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Neoplasia Flashcards

1
Q

Define cancer?

A

Genetic disorder caused by mutations that are acquired spontaneously or through environmental insult. Cancers show increased DNA methylation and histone modification. These mutations alter growth, survival and senescence. These mutations are also heritable.

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2
Q

What are the hallmarks of cancer?

A

1) Self-sufficiency in growth signals;
2) Lack of response to growth inhibitory signals;
3) Evasion of cell death;
4) Limitless replicative potential (immortality);
5) Angiogenesis to maintain growth;
6) Ability to metastasise;
7) Reprogramming of metabolic pathways (e.g aerobic glycolysis);
8) Ability to evade immune system.

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3
Q

What does the suffix -oma denote? What are the types?

A

It implies a benign tumor.
Fibrous tissue - fibroma;
Cartilaginous - chondroma;
From gland patters and glands - adenoma;
On surfaces with finger like fronds - Papilloma;
Above a mucosal surface - polyp;
Hollow cystic masses - cystadenoma;

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4
Q

What are sarcomas?

A

Malignant neoplasms in solid mesenchymal cells and their derivatives.

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5
Q

What are leukaemias / lymphomas?

A

Malignant neoplasms of mesenchymal cells of the blood.

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6
Q

What is the importance of stromal cells in the development of a neoplasm?

A

Carries blood supply and provides support and growth to parenchymal cells?

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7
Q

What are the subdivisions of carcinomas (epithelial)?

A

Adenocarcinoma (glandular), squamous cell carcinoma, can be named based on effected organ and poorly differentiated / undifferentiated.

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8
Q

What is the most common mixed tumor that arises through divergent differentiation?

A

Mixed tumor of the salivary gland - epithelial components through fibromyxoid stroma (possibly containing cartilage or bone). They are derived from epithelial and myoepithelial cells, therefore termed polymoprhic adenomas).

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9
Q

What is the term given to the mixed tumor containing proliferating ductal elements contained within neoplastic fibrous tissue?

A

Fibroadenoma

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10
Q

What is a teratoma?

A

Mixed tumour that contains cells or tissue representative of one or more germ cell layer form totipotent germ cells such as those in the testes or ovaries (sequestered midline embryonic rests).

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11
Q

What is a hamartoma?

A

Disorganised tissue involving indigenous tissue - possibly developmental malformation; but evidence of translocations (neoplastic).

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12
Q

What is a choristoma?

A

Congenital heterotopic rest of cells - i.e cells are in the wrong place (pancreas cells / tissue in intestines). Of trivial significance.

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13
Q

What are the exceptions to the nomenclature regarding benign and malignant cells? i.e which cancers have the suffix -oma but are malignant?

A

Lymphoma, mesothelioma, melanoma and seminoma.

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14
Q

What feature of benign tumors means that they rarely develop into malignancy?

A

The fact that benign tumours change little in genotype over time.

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15
Q

What are the four criteria on which the benign or malignant nature of a tumor are determined?

A

Differentiation and anaplasia, rate of growth, local invasion and metastasis.

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16
Q

Is the neoplasm seen in well differentiated cells in which mitosis is rare and in the normal configuration benign or malignant?

A

Benign.

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17
Q

Is the neoplasm seen in undifferentiated cells (or moderately well differentiated cells) benign or malignant?

A

Malignant.

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18
Q

What difficulty may arise in classifying a tumor as benign or malignant based on cell differentiation?

A

Some malignant tumors are well differentiated.

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19
Q

Though thickness of the stroma does not help with classifying tumors (as it is necessary for the growth of all neoplasms) what does it determine?

A

The thickness of the stroma determines the consistency of the tumor as some cancers result in a thick fibrous stroma (desmoplasia) and are termed scirrhous).

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20
Q

What is the term given to undifferentiated neoplasms?

A

Anaplasia - dedifferentiation of cells. Some cancers arise from proliferation of stem cells which fail to differentiate as well.

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21
Q

What are the pleomorphisms displayed by anaplastic cells?

A

Large hyperchromatic nuclei; giant cells with a large / multiple nuclei; coarse, clumped chromatin; large nucleoli; mitoses are numerous and atypical (due to multiple spindles there may be tripolar or quadripolar mitotic figures; loss of polarity.

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22
Q

What are some un-anticipated functions of well differentiated cancer?

A

Elaboration of foetal proteins (ectopic hormones from nonendocrine origin) e.g release of ACTH, parathyroid hormone, insulin, glucagon etc from lung carcinomas.

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23
Q

What is dysplasia?

A

Non-neoplastic disorder of cells losing uniformity in architectural orientation displaying many of the same pleomorphisms seen in anaplasia.

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24
Q

What is special about the mitosis seen in dysplasia of the epithelium?

A

Mitosis can be observed in all germ layers not just the basal layer - disorder fo scrambling dark basal appearing cells (squames).

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25
What is carcinoma in situ?
Marked dysplastic changes involving the entire epithelium (preinvasive stage of cancer).
26
If the inciting cause of a mild or moderate dysplasia that does not involve the entire epithelium is removed can complete regression occur?
Yes
27
What factors affect the rate of growth of a tumor (benign or malignant)?
Level of circulating hormones (oestrogen leads to rapid growth of leiomyomas of the uterus); blood supply; pressure constraints (adenomas of pituitary gland constrained by the sella turcica - necrosis due to compressed blood supply).
28
What is the relationship between the rate of growth of a malignant tumor and its level of differentiation?
Rate of growth is inverse proportional to level of differentiation.
29
What would cause a relatively slow growing tumor to suddenly begin growing rapidly?
Emergence of an agressive subclone of transformed cells.
30
Why do rapidly growing malignant tumors often contain a central area of ischaemic necrosis?
Tumor blood supply fails to keep up with oxygen needs of expanding cell mass?
31
What is the function of stem cells in a tumor?
As there is continues growth of short lived cells such as blood elements and epithelial cells a population of long-lived and self - renewing stem cells are required.
32
How are stem cells sustained in tissues?
Paracrine factors secreted by support cells.
33
What features indicate that tumors must contain cells with stem like properties?
The immortality provided by the fact that stem cells divide asymetrically into cells with limited proliferative potension and those that maintain stem cell potential.
34
What are the implications for cancer treatment posed by the presence of stem cells in tumors?
To cure a cancer one must eliminate the immortal stem cells; as stem cells express factors such as multiple drug resistance - 1 they are resistant to chemotherapeutic drugs.
35
How does the capsule around an adenoma develop?
It is formed by the stroma of the host tissue as the parenchymal cells atrophy under pressure as well as the stroma of the tumor.
36
What type of cleavage place in present around leiomyoma of the uterus?
A zone of compressed and attenuated normal myometrium.
37
In which benign tumor is demarcation unlikely to be seen?
In vascular neoplasms of the dermis.
38
How does cancer grow?
By progressive infiltration, invasion, destruction and penetration of surrounding tissues.
39
What is a metastases?
A secondary implant of a tumor that is discontinuous with the primary tumor located in a remote tissue.
40
Which tumors are highly invasive locally but rarely metastasise?
Basal cell carcinomas of the skin and primary tumors of the CNS.
41
Which tumor most quickly metastasises?
Osteogenic sarcomas - metastasise to the lungs at time of discovery.
42
What are the three pathways of dissemination of malignant tumors?
Seeding within body cavities; lymphatic spread; hematogenous spread.
43
What is the most characteristic cancer that spreads via seeding within the body cavity?
Cancer of the ovary - covering of the peritoneal cavity (may not invade underlying tissue.
44
Penetration of the cerebral ventricles and spreading by CSF to implant on the meningeal surface is characteristic of which tumors?
Medulloblastoma and ependymoma (neoplasms of the CNS).
45
What type of spread of more typical of carcinomas and sarcomas respectively?
Lymphatic and hematogenous respectively.
46
Dissemination of neoplasms is dependent on location and organisation of the lymphatic drainage, how would a lung carcinomas arising in the respiratory passage spread?
Regional bronchial lymph nodes first then thracheobronchial and hilar nodes.
47
Dissemination of neoplasms is dependent on location and organisation of the lymphatic drainage, how would carcinomas of the breast spread?
As it arises in the upper outer quadrant most frequently it would first spread to the axillary nodes; but medial lesions would spread along the internal mammary artery as drainage is through the chest wall - both cases leading to seeding of the supra and infraclavicular nodes.
48
What are skip metastases?
Cells traverse lymphatic channels within immediate nodes (sentinel lymph nodes) becoming trapped in subsequent nodes or all lymph nodes reaching vascular compartment via thoracic duct?
49
Why is histopathological verification of tumor within an enlarged lymph node required?
Necrotic products and tumor antigens lead to lymphadenitis and sinus histiocytosis.
50
Why are the liver and lungs the most frequent site of hematogenous dissemination?
Portal drainage goes to the liver and caval blood flows to the lungs?
51
Why do carcinomas in the thyroid and prostate frequently metastasise in vertabrae?
As they are near the vertebral column they embolise through the paravertebral plexus?
52
Which carcinomas frequently grow within veins?
Renal cell carcinoma invades renal vein up the vena cava to the right side of the heart and HCC penetrates teh portal vein and hepatic radicles.
53
What kind of inheritance is demonstrated in retinoblastoma (40% being familial)?
Autosomal dominant (occurs bilaterally with increased chance of developing osteosarcoma).
54
Name the most frequently occuring autosomal recessive syndromes of defective DNA repair?
Xeroderma pigmentosum, Ataxia-telangectasia, Bloom syndrome and Fanconi anemia.
55
What are the most common preneoplastic lesions?
Squamous metaplasia / dysplasia of the bronchial mucosa (smokers); endometrial hyperplasia / dysplasia (unopposed estrogenic stimulation); Leukoplakia (oral cavity, vulva or penis); villous adenomas of colon.
56
Which regulatory gene classes are involved in oncogenesis?
Growth - promoting oncogenes; growth - inhibiting tumor supressor genes; genes that regulat apoptosis and genes involved in DNA repair (growth and survival).
57
What are the most significant examples of a governor and guardian gene respectively?
RB (stops cellular proliferation [deletion of 13q14]) and TP53 (sensing and repairing DNA damage / activating apoptosis [deletion of 17p]) respectively.
58
How many alleles are required for function of TSGs?
Often only one copy of an allele is required (for deactivation of TSG, typically one has a point mutation and the other a deletion [LOH]) however it is becoming more apparent that TSGs suffer from haplo-insufficiency as well.
59
What are the common non-random structural abnormalities in tumor cells?
Balanced translocations, deletions and cytogenetic manifestations of gene amplification.
60
Explain fully how translocation results in overexpression of proto-oncogenes and malignancy.
By removal from normal regulatory elements and placing them under control of inappropriate promoters. (Burkitt-lymphoma - translocation between 8 and 14 leading to overexpression of MYC and impacting Ig heavy chain regulation; in B cell lymphomas translocations between 14 and 18 leads to overexpression of anti-apoptotic gene BCL - 2 driven by Ig gene elements [14]).
61
How does oncogenic translocation to create fusion genes lead to malignancy?
The new fusion genes are able to encode novel chimeric proteins such as in the Ph chromosome (22 and 9) in myelogenous leukemia showing BCR - ABL rearrangement and tyrosine kinase activity.
62
Why are lymphoid cells most commonly the target of gene rearrangements?
They purposefully make DNA breaks in Ab or T cell receptor gene recombinations.
63
What common translocation occurs frequently in myeloid neoplasms / sarcomas such as Ewing sarcoma (resulting in fusion of EWS transcription factor and Fli - 1)?
t(11;22)(q24;12)
64
Explain TMPRSS-ETS fusion gene carcinogenesis?
ETS transcription factor is placed under the control of TMPRSS promoter which androgen dependent leading to proliferation.
65
Explain how HMGA2 (TF) gene rearrangement leads to malignancy.
3 prime UR is removed so no negative regulatory microRNA binding site.
66
What is a double minute?
Multiple small extrachromosomal structures seen as a result of gene amplification.
67
What are homogenously staining regions?
Insertion of amplified gene into new chromosomal location - visually they lack a banding pattern so appear homogenous in a G - banded karyotype.
68
In which type of tumors are amplification of the NMYC and ERBB2 (HER2/NEU) genes involved?
Neuroblastoma and breast cancer.
69
How is aneuploidy avoided in the normal cell cycle?
At the mitotic checkpoint before anaphase productive attachments of chromosomes to spindle microtubules should be made or apoptosis will be triggered.
70
How does miRNA lead to increased proliferation, reduced apoptosis, increased invasiveness and angiogenesis?
Reduced miRNA leads to reduced translational repression and over-expression of ono-proteins (BCL2 in apoptosis and RAS and MYC in lung tumors and B cell leukemias) and increased miRNA can lead to an increase in translational repression of TSGs.
71
What are the main epigenetic methods by which tumors form?
Methylation (hypomethylation in general and hypermethylation of promotor regions of TSGs) and histone modification.
72
What phenomena leads to cancers becoming more agressive and less responsive to therapy over time?
The appearance of sub-clones that are less antigenic and are able to avoid the hosts immune system (becoming heterogenous).
73
What are the two growth factor mediated ways that cancer cells achieve growth - sufficiency?
Producing the growth factor that the cell has the receptor for (PDGF in glioblastoma and TGF-alpha in sarcomas) and interaction with the stroma to produce GF.
74
What are the GF receptor and non-receptor tyrosine kinase mechanisms by which cancer cells achieve growth - sufficiency?
Via mutation of the receptor in which it does not require stimulation from GFs and increased quantity of receptors leading to hyper-responsiveness such as with EGF receptor families (ERBB1 in squamous cell carcinomas and ERBB2 in breast cancer).
75
What are the downstream signal-transducing protein mechanisms by which cancer cells achieve growth - sufficiency?
Second messenger system or a cascade of phosphorylation and activation of signal transduction molecules.
76
How does the RAS protein increase cell proliferation?
When stimulated by EGF or PDGF for example the associated GDP is phosphorylated to GTP and RAS become activated and converges on the nucleus flooding it with proliferation signals. This is short lived due to the activity of GTPase. BRAF which is in the kinase pathway is mutated commonly in melanomas so other downstream molecules of RAS are also mutated. Activation in cancer occurs as a result of a point mutation in the GTP binding pocket or the region responsible for GTP hydrolysis (loss of function).
77
How does ABL protein increase cell proliferation in chronic myelogenous leukemia?
ABL is translocated from 9 to 22 next to the BCR. The hybrid maintaining the tyrosine kinase domain allowing tyrosine kinase activity to occur unfettered; the ABL-BCR hybrid activates the RAS downstream signals.
78
Which oncogenes lead to deregulation of transcription of DNA?
MYC, MYB, JUN, FOS and REL regulating growth promoting genes such as cyclins.
79
Which genes does MYC activate and repress?
Activates: growth promoting genes (CDK); Repressed: CDKIs. MYC also upregulates promotion of aerobic glycolysis and increased utilisation of glutamine (t(8;14)).
80
Mutations in genes coding for and amplifying which proteins leads to mis-regulation of the G1 - S checkpoint?
Cyclin D (breast, oesophagus, liver, lymphomas and plasma cell tumors) and CDK4 mutations (melanomas, sarcomas, glioblastomas) are most common. However, disabling of senescence and apoptosis mechanisms is also required.
81
How does HPV prevent Rb from inhibiting E2F?
The E7 protein binds to phosphorylated Rb stopping it form binding to E2F and inducing transcription.
82
How does Rb prevent movement of the cell cycle from G1 - S?
By causing the cell to reenter G0 (quiescence) or to permanently exit the cell cycle (senescence).
83
How does p53 thwart neoplastic transformation?
Quiescence, senescence or apoptosis.
84
What affect does MDM2 have on p53? How is this affect counteracted under stress?
It destroys p53 and is instrumental in its short 20 minute half-life. Under stress protein kinases such as ATM catalyse modification of p53 allowing it to be released from MDM2.
85
By what novel mechanism does p53 activation lead to repression of gene function?
The activation of miRNAs leads to the repression of proliferative genes such as cyclins and BCL2 for example.
86
What is Li-Fraumeni syndrome?
When only one functional p53 allele is inherited.
87
How is p53 affected by HBV and EBV?
The DNA virus' proteins can bind to p53 and nullify its protective function.
88
How does TGF-B cause tumor suppression?
TGF-B binds to TGF-B receptors 1 and 2 leading to dimerisation and activation of cascade that causes transcription of CDKI which suppress growth and represses growth promoting genes such as MYC, CDK2, CDK4 and cyclins A and E.
89
What common mutations lead to dysfunction of TGF-B?
Mutation of the TGF-B receptor 2 or if a component of the TGF-B signalling pathway is mutated. (If p21 is mutated and MYC persists the tumor uses downstream signalling pathways to evade the immune system and promote angiogenesis).
90
Explain contact inhibition.
Usually cell - cell contact in monolayers suppresses proliferation. This is abolished via homodimeric interactions between cadherins.
91
Explain how E-cadherins lead to suppression of contact inhibition.
Homozygous loss of NF2 can lead to neurofibromatosis. Loss of APC leads to adenomatous polyposis coli by translocation of beta catenin to the nucleus to activate cell proliferation used in the WNT signalling pathway (WNT inhibits the breakdown of beta catenin). APC usually leads to the degradation of beta catenin. This leads to inappropriate transcription of growth promoting genes such as cyclin D1 and MYC and regulators TWIST and SLUG.
92
Explain the mechanism behind the extrinsic pathway of cell death.
TNF receptors bind to their ligands leading to receptor trimerisation attracting the adaptor protein FADD that recruits procaspase - 8 which is cleaved to produce caspase - 8 which activates caspase 3 cleaving DNA causing cell death.
93
Explain the mechanism behind the intrinsic pathway of cell death.
Triggered by stress, injury or withdrawal of survival factors. There is increase in BAX and BAK activity as BCL2 and BCLXL are inactivated by BH3 proteins BID, BAD, PUMA. BAK and BAX form pores in the mitochondrial membrane leading to the release of cytochrome C which binds to APAF-1 activating caspase - 9 which activates caspase - 3.

Pathomorphology (5 decks)

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