Neoplasia - SRS, RM, KS and anyone else willing to pitch in. Currently done through slide 97/129 Flashcards
Give 2 definitions of tumor.
- a swollen part; swelling; protuberance
- an uncontrolled, abnormal, circumscribed growth of cells in any animal or plant tissue; neoplasm
What is a benign tumor?
One that does not typically kill. Usually the name ends in -oma
What do we call a tumor with the potential to kill?
Malignant
What two components do all tumors have?
Parenchyma - made up of neoplasm arises from one genetically altered cell.
Stroma - host derived, non-neoplastic supporting tissue
Characterize the origin of the parenchyma of a tumor.
Clonal: entire parenchyma arises from one genetically altered cell.
What term would be applied to a “rock hard stroma” of a tumor?
Scirrhous desmoplastic reaction
What is a carcinoma?
epithelial malignant neoplasm
How does a carcinoma in situ cause metastasis?
It does not.
What is a sarcoma?
mesenchymal malignant neoplasm
What is a mass producing malignancy formed by lymphoid cells called?
Lymphoma
What is a non-mass producing malignancy of hematopoetic cells called?
Leukemia
What would you call a combined mesenchymal and epithelial malignancy?
carcinosarcoma
What is the name for a melanocytic malignant neoplasm?
Melanoma
Walk through the stepwise development of a cancer.
- Normal cell suffers initiating mutation
- Initiated precursor suffers additional mutation impacting genomic integrity
- Precursor with mutator phenotype accumulates additional driver mutations
- Founding cancer cell accumulates further mutations and clones emerge
- Genetically heterogeneous cancer arises
What are the benign and malignant types of stratified squamous tumors?
- Squamous cell papilloma
- Squamous cell carcinoma
What are the benign and malignant types of basal cells of skin or adnexa tumors?
- Benign - None
- Malignant - Basal cell carcinoma
What are the benign tumor types arising from epithelial lining of glands or ducts?
- Adenoma
- Papilloma
- Cystadenoma
What are the malignant types that arise from epithelial lining of glands or ducts?
- Adenocarcinoma
- papillary carcinomas
- cystadenocarcinoma
What are the benign and malignant types of tumors that arise from respiratory passages?
Benign - Bronchial adenoma
Malignant - Bronchiogenic carcinoma
What are the benign and malignant types of tumors that arise from renal epithelium?
Benign - Renal tubular adenoma
Malignant - Renal cell carcinoma
What are the benign and malingnant types of tumors that arise from liver cells?
Hepatic adenoma
Hepatocellular carcinoma (Hepatoma)
What are the benign and malignant types of tumors that arise from urinary tract epithelium (transitional)?
Bening - Transitional cell papilloma
Malignant - Transitional cell carcinoma
What are the bening and malignant types of tumors that arise from placental epithelium?
Benign - Hydatidiform mole
Malignant - Choriocarcinoma
What are the benign and malignant types of tumors that arise from testicular epithelium (germ cells)?
Benign - none
Malignant - Seminoma or Embryonal carcinoma
What are the benign and malignant types of tumors of melanocytes?
Benign - melanocytic nevus
malignant - malignant melanoma
What are the benign types of connective tissue and derivative tumors?
Fibroma
Lipoma
Chondroma
Osteoma
What are the malignant tumors of connective tissues and derivatives?
Fibrosarcoma
Liposarcoma
Chondrosarcoma
Osteogenic sarcoma
What are the benign and malignant cancer types that arise from blood vessels?
Benign: Hemangioma
Malignant: Angiosarcoma
What are the benign and malignant cancers that arise from lymph vessels?
Benign: Lymphangioma
Malignant: Lymphangiosarcoma
What are the benign and malignant cancers that arise from mesothelium?
Benign: Benign Fibrous tumor
Malignant: Mesothelioma
benign and malignant from hematopoietic cells
Benign: none
Malignant: Leukemias
What are the benign and malignant cancers that can arise from lymphoid tissue?
Benign: none
Malignant: Lymphomas
What are the benign and malignant tumors that can arise from smooth muscle?
Benign: Leiomyoma
Malignant: Leiomyosarcoma
What are the benign and malignant cancers that can arise from striated muscle?
Benign: Rhabdomyoma
Malignant: Rhabdomyosarcoma
What is a polyp?
When a neoplasm - either benign or malignant - produces a macroscopically visibile projection above a mucosal surface and projects into the lumen.
What histological findings would you expect to find with a leiomyoma of the uterus?
Leiomyoma “FIBROID” - benign tumor of smooth muscle
Tumor should be well-differentiated bundles of smooth muscle that are almost identical in appearance to normal smooth muscle cells in myometrium
What should an adenoma of the thyroid look like?
Adenoma = benign tumor
Well -differentiated colloid-filled thyroid follicles
Benign tumors are generally well-differentiated
What would an adenocarcinoma of the colon look like, histologically?
Adenocarcinoma = Malignant tumor
Glands that are irregular in shap and size, do not resemble normal glands
Tumor is considered differentiated due to presence of glands
Is a well-differentiated tumor malignant?
It can be, morphological distinction between normal parenchymal cells and neoplastic cells can be subtle
What is anaplasia?
Lack of differentiation between normal parenchymal cells and neoplastic parenchymal cells
- in other words, neoplastic cells and normal cells will be different morphologically and functionally
- often considered a hallmark of malignancy
- Implies “dedifferentiation”, or loss of the structural and functional differentiation of normal cells
- Tissues are very poorly-differentiated
- Cells appear more bizarre
- Almost always indicative of malignancy
What does the term “mixed tumors” refer to?
What is this?
More than one neoplastic cell type
- usually derived from one germ cell layer
- PIC: Mixed Tumor Parotid Gland- epithelial cells forming ducts (central glandular structures) and myxoid stroma that resembles cartilage (Top Left: white)
What types of mixed tumors can grow from the salivary glands?
Pleomorphic adenoma
- benign mixed tumor salivary origins
Malignant mixed tumor of salivary gland origin
What is a Wilm’s tumor?
Malignant mixed tumor of renal anlage
What does the term “teratogenous” refer to?
Derived from more than one germ cell layer, more than one neoplastic cell type
What type of teratogenous tumors can grow in totipotential cells in gonads or in embryonic rests?
Benign: Mature cystic teratoma - dermoid cyst
Malignant: Immature teratoma, teratocarcinoma
A histological slide of a mixed tumor of the parotid gland was shown. Why was it considered a mixed tumor?
Contained epithelials forming ducts and myxoid stroma that looked like cartilage
Mixed because it was derived from more than one germ cell layer
What is a teratoma?
Tumor arising from totipotential germ cells which have the capacity to differentiate along the three germ layers: endoderm, ectoderm and mesoderm
A teratoma that contains a single tissue type is called a …?
Monodermal teratoma
An immature teratoma is generally regarded as benign or malignant? How many immature tissue types can it contain?
Considered malignant
Can only be one immature element - immature cartilage, neural tissue, etc.
What is a malignant teratoma?
Malignancy/carcinoma arising within mature teratoma
Endoderm gives rise to what structures in the embryo, and in adults?
Embryo: embyronic gut
Adults:
inner linings of respiratory & digestive tracts
glands - liver and pancreas
What does mesoderm give rise to in embryos and in adults?
Embryos:
Somites
Mesenchyme
Notochord
Adults:
Somites create muscle, outer coverings of internal organs, gonads and excretory system
Mesenchyme creates bones and cartilage, circulatory system, dermis
What does ectoderm give rise to in adults?
Epidermis
Brain and nervous system
Where are some common sites for teratomas?
1, Ovary and testis
- Midline of body
- pineal body
- base of skull
- mediastinum (anterior)
- retroperitoneal
- sacrococcygeal
An immature teratoma includes what type of tissue elements?
Immature mesenchyme, neural and/or blastemal elements
What is a hamartoma?
A benign non-neoplastic tumorlike malformation resulting from faulty development in an organ and composed of abnormally arranged tissue elements normally present in that organ
What is a choristoma?
•congenital heterotopic (ectopic) rest of cells (tissue)
Not a neoplasm
Normal tissue, abnormal location
What is Cowden Syndrome?
Mode of transmission/inheritance?
Symptoms?
Morbidity?
Part of the PTEN hamartoma tumor syndrome (PTHS) (Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome)
Autosomal dominant genetic disorder
Multiple hamartomas
- Usually skin and thyroid gland hamartomas
- May cause symptoms or even death
Additional growths in many parts of the body (mucosa, the GI tract, bones, CNS, eyes, and the genitourinary tract).
Morbidity - associated with ↑ occurrence of malignancies, usually in the breast, endometrium or thyroid.
What is the difference between hyperplasia, metaplasia, and dysplasia?
Hyperplasia - same tissue type, more of it
Metaplasia - growth of different tissue or cell type
Dysplasia - growth of abnormal tissue, or abnormally developed tissue
- expansion of immature cells
What happens in eosinophilic esophagitis?
Basal cell hyperplasia
What happens in Barrett esophagus?
Metaplasia, change from squamous to glandular tissue secondary to chronic irritation from acid reflux
What is the progression seen in squamous epithelial dysplasia?
Normal
Low grade/mild - koilocytic atypia
High grade/moderate - progressive atypia and expansion of immature basal cells above the lower third of epthelial thickness
High grade/severe - diffuse atypia, loss of maturation, expansion of the immature basal cells to the epithelial surface
Where can squamous epithelial dysplasia occur?
This can occur in any normal or metaplastic squamous epithelium at any body site
e.g. cervix, anus, oral cavity, skin, bronchus, etc.
What sorts of histological findings would you associate with a carcinoma in situ?
Epithelium entirely replaced by atypical dysplastic cells
No orderly differentiation of squamous cells
Basement membrane intact
no tumor in subepithelial stroma
Failure of normal differentiation
Marked nuclear and cellular pleomorphism
Numerous mitotic figures
With what test is squamous epithelial dysplasia of the cervix diagnosed?
Via cervical cytology, with a pap smear
What should you see, histologically, on a normal cervical cytology versus an abnormal?
Normal
large, flattened squamous cells and groups of metaplastic cells
neutrophils interspersed
Abnormal
numerous malignant cells with pleomorphic, hyperchromatic nuclei
normal PMNs interspersed
What are some characteristics of malignant neoplasia?
- Differentiation and anaplasia
- Rate of growth
- Local invasion
- Metastasis
How is differentiation/anaplasia different between benign and malignant tumors?
Benign:
Well differentiated; structure sometimes typical of tissue of origin
Malignant:
Some lack of differentiation with anaplasia; structure often atypical
How is the rate of growth different between benign and malignant tumors?
Benign:
Usually progressive and slow; may come to a standstill or regress; mitotic figures rare and normal
Malignant:
Erratic and may be slow to rapid; mitotic figures may be numerous and abnormal
How is local invasion different between benign and malignant tumors?
Benign:
Usually cohesive expansile well-demarcated masses that usually do not invade or infiltrate surrounding normal tissues
Malignant:
Locally invasive, infiltrating surrounding tissue; sometimes may be misleadingly cohesive and expansile
How is metastasis different between benign and malignant tumors?
Benign:
absent
Malignant:
Frequent, more likely with large undifferentiated tumors
What are the exceptions that benign tumors can have to the ‘rules’ of differentiation, rate of growth, local invasion, and metastasis?
Differentiation/anaplasia:
Premalignant cytologic changes are anaplastic (cervical dysplasia)
Rate of growth:
Benign conditions can grow rapidly (inflammatory pseudotumors)
Local Invasion:
Benign conditions can be infiltrative (fibromatoses)
Metastasis:
Benign conditions can spread (endometriosis)
some relatively normal looking neoplasms can metastasize and cause death (well-differentiated leiomyosarcoma)
How do we determine when there is a malignancy/cancer?
“When the lesion has the potential to metastasize and cause death”
i.e. When the characteristics of the lesion are similar to those of other lesions previously noted to have metastasized and caused death!
What is differentiation?
how closely the tumor cells resemble the corresponding normal parenchymal cells
What is the difference between well-differentiated, moderately-differentiated, poorly-differentiated, and undifferentiated tumor cells?
- Well-differentiated – closely resembles normal
- Moderately-differentiated – sort of resembles normal
- Poorly-differentiated – does not resemble normal
- Undifferentiated - The tissue of origin cannot be determined based on the histopathologic appearance of the neoplasm
What level of differentation do malignant tumors have? Benign?
- Benign tumors are usually well-differentiated
- Malignant tumors can have any level of differentiation
What histological findings are found with anaplastic cells?
- Pleomorphism - marked variation in size and shape of the cells and/or nuclei.
- Abnormal nuclear morphology -hyperchromatic, large nuclei, bizarre nuclear shapes, prominent nucleoli
- Increased mitotic activity, and atypical mitoses
- Loss of polarity - orientation is markedly disturbed
What are some differences between benign and malignant tumors in terms of cell size?
Benign: 2-5x normal
Malignant: 2-100x normal
What are some differences between benign and malignant tumors in terms of mitotic rate?
Benign:
normal or up to 2-3x increase
Malignant:
2-20x increase, with atypical mitoses
What are some differences between benign and malignant tumors in terms of symmetry?
Benign:
symmetric
Malignant:
asymmetric
What are some differences between benign and malignant tumors in terms of margins?
Benign:
circumscribed
Malignant:
indistinct
What are some differences between benign and malignant tumors in terms of necrosis?
Benign:
uncommon
Malignant:
common
What are 3 common features of malignancy?
Hyperchromaticity
Desmoplasia
Angiogenesis
What is hyperchromaticity?
- marked increase in DNA content per nucleus (more intense staining by Hematoxylin (H of H&E)
- A disproportionate increase in DNA density is seen even when there is no significant enlargement of the nucleus
What is desmoplasia?
Increased fibrous tissue
What is angiogenesis? What happens to tumors without it?
- increased blood vessels
- Ischemic tumor necrosis occurs with insufficient angiogenesis
What are the 2 types of angiogenesis?
Neo-angiogenesis
- vessels sprout from existing capillaries
Vasculogenesis
- endothelial cells are recruited from the bone marrow
What findings are associated with a gross specimen of a fibroadenoma of the breast? Histological findings?
Tan color
Encapsulated small tumor
sharply demarcated from breast tissue
Fibrous capsule delimits tumor from surrounding tissue
What findings are associated with a gross specimen of an invasive ductal carcinoma of the breast? Histological findings?
Lesion is retracted
Infiltrating the surrounding breast tissue
Stony hard on palpation
Histology:
invasion of breast stroma and fat be nests and cords of tumor cells
absence of well-defined capsule
A benign tumor of the smooth muscle of the uterus would be called what? What 6 characteristics would you expect?
Leiomyoma
- small
- well-demarcated
- slow growing
- noninvasive
- nonmetastatic
- well differentiated
A malignant tumor of the smooth muscle of the uterus would be called what? What 6 characteristics would you expect?
Leiomyosarcoma
- large
- poorly differentiated
- rapidly growing with hemorrhage and necrosis
- locally invasive
- metastatic
- poorly differentiated
Grading neoplasms is done with what 2 scales?
Histological
- essentially grades differentiation
Nuclear grade:
- essentially grades bizarreness/pleomorphisms
What is the gleason scale?
Grading scale for adenocarcinomas of the prostate
Explain the steps of the Gleason Scale, from 1-5.
Well Differentiated
- Small, uniform glands
- More space (stroma) between glands
Moderately differentiated
- Distinct infiltation of cells from glands at margins
Poorly differentiated, anaplastic
- Irregular masses of neoplastic cells with a few glands
- Lack of or occasional glands, sheets of cells
What 9 changes would you expect to see with malignant transformation?
Self-sufficiency in growth signals
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasize
Defects in DNA repair
Alterations in cell metabolism (e.g. Warburg effect)
Ability to evade host immune response
With alterations in malignant transformation, what does self-sufficiency in growth signals mean?
capacity to proliferate without external stimuli
oncogene activation with oncoprotein production (gain of function)
With alterations in malignant transformation, what does insensitivity to growth-inhibitory signals mean?
May not respond to molecules that are inhibitory to the proliferation
- TGF-β dysfunction
- cyclin-dependent kinase inhibitor dysfunction
With alterations in malignant transformation, what does evasion of apoptosis mean?
May be resistant to programmed cell death
- p53 and other tumor suppressor gene inactivation (loss of function)
- activation of anti-apoptotic genes (gain of function)
- inactivation of apoptotic genes (loss of function)
With alterations in malignant transformation, what does limitless replicative potential mean?
•unrestricted proliferative capacity avoiding cellular senescence
With alterations in malignant transformation, what defects in DNA repair are expected?
May fail to repair DNA damage (loss of function)
- genomic instability
- mutations in proto-oncogenes and tumor suppressor genes
What are the 10 hallmarks of cancer?
- Evading growth suppressors
- Enabling replicative immortality
- Tumor-promoting inflammation
- Activating invasion and metastasis
- Genomic instability
- Inducing Angiogenesis
- Resisting cell death
- Deregulating cellular energetics
- sustaining proliferative signaling
- avoiding immune destruction
What gives it away?
Immature Teratoma
Immature mesenchyme, neural and/or blastemal elements
**Dark banding areas=undifferentiated cells–>might be malignant***
Who am I?!
- Well-differentiated squamous cell carcinoma of the skin
- The tumor cells similar to normal squamous epithelial cells
- with intercellular bridges and nests of keratin pearls (arrow)
- growing all over the place.
Why? Most worrisome aspect?
Malignant Teratoma
-Carcinoma, sarcoma and/or germ cell malignancy in teratoma
***Bottom Left: If Brusk Carcinoma? Glandular tissue àwould give chemo
What do you see here?
R side: thickening, loss of maturation= cells at top look like bottom.
DYSPLASIA
- lack maturation
- nuclear enlargement
- loss of normal arrangment (nuclear)
What defines each type? Rank?
- This can occur in any normal or metaplastic squamous epithelium at any body site
- cervix, anus, oral cavity, skin, bronchus, etc.
- CIN I-Mild halos at top L from HPV
- CINII – Moderate Lower 2/3 involved
- CIN III/CIS Severe Dysplasia
- CIS- Carcinoma In Situ- immaturity Full thickness of epitelium
In this example BM is intact- until there is invasion it will kill the patient
What are the 3 main factors for determining the rate of cancer growth?
- Doubling time of tumor cells
- Fraction of tumor cells in the replicative pool
- Rate at which cells are shed/die
Solid tumors that are detected clinically have….?
already completed a major portion of its life span
In addition to doubling time, fraction of cells in replicative pool, and rate of death, what other factors influence tumor growth?
Blood supply - think angiogenesis inhibitors for treatment
Hormonal factors - estrogen/testosterone blockers for Tx
emergence of aggressive sub-clones
What is the smallest clinically detectable tumor mass? How many cells is this? Doubling times?
smallest mass = 1 gram
30 doublings
10^9 cells
What class of immune cells recognizes tumor cells?
CD8+ T cells
Normal host cells will display what type of antigens, leading to a what type of response in what type of immune cell?
Normal cells display multiple MHC-associated self antigens
CD8+ T cells will have no response
What sorts of ‘clues’ are expressed by tumor cells that lead to recognition by the host’s immune system?
Tumor cells will express different types of tumor antigens
For example:
oncogene or mutated suppressor gene products
mutated self proteins
Overexpressed or aberrantly expressed self proteins
oncogenic virus
What are 3 mechanisms by which tumor cells evade host immunity?
- Failure to produce tumor antigen, antigen-loss variant of tumor cell
- leads to lack of T-cell recognition of tumor - Mutations in MHC gene or genes needed for antigen processing, class I MHC deficient tumor cell
- leads to lack of t-cell recognition of tumor - Production of immunosuppressive proteins or expression of inhibitory cell surface proteins
- leads to inhibition of t-cell activation
What is the Warburg Effect?
Metabolic alteration in tumor cells - switch to aerobic glycolysis
Tumor cells will shift their glucose metabolism away from O2-hungry mitochondria to aerobic glycolysis leading to lactose fermentation
In addition to tumor cells, what other types of tissues do you see the Warburg Effect in?
embryonic tissues
What is the advantage of the Warburg Effect for tumor cells?
•Provides metabolic intermediates used in synthesis of cellular components
How can clinicians exploit the Warburg Effect for better patient outcomes?
Aerobic glycolysis leading to lactose fermentation allows visualization of tumors via positron emission tomography (PET)
In normal non-proliferative tissues, how do cells react to normal and low concentrations of oxygen?
In normal ppO2:
oxidative phosporylation happens
glucose → pyruvate
pyruvate oxidized in mitochondria
In low ppO2:
anaerobic glycolysis happens:
glucose → pyruvate
pyruvate → lactate, not into mitochondria
How do cancer cells respond to different levels of O2?
Cancer cells will convert most glucose to lactate regardless of ppO2.
- also seen in normal proliferative tissues
What is metastasis? What type of tumor metastasizes?
Metastasis is the spread ot a tumor to sites that are physically discontinuous with the primary tumor
Metastasis = malignant
What is local invasion?
Growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue.
Benign tissues will grow as expanding, cohesive masses and remain localized to point of origin.
- often lack capacity to infiltrate, invade, or metastasize to distant sites
What is the general sequence of events in the sequence of events leading to invasion of the epithelial basement membrane by tumor cells?
Tumor cells detach from each other due to reduced adhesiveness and attract inflammatory cells. Intercellular junctions are loosened.
Proteases secreted from tumor cells and inflammatory cells degrade the basement membrane, ECM.
Binding of tumor cells to proteolytically generated binding sites and tumor cell migration and invasion follow.
What characteristics of a tumor make it more likely to metastasize?
Rapidly growing
larger
more aggressive
What percent of new cancer diagnosis will be metastatic?
30%
What are the patterns of metastasis?
Direct seeding of body cavities or surfaces
Lymphatic spread
Hematogenous spread
What happens with hematogenous spread of metastatic cancers?
Venous invasion with tumor cells into capillary bed
direct transplantation by surgical intervention
What types of cancers or venous systems make for hematogenous spread?
Portal blood supply from gut into liver
Caval blood supply traveling to lungs
Hepatic, renal and adrenocortical cancers propagate in veins
What is the proto-oncogene associated with Adenocarcinoma of the lung? Give both names
ERBB1 (EGFR)
What is the proto-oncogene associated with breast carcinoma? Give both names.
ERRB2 (HER)
In adenocarcinoma (ERBB1/EGFR) and Breast carcinoma (ERRB2/HER) What is the mode of activation?
Mutation amplification
What conditions does a point mutation in the RET gene lead to?
(3)
- Multiple endocrine neoplasia Type 2A
- Multiple endocrine neoplasia Type 2B
- Familial Medullary thyroid carcinoma
If the ALK gene undergoes translocation, fusion, or point mutation, what conditions may arise?
(3)
- Adenocarcinoma
- Certain lymphomas
- Neuroblastoma
A point mutation in the KRAS gene which encodes a GTP-Binding protien is associated with what tumors? (3)
- Colon
- Lung
- Pancreatic
He indicated this was a pretty important one…
What would a point mutation in the GNAS gene lead to? (2 - kinda)
- Pituitary adenoma
- Other endocrine tumors
What does an NRAS mutation lead to potentially?
Melanomas
Hematologic malignancies
(Think he said this one was more of a later on type information)
If point mutation affected the ABL gene, what conditions could arise?
- Chronic myeloid leukemia
- acute lymphoblastic leukemia (don’t really need to focus on this now)
A translocation event occurs that leads to the patient having chronic myelogenous leukemia… what genes are involved, and what is the end product of the translocation?
Translocation: (9;22)(q34;q11)
Affects: ABL 9q34 and BCR 22q11
What does a point mutation or translocation involving the BRAF gene lead to?
(3)
- Melanomas
- Leukemias
- Colon carcinoma
What could a translocation involving C-MYC lead to?
Burkitt lymphoma
What could an amplification of N-MYC lead to?
Neuroblastoma
Small cell carcinoma of the lung
What could an amplification of the L-MYC gene lead to?
Small cell carcinoma of the lung
What could arise d/t a translocation event involving CCND1 (Cyclin D)?
Mantle cell lymphoma
Multiple myeloma
What genes are affected in chronic myelogenous lymphoma translocations?
ABL 9q34/BCR 22q11
What genes are involved in the translocation event that leads to Burkitt lymphoma?
c-MYC 8q24
IGH 14q32
What is the translocation that you end up with in Burkett’s lymphoma?
(8;14)(q24;q32)
What genes are involved in Ewings Sarcoma?
FLI1 11q24
EWSR1 22q12
What is the translocation result you get in cases of Ewing Sarcoma?
(11;22)(q24;q12)
What are the four cell cycle components and inhibitors that he told us we need to know that are frequently mutated in cancer?
- CDK4; D cyclins
- INK4/ARF Family (CDKN2A-C)
- RB
- P53
What is the normal role of CDK4; D cyclins?
Form a complex that phosphorylates RB, allowing the cell to progress through the G1 restriction point
What is the role of INK4/ARF family (CDKN2A-C)?
- p16/INK4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB
- p14/ARF increases p53 levels by inhibiting MDM2 activity
What is the role of RB in the cell?
Tumor suppressive “pocket” protein that binds E2F transcription factors in its hypophosphorylated state, preventing G1/S transition; also interacts with several transcription factors that regulate differentiation
What is the normal role of P53 in the cell cycle?
- Tumor suppressor
- causes cell cycle arrest and apoptosis
- requird for G1/S checkpoint and is a main component of the G2/M checkpoint
In cancers why might you see increased levels of P53 or RB?
The proteins are present, just mutated to the point where they do not function. Thus, produced and present just not working.
What famillial syndrome gives rise to…
- neuroblastoma
- juveline myeloid leukemia
and what gene is mutated?
- Neurofibromatosis type 1 (neurofibromas and malignant peripheral nerve sheath tumors)
- NF1
What famillial syndrome gives rise to Schwannomas and meningiomas?
What gene is mutated?
- Neurofibromatosis type 2 (acoustic schwannoma and meningioma)
- NF2
What familial syndrome gives rise to…
- retinoblastoma
- osteosarcoma
- carcinomas of the…
- breast
- colon
- lung
And, what gene is mutated?
- Familial retinoblastoma syndrome (retinoblastoma, osteosarcoma, other sarcomas)
- RB
What familial syndrome commonly leads to renal cell carcinomas?
What gene is mutated?
- Von Hippel Lindau syndrome (cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma)
- VHL
What is Li-Fraumeni syndrome due to?
What does it lead to?
D/T loss of P53 from a mutation to TP53 gene.
Leads to development of most human cancers.
What are BCRA1 and BCRA2 implicated in?
Familial breast and ovarian carcinoma; carcinomas of male breast; chronic lymphocytic leukemia (BRCA2)
What does a mutation in MEN1 lead to?
- Multiple endocrine neoplasia type I (MEN1)
- Pituitary adenoma
- parathyroid endocrine tumors
- pancreatic endocrine tumors
What are the 7 steps of the metastatic cascade - hematogenous spread of a tumor?
1) Changes (“loosening up”) of tumor cell-cell interactions
2) Degradation of ECM
3) Attachment to ECM components
4) Migration (locomotion ) of tumor cells
5) Clumping in vessels
6) Adhesion to the endothelium
7) Egress through the vascular basement membrane
If a person has a problem with E-Cadherin, what would they be predisposed to developing?
Increased Risk of GI cancers.
(Though not in slides, he talked about this a couple of times)
What is this?
Liver studded with metastatic cancer
Top right is a normal axillary lymph node.
Bottom left is taken from a patient with metastatic breast carcinoma.
What do you see happening here?
Encircled are aggregates of tumor cells metastasizing to the subcapsular sinus.
The subcapsular sinus is the first plase cancer will metastasize to in a lymph node.
What is depicted in A - The blue circle, and B- the green circle?
A – Micrometastasis
B – Subcapsular histiocytosis - Epitheliod macrophages (he called them this in lecture)
What is Cachexia?
Cancer Cachexia is caused by what main process?
- •Progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia
- •TNFα and IL-1 produced by macrophages in response to tumor cells or by the tumor cells themselves mediates cachexia
What is a paraneoplastic syndrome?
•Symptom complexes that cannot readily be explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose, are known as paraneoplastic syndromes.
What are the two paraneoplastic syndromes associated with small-cell carcinoma of the lung?
Cushing Syndrome
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
What paraneoplastic syndrome is associated with squamous cell carcinoma of the lung?
Hypercalcemia
How does squamous cell carcinoma of the lung cause hypercalcemia?
(4)
- Parathyroid hormone-related protein (PTHRP),
- TGF-α,
- TNF,
- IL-1
Why do paraneoplastic syndromes only occur with malignant tumors?
They actually occur with both malignant AND benign tumors. Ha!
What paraneoplastic syndrome does renal carcinoma classically present with?
What causes this?
Polycythemia
Erythropoietin
A patient presents to the clinic with diarrhea, cramps, nausea, vomiting, wheezing, dyspnea and cough.
On physical exam you find hepatomegaly, cutaneous flashes and apparent cyanosis.
The patient if diagnosed with hepatocellular carcinoma. What is the paraneoplastic sydrome this patient has?
What might you see in their heart?
- Carcinoid syndrome
- Heart
- Pulmonic and tricuspid thickening and stenosis
- endocardial fibrosis
What paraneoplastic syndrome is associated with…
- hepatocellular carcinoma
- bronchial adenoma (carcinoid)
- pancreatic carcinoma
What is the causal mechanism?
Carcinoid syndrome
Serotonin
Bradykinin
What can carcinoid syndrome easily be mistaken for?
Type I hypersensitivity
Myasthenia gravis is a paraneoplastic syndrome associated with what cancer?
So what should the first thing we look for be when a patient presents with myasthenia gravis?
- Thymic neoplasms
- Bronchogenic carcinoma
Check for thymomas
What paraneoplastic syndrome is associated with…
Gastric carcinoma
Lung carcinoma
Uterine carcinoma
and what is a giveaway physical finding you should be aware of?
Acanthosis nigricans
Armpits will be much darker than they should be.
A patient presents with muscle weakness and a helicotrope rash. They have cancer.
What is the paraneoplastic syndrome?
What is the likely cancer candidate?
Dermatomyositis
Bronchogenic Breast Carcinoma
You have two patients to see today in your oncology rounds, one has pancreatic carcinoma and the bother has bronchogenic carcinoma. The attending physician asks you what the associated paraneoplastic syndromes are for each.
You answer?
Inside your head you again consider what a douche your attending is, while you verbally respond…
Both those cancers are associated with venous thrombosis, (and, showing off, you add) also known as Trousseau phenomenon.
What paraneoplastic syndrome is associated with…
Acute promyelocytic leukemia
Prostatic carcinoma
???
Disseminated intravascular coagulation
Your patient has valve leaflet vegetations d/t hypercoagulative state. They have advanced cancer. What is the paraneoplastic syndrome they are enduring?
Nonbacterial thrombotic endocarditis
What is the initiator in the 2 hit hypothesis?
The thing that does the direct damage to the DNA
What is the incidence of a cancer?
•probability of being diagnosed with a disease during a given period of time
TQ alert in these
How is the incidence of cancer calculated?
Expressed?
- number of new cases of a disease divided by the number of persons at risk
- usually expressed as new cases/year per 100,000 population
What is the prevalence of cancer?
•the total number of cases of disease existing in a population
How is prevalence calculated?
Expressed?
- total number of cases of a disease existing divided by the total population
- Usually expressed as total cases per 100,000 persons
For women, what cancer has the highest incidence?
Highest mortality?
Incidence - Breast
Mortality - Lung
For men what cancer has highest incidence?
Mortality?
Incidence - prostate
Mortality - Lung
This sample showing “small round blue cell tumors” was most likely taken from what age patient?
What are the four common cancers this could be a sample from?
Infant or childhood
- •Neuroblastoma
- •Wilms tumor (nephroblastoma)
- •Retinoblastoma
- •Acute leukemias
In 1775 london, Sir Percival Pott made a connection between chimney sweep’s exposure to soot and a type of cancer. What type of cancer whas it?
Squamous cell carcinoma of the scrotum
Sorry for the image… I had to. He said there would be a TQ on this. Now you won’t forget it… EVER.
The population of Japan historically has had a higher incidence of gastric cancer than japanese populations that have migrated to the USA. What caused this?
Some component of diet, possibly the preservative techniques used.
What is the classic example of a chemical carcinogen that contributes to oral cancer?
Betel nuts
Arsenic is an example of an occupational agent that is carcinogenic. What cancers does this cause?
- Skin carcinoma
- Lung carcinoma
What cancers does asbestos lead to?
- Lung,
- esophageal,
- gastric, and
- colon carcinoma;
- mesothelioma
Where can mesothelioma arise apart from the lungs?
Testes
What cancer does benzene lead to?
Acute myeloid leukemia
What cancer does Radon and its decay products lead to?
What populations are at risk for this?
Lung cancer
Workers in quarries and underground mines
What cancer does PVC exposure lead to?
NONE!!! This is one of his hot buttons. Know that it’s Vinyl Chloride, a component in the manufacture of PVC, that is carcinogenic.
Ok, so what does vinyl chloride exposure predispose you to?
Hepatic Angiosarcoma
What are the oncogenic RNA viruses? What conditions are they associated with?
(2)
- •HTLV-1 – adult T-cell leukemia/lymphoma
- •HCV – hepatocellular carcinoma
What are the oncogenic DNA viruses??
(6)
- HBV
- HPV
- HHV-8
- EBV
- CMV
- Merkel cell polyomavirus
What does infection with HBV predispose one to?
Hepatocellular carcinoma
What does infection with HPV predispose one to?
(types 1,2,4,6,7,11, 16,18)
(4)
carcinomas of…
- Cervix
- Anus
- Penis
- Oropharynx
What fungus is associated with cancer? What toxin does it have that is related to this?
Finally what is the cancer?
- Aspergillus
- Aflotoxin B1
- hepatocellular carcinoma (P53 mutation)
What is infection with HHV-8 associated with? (2)
- Kaposi sarcoma
- Primary effusion lymphoma
What three things is EBV associated with?
- Burkitt lymphoma,
- Hodgkin lymphoma
- nasopharyngeal carcinoma
What cancer is CMV (HHV-5) infection associated with?
Mucoepidermal carcinoma
What cancer is merkel cell polyomavirus associated with?
Merkel cell Carcinoma
What are the parasites associated with cancer? (3)
What cancers are each associated with?
- Schistosoma haematobium – bladder cancer
- Schistosoma japonicum – colon cancer
- Opisthorchis viverrini – cholangiocarcinoma
H. pylori infection predisposes one to develop what two cancers?
- Extranodal marginal zone (MALT) lymphoma
- Gastric adenocarcinoma
A large # of cancer types have combined environmental influences and hereditary predispositions. What does this mean in the context of the two hit theory?
- Hit 1 in first mutated gene (abnormal) is inherited
- Hit 2 in second mutated gene (originally normal) is acquired
What are the four identified genetic predispositions to cancer?
- Defective DNA-Repair Syndromes
- Famillial Cancers
- Autosomal Dominant Inherited Cancer syndromes
- Interactions of genetic and non-genetic factors
What are five inherited autosomal recessive syndromes of defective DNA repair that Dr. Gomez put on the slide but didn’t discuss?
- Xeroderma pigmentosum (nucleotide excision repair of cross-linked pyrimidine dimers)
- Hereditary nonpolyposis colon cancer syndrome (DNA mismatch repair)
- Ataxia-telangiectasia (DNA repair by homologous recombination)
- Bloom syndrome (DNA repair by homologous recombination)
- Fanconi anemia (DNA repair by homologous recombination)
What are the autosomal recessive Defective DNA repair conditions we covered?
- Xeroderma Pigmentosa
- Ataxia Telangiectasia
- Bloom Syndrome
- Fanconi Anemia
Name the condition
- FA process defects associated with aplastic anemia, hypopigmentation, café-au-lait spots, skeletal problems, defects of the genitourinary tract; gastrointestinal tract; heart; eye and ears with hearing loss and acute myeloid leukemia
Fanconi anemia
Name the condition -
- Helicase abnormality associated with short stature, sun-sensitive skin changes, an increased risk of cancer, and other health problems
Bloom syndrome
Name the condition
-
•ATM gene defect (involved in DNA repair) associated with progressive difficulty with coordinating movements, weakened immune system, leukemias and lymphomas
Ataxia Telangiectasia
Name that condition
-
•Nucleotide excision repair abnormality associated with extreme sensitivity to ultraviolet (UV) rays affects the eyes and skin (cancers), may also have CNS problems (increased pyrimidine dimers)
Xeroderma pigmentosa
What is the autosomal dominant defective DNA repair condition we were presented with?
Hereditary nonpolyposis colorectal cancer (HNPCC) = Lynch syndrome
Name that condition!
•DNA mismatch repair abnormality leading to microsatellite instability associated with colorectal, endometrial, gastric, ovarian, ureteral, CNS, small bowel, hepatobiliary tract and skin cancers
Hereditary nonpolyposis colorectal cancer (HNPCC) = Lynch syndrome
This is an example of defective DNA repair. This condition carries increased risk for skin cancers d/t exposure to UV. UV causes cross-linking of pyrimidine residues which prevents normal DNA replication. What process is impaired in this patient?
Nucleotide Excision repair - several proteins are involved in this. Loss of any one can give rise to Xeroderma Pigmentosum
Inherited cancer syndromes are usually a point mutation in a single ellele of a tumor supressor gene. The second event that incites tumorigenesis involves a second mutation in the other remaining previously normal allele.
What are three example of this?
What is the age of onset?
What are two other characteristics?
- •Retinoblastoma
- •Familial adenomatous polyposis
- •MEN syndromes
- Early age at onset
- Tumors arising in ≥2 close relatives of the index case
- Multiple or bilateral tumors
What is the inheritance pattern for each of these conditions?
Retinoblastoma
Li-Fraumeni syndrome (various tumors)
Melanoma
Familial adenomatous polyposis/colon cancer
Neurofibromatosis 1 and 2
Breast and ovarian tumors
Multiple endocrine neoplasia 1 and 2
Hereditary nonpolyposis colon cancer
Nevoid basal cell carcinoma syndrome
Cowden syndrome (epithelial cancers)
Peutz-Jegher syndrome (epithelial cancers)
Renal cell carcinomas
Autosomal Dominant
For each of these, name the gene associated with them!!!!
Retinoblastoma
Li-Fraumeni syndrome (various tumors)
Melanoma
Familial adenomatous polyposis/colon cancer
Neurofibromatosis 1 and 2
Breast and ovarian tumors
Multiple endocrine neoplasia 1 and 2
Hereditary nonpolyposis colon cancer
Nevoid basal cell carcinoma syndrome
Cowden syndrome (epithelial cancers)
Peutz-Jegher syndrome (epithelial cancers)
Renal cell carcinomas
Retinoblastoma - RB
Li-Fraumeni syndrome (various tumors) - P53
Melanoma - P16/INK4A
Familial adenomatous polyposis/colon cancer- APC
Neurofibromatosis 1 and 2 - NF1, NF2
Breast and ovarian tumors - BRCA1, BRCA2
Multiple endocrine neoplasia 1 and 2 - MEN1, RET
Hereditary nonpolyposis colon cancer - MSH2, MLH1, MSH6
Nevoid basal cell carcinoma syndrome - PTCH
Cowden syndrome (epithelial cancers) - PTEN
Peutz-Jegher syndrome (epithelial cancers) - LKB=STK11
Renal cell carcinomas - VHL
What is the eponym for MEN1?
What are the three P’s of MEN1?
Werner syndrome
- Pituitary adenoma
- parathyroid hyperplasia
- pancreatic tumors
What is the common thread between MEN2A, B and FTMC?
Medullary Thyroid cancer d/t RET mutation
What are the differences between MEN2A and B?
MEN2A - has parathyroid hyperplasia
MEN2B - Has marfanoid body habitus and mucosal neuromas
What are two examples of nonhereditary predisposing conditions for cancer? What are examples of these?
Chronic inflammation
- Persistent regenerative cell replication (cirrhosis—hepatocellular carcinoma), (chronic skin fistula—SCC)
- Helicobacter pylori gastritis
- Viral hepatitis
- Chronic ulcerative colitis
- Chronic pancreatitis
Precancerous conditions such as repair followed by dysplasia
- Leukoplakia of the oral cavity, vulva or penis
- Villous adenoma of the colon
- Chronic atrophic gastritis-pernicous anemia
- Chronic ulcerative colitis
- Solar keratosis of the skin
What neoplasm is associated with asbestosis and silicosis?
What is the etiologic agent?
- Mesothelioma
- Lung Carcinomas
Asbestos fibers and silica particles
What neoplasm is associated with IBS?
Colorectal cancer
What neoplasm is associated with lichen sclerosus et atrophicus?
Vulvar squamous cell carcinoma
What neoplasm is associated with Sjögren syndrome, Hashimoto thyroiditis?
MALT Lymphoma
What is Schistomiasis the etiologic agent for?
Bladder carcinoma and the associated chronic cystitis
What, in the USA, causes bladder cancer?
Smoking!
