign: fibroma
Malignant: fibrosarcoma
What are the names for benign and malignant lesions of smooth muscle?
Benign: leiomyoma
Malignant: leiomyosarcoma
What are the names for benign and malignant lesions of skeletal muscle?
Benign: Rhabdomyoma
Malignant: Rhabdomyosarcoma
What are the names for benign and malignant lesions of vessels?
Benign: angioma
Malignang: angiosarcoma
What is the name for malignant neoplasms of leukocytes?
Leukemia
What is the name for malignant neoplasms of lymphoid tissue?
Lymphoma
Review the following slides related to morphology of mesenchymal tumors.
Fill in the table:
Metastasis is commonly associated with what kinds of lesions?
Large primary neoplasms, rapidly growing tumors, anaplasic (poorly differentiated) tissue/lesions
What tumors tend to metastasize via lymphatics?
Carcinomas
What tumors tend to metastasize via blood?
Sarcomas
Which tumors spread over body surfaces?
Tumors in the body cavity (GI, ovarian)
What are the clinical implications of an encapsulated tumor?
Benign: enclosed in a capsule of dense fibrous tissue
Malignant: INVADE through capsule
What are the clinical implications of an expansile margin and an invasive margin in tumors?
Expansile: a well-circumscribed mass (eg. benign fibroadenoma in breast) can be taken it out easily by a surgeon
Invasive: infiltrating “fingers” of tumor cells (eg. malignant ductal carcinoma, osteosarcoma) can’t be easily removed by a surgeon –> they have to cut a wider margin or take out the entire breast
Which of the following is normal? Well differentiated? Moderately differentiated? Poorly differentiated?
See powerpoint notes
Which of the following is normal? Well differentiated? Moderately differentiated? Poorly differentiated?
See powerpoint notes
Contrast the following features in benign and malignant tumors:
Growth rate
MItotic figures
Apoptosis
Growth rate: greater for malignant neoplasms than benign neoplasms
Mitotic figures: greater for malignant neoplasms than benign neoplasms (can also use Ki-67 staining to distinguish tumor cells from normal cells)
Apoptosis: greater in rapidly dividing tumors than in slow growing tumors
What factors influence growth rateof tumors?
Rate of cell proliferation and cell death
Blood supply
Growth factors and hormones
What are the six hallmarks of cancer?
Sustaining Proliferative Signaling
Evading Growth Suppressors
Resisting Cell Death
Enabling Replicative Immortality
Inducing Angiogenesis
Activating Invasion and Metastasis
What are two enabling characteristics of cancer?
Genome Instability and Mutation
Tumor-Promoting Inflammation
What are two emerging hallmarks of cancer?
Reprogramming Energy Metabolism
Evading Immune Destruction
