Amyloidosis and Neoplasia Flashcards
(123 cards)
1
Q
What is localized amyloidosis?
A
- Amyloid deposits limited to single organ or tissue, w/o involvement of any o/site in body -> may be grossly detectable nodular masses or only on micro exam
- Nodular deposits most often in lung, larynx, skin, bladder, tonuge, and around eye
- Frequently, infiltrates of lymphocytes and plasma cells in amyloid periphery
- In some cases, amyloid is AL protein, and may represent localized form of plasma cell derived amyloid
2
Q
Is this pancreatic sample benign or malignant? Describe what you see here.
A
- Malignant
- From left to right:
1. Residual, non-neoplastic pancreas (acini)
2. Intervening fat (white tissue)
3. Edge of the tumor = poorly formed glands
2
Q
How does the NMYC gene get amplified? In which type of cancer does this happen?
A
- In NEUROBLASTOMAS
- Either as:
1. Extra-chromosomal double minutes, or as a
2. Chromosomally integrated, homogeneous staining region (HSR)
3
Q
What type of tumor is most associated with an overexpressed HGMA2 gene?
A
Parotid pleomorphic adenoma
3
Q
Describe amyloidosis in the heart.
A
- May occur in any form of systemic amyloidosis, but major organ involved in senile systemic amyloidosis
- Heart may be enlarged and firm, but more often shows no significant changes on gross inspection
- Histologically, deposits begin as focal subendocardial accumulations w/in the myocardium b/t muscle fibers
1. Subendocardial -> conduction system may be damaged, accounting for electrocardiographic abnormalities noted in some patients
2. Myocardial deposits -> expansion eventually causes pressure atrophy of myocardial fibers
4
Q
What type of tumor is most associated with an overexpressed MYC gene?
A
Burkitt lymphoma
4
Q
What is p53?
A
- Tumor suppressor protein that can:
1. Activate DNA repair proteins for damaged DNA
2. Arrest growth by holding cell cycle at G1/S regulation point on DNA damage recognition (to allow time for repair)
3. Initiate apoptosis if DNA proves to be irreparable
4
Q
What are CDK inhibitors?
A
Enforce the cell-cycle checkpoints by modulating CDK-cyclin complex activity
4
Q
What is transthyretin? What are the associated diseases?
A
- Transthyretin (TTR): normal serum protein that binds and transports thyroxine and retinol
- Familial amyloid polyneuropathies: genetic disorders in which several distinct forms of TTR (and its fragments) are deposited (amyloidosis)
- Normal TTR is also deposited in the heart of aged individuals (senile systemic amyloidosis); image on card
5
Q
What are the 2 most important tumor suppressor genes?
A
RB and TP53, both of which encode proteins that inhibit G1/S progression
6
Q
Describe amyloidosis of the spleen.
A
- May be inapparent grossly, or may cause moderate to marked splenomegaly (up to 800 g)
- One of two patterns of deposition:
1. Largely limited to splenic follicles (white pulp), producing tapioca-like granules on gross inspection, designated sago spleen
2. In walls of splenic sinuses and CT framework in red pulp. Fusion of early deposits -> large, maplike areas of amyloidosis, or lardaceous spleen
7
Q
What is endocrine amyloid?
A
- Micro deposits of localized amyloid in some endocrine tumors, i.e.:
1. Medullary carcinoma of thyroid gland: A Cal from calcitonin precursor, a polypeptide hormone (essential dx feature)
2. Islet tumors of the pancreas: AIAPP, islet amyloid peptide precursor
3. Pheochromocytomas, undifferentiated stomach carcinomas, and islets of Langerhans in T2D
8
Q
What is a sarcoma?
A
A malignant neoplasm of mesenchyme-derived tissue (i.e., loose connective tissue)
9
Q
What is anaplasia? Describe some of its features.
A
- Lack of visible differentiation of malignant tumor cells, giving them the appearance of primitive, unspecialized cells
- Features of anaplastic cells:
1. Larger than differentiated cells
2. Higher nuclear/cytoplasmic ratio (bigger nuclei, less cytoplasm)
3. Pleomorphic (varying in size and shape)
4. Nuclear abnormalities: angulated shape, hyperchromatism, clumped chromatin, mitoses, nucleoli
9
Q
Why are malignant tumors more likely to have a less round shape (3)?
A
May disrupt spherical growth pattern via:
- Subclones of malignant tumor are more likely to have additional mutations making them grow faster
- Subclones around periphery can grow faster and invade surrounding tissue
- Parts of rapidly growing malignant tumor can outgrow their blood supply, undergo necrosis, and shrink
9
Q
What type of tumor is most associated with a TMPRSS-ETS fusion gene?
A
Prostate adenocarcinoma
9
Q
There are 2 principle common mechanisms of disease in failed targeted therapy - what are they?
A
- Downstream mutations in signaling pathways to cell proliferation ruin the effectiveness of treatment targeted to upstream mutations earlier in the pathway
- Upstream alternative pathways in signaling cell proliferation ruin the effectiveness of treatment targeted to downstream mutations later in the pathway
9
Q
How is beta-microglobulin associated with amyloidosis?
A
- A component of MHC I molecules, and a normal serum proteint
- Identified as the amyloid fibril subunit (AB2m) in amyloidosis that complicates the course of patients on long-term hemodialysis
- Associated disease: chronic renal failure
9
Q
How are prions implicated in amyloidosis?
A
- In a minority of cases of prion disease in CNS, misfolded prion proteins aggregate in EC space
- Acquire structural and staining characteristics of amyloid protein
10
Q
What is the primary distinguishing feature of malignant vs. benign tumors?
A
Malignant tumors are infiltrative or invasive into native, or other tissue
11
Q
What is the treatment for patients with advanced melanomas harboring activating BRAF mutations?
A
- BRAF inhibitors, i.e., Vemurafenib, an oral, selective inhibitor of the BRAF mutant kinase -> shuts down ERK signaling in pts with advanced melanomas
- BRAF mutation at codon 600 in about 50% of pts. with melanoma causes dependence on ERK signaling (pathway = RTK -> RAS -> BRAF -> MEK -> ERK -> cellular proliferation)
- Study showed 81% unconfirmed response rate in V600E+ pts when tx with Vemurafenib
- The attached image shows potential mechanisms for acquired resistance to BRAF inhibition
13
Q
What is a malignancy?
A
- Cancer: neoplasm that invades and/or metastasizes
14
Q
How is MYC level related to Burkitt lymphoma?
A
- Fastest growing human tumors (e.g., Burkitt lymphoma) virtually always have a chromosomal translocation involving MYC and have the highest levels of MYC
15
Q
What is the most common type of abnormality involving proto-oncogenes in human tumors?
A
- Point mutations of RAS family genes
- 3 RAS genes: HRAS, KRAS and NRAS
1. About 20% of all human tumors express mutated RAS proteins, but in some types of cancers the freq of RAS mutations is much higher
2. 90% of pancreatic adenocarcinomas contain a RAS point mutation, as do about 50% of colon, endometrial, and thyroid cancers and about 30% of lung adenocarcinomas and myeloid leukemias
16
What is an adenoma?
Benign epithelial neoplasm forming or derived from glands
17
What is this?
- Sessile colon polyp (in the center of the image)
- Polyp: macroscopic projection above a mucosal surface, or a bump/nodule on a stalk
1. Pedunculated: on a stalk
2. Sessile: flat, like a plateau
18
What are 4 ways in which benign neoplasms are different from malignant neoplasms? Describe these differences.
1. Degree of differentiation
A. Benign: resemble tissue of origin and are well differentiated; more likely to retain functions of their cells of origin
B. Malignant: less well differentiated, or completely undifferentiated (anaplastic); sometimes acquire unexpected functions due to derangements in differentiation
2. Rate of growth: benign slow, malignant fast (often with hemorrhage and necrosis)
3. Local invasiveness
A. Benign: circumscribed and have a capsule
B. Malignant: poorly circumscribed and invade surrounding normal tissues
4. Distant spread: benign localized at site of origin, malignant metastasize to distant sites
19
What is oncogene addiction? Provide an example.
- **Definition**: tumor cells highly dependent on the activity of one or more oncogenes (**EX**: BCR-ABL and CML)
- Signaling through BCR-ABL tyrosine kinase is required for most CML tumor cells to proliferate and survive, so inhibition of its activity is a highly effective therapy
- _NOT a cure_: while proliferating component of tumor is suppressed by BCR-ABL inhibitors, rare CML “stem cells” harboring BCR-ABL fusion gene persist b/c these cells don't need BCR-ABL signals for survival -\> therapy with BCR-ABL inhibitors continued indefinitely, or these malignant stem cells will spawn proliferating offspring and fullblown leukemia will return
- **Important Concept**: there are “stem-like” cells in some cancers that may be esp resistant to therapy
20
What is a neoplasm?
- Tumor: an autonomous, irreversible, clonal benign or malignant cell proliferation outside of normal control by growth factors, contact inhibition, etc.
20
What is a carcinoma?
A malignant neoplasm of epithelial cells
21
Which checkpoint is more important in cancer, G1-S or G2-M?
G1-S
22
What is the prognosis for people with generalized amyloidosis?
- Poor -\> those with AL amyloidosis (not including multiple myeloma) have median survival of 2 years after diagnosis
- Persons with myeloma-associated amyloidosis have an even poorer prognosis
23
What is a metastasis?
- Secondary tumor site discontinuous with the primary site
25
What are the most common sites biopsied for amyloidosis detection? What other tests can be used for diagnosis?
- Diagnosis of amyloidosis depends on the histologic demonstration of amyloid deposits in tissues
- Most common sites biopsied are:
1. Kidney when renal manifestations are present
2. _Systemic_: A) rectal or gingival tissues, B) ab fat aspirates stained with Congo red (specific, but low sensitivity)
3. _AL amyloidosis_: serum and urine protein electrophoresis and immunoelectrophoresis
4. _Scintigraphy_ w/radiolabeled serum amyloid P component rapid and specific b/c SAP binds and reveals amyloid -\> also gives measure of extent of amyloidosis, and can be used to _follow pts in tx_
26
Describe the microscopic characteristics of amyloid (via electron microscopy and Congo Red staining).
- EM: all types of amyloid consist of continuous, non-branching fibrils with a _diameter of 7.5-10nm_ (can be up to six fibrils in e/fiber, wound around e/o w/regularly spaced binding of Congo red dye)
- X-ray crystallography and IR spectroscopy show characteristic cross-beta-pleated sheet conformation
1. This conformation is seen regardless of clinical setting or chemical composition, and is reason for distinctive Congo red staining and _birefringence_ of amyloid (_apple-green_ under polarized light)
27
What are the clinical manifestations of GI and tongue amyloidosis?
- GI: may be entirely asymptomatic, or may present in a variety of ways -\> deposits in stomach and intestine may lead to malabsorption, diarrhea, and disturbances in digestion
- TONGUE: may cause sufficient enlargement and inelasticity to hamper speech and swallowing
28
Where do all signal transduction pathways converge? What is a mitogen?
- _The nucleus_, where deregulated mitogenic signaling pathways cause inappropriate and continuous stimulation of nuclear transcription factors, driving growth-promoting genes
- _Mitogen_: chemical substance that encourages a cell to commence cell division, triggering mitosis
28
What does amyloidosis look like under electron microscopy? How do you distinguish b/t the different types microscopically?
- Amorphous nonoriented thin fibrils
- AA, AL, and ATTR types can be distinguished by specific immunohistochemical staining (b/c all show birefringence under fluorescent light in Congo red staining due to beta-pleated configuration of amyloid fibrils)
28
What are the clinical manifestations of cardiac amyloidosis?
- May present as an insidious congestive heart failure
- Most serious aspects of cardiac amyloidosis are conduction disturbances and arrhythmias, which may prove fatal
- Occasionally, cardiac amyloidosis produces a restrictive pattern of cardiomyopathy and masquerades as chronic
constrictive pericarditis
29
What is BRAF? Why are its mutations important?
- **BRAF**: a serine/threonine protein kinase that sits at the top of a cascade of o/serine/threonine kinases of the MAPK family. Like activating RAS mutations, activating mutations in BRAF stimulate each of these downstream kinases and ultimately activate transcription factors
- _Mutations in BRAF_, a member of the RAF family, in close to 100% of hairy cell leukemias, more than 60% of melanomas, 80% of benign nevi, and smaller % of a wide variety of other neoplasms, including colon carcinomas and dendritic cell tumors
29
Why is MYC so important when considering growth autonomy?
- Virtually all pathways that regulate growth impinge on MYC, and under normal circumstances, MYC protein concentrations are tightly controlled at the level of transcription, translation, and protein stability
- Several single nucleotide polymorphisms (SNPs) strongly linked to an elevated risk of cancers, like prostate and ovarian carcinoma, fall w/in a large region devoid of recognizable genes next to MYC, suggesting these genetic variants alter the function of enhancer elements regulating MYC expression
31
What is this?
Hamartoma: mass of mature, but disorganized, tissue indigenous to its site (devo anomaly)
31
What are the clinical manifestations of vascular amyloidosis?
- Causes vascular fragility that may lead to bleeding, sometimes massive, that can occur spontaneously or following seemingly trivial trauma
- In some cases, AL amyloid binds and inactivates factor X, a critical coagulation factor, leading to a life-threatening bleeding disorder
32
Is this tumor benign or malignant? Why or why not?
- Benign, tan tumor of the adrenal medulla with:
1. Cohesive, expansile local growth (compressing gold-colored adrenal cortex around it), and
2. Maintaining an oval shape
33
What does amyloidosis look like histologically?
- Deposition is always EC, and begins between cells, often closely adjacent to basement membranes
- As amyloid accumulates, it encroaches on cells, in time surrounding and destroying them
- In the form associated with plasma cell proliferation,
perivascular and vascular deposits are common
- The histologic diagnosis of amyloid is based almost entirely on its staining characteristics (i.e., Congo red and birefringence under polarized light
34
Can inhibitors of EGFR and ALK be used to cure lung cancer?
- **No**: while INH of EGFR in pts w/ERBB1 mutations or EML4-ALK fusion genes produce similar therapeutic responses to ERRB2/HER2 INH, none of these targeted therapies cure advanced lung adenocarcinomas
- In treated pts, tumors often acquire activating mutations in some other signaling molecule, most often another tyrosine kinase, sidestepping the effects of the drug, & resulting in resistance to the targeted therapy
- Lung cancers that devo resistance to EGFR INH often have amplifications in MET, which encodes a different receptor tyrosine kinase -\> one of the most daunting clinical problems in tx of advanced cancers is the presence of **SUBCLONES** in genetically heterogeneous tumor cell pop that are resistant to targeted therapies
35
Which gain of function mutations are most important in regards to cell cycle progression and cancer?
- Gain-of-function mutations in D cyclin genes and CDK4 create oncogenes that promote G1/S progression in lymphoid tumors and gene amplification has a similar effect in a variety of solid tumors.
- Amplification of the CDK4 gene also occurs in melanomas, sarcomas, and glioblastomas.
- Mutations affecting cyclin B, cyclin E, and other CDKs also occur, but are much less frequent, probably b/c of preeminent importance of G1/S transition in regulating tumor growth rates
37
What organ is this? Is this benign or malignant?
- Pancreas
- Malignant, but need microscopy to tell b/c *sort of* oval and *sort of* circumscribed
38
Is a fibrous capsule more characteristic of benign or malignant tumors?
Benign
38
Amyloidosis with plasma cell proliferations more often involves which organs?
- Heart, GI tract, respiratory tract, peripheral nerves, skin, and tongue
- However, amyloidosis associated with plasma cell proliferations cannot reliably be distinguished from the secondary form by its organ distribution
39
Does this look benign or malignant? Why?
- Thyroid adenoma
- Benign: perfectly round, in this case
1. Autonomous growth of a monoclonal cell proliferation in soft, yielding tissue tends to create a spherical mass
- _A round, spherical mass is more characteristic of a benign tumor than a malignant one_
41
What type of tumor is most associated with an overexpressed BCL2 gene?
Follicular lymphoma
41
How does growth autonomy occur? Via what molecular mediators?
- May occur as a consequence of mutations affecting the transcription factors that regulate the expression of pro-growth genes and cyclins
- These include the products of the MYC, MYB, JUN, FOS and REL proto-oncogenes
1. Of these, **MYC** is most commonly involved in human tumors
43
What is a choristoma?
Estopic rest = mass of normal tissue present outside its normal site (developmental anomaly)
44
How many different proteins can aggregate and form fibrils with the appearance of amyloid? What implications does this have?
- _More than 20 _
- 3 major, and several minor biochemical forms (in other notecard) that are deposited by different pathogenic mechanisms
- Amyloidosis should NOT be considered a single disease, but rather a group of diseases that deposit similar-looking proteins -\> _remarkably uniform physical organization of amyloid protein _
45
What is familial Mediterranean fever?
- One of a variety of heredofamilial amyloidoses, which are rare, and occur in limited geographic areas
- Autoinflammatory syndrome associated w/excessive IL-1 in response to inflammatory stimuli -\> attacks of fever and inflam. of serosal surfaces, i.e., peritoneum, pleura, synovial membrane
- Widespread (sometimes), AA type amyloidosis
- Gene encodes **pyrin **complex of proteins that regulate inflam via proinflam cytokines
- Armenian, Sephardic Jewish, Arabic
46
Is amyloidosis apparent on macroscopic evaluation?
- Maybe
- When amyloid accumulates in larger amounts, the organ is frequently enlarged and the tissue appears gray with a waxy, firm consistency
46
What are the clinical manifestations of renal amyloidosis?
- Proteinuria that may be severe enough to cause the nephrotic syndrome
- Progressive obliteration of glomeruli in advanced cases ultimately leads to renal failure and uremia
- Renal failure is a common cause of death
47
What is going on here?
Amyloidosis of the kidney: most common and most potentially serious form of organ involvement in amyloidosis
48
What is this?
Choristoma (mass of normal tissue present outside its normal site): notice the several different types of tissue identified
48
What is this?
- Ovarian teratoma making hair and sebum (yellow stuff)
- Teratoma (aka, mixed germ cell tumor: benign or malignant neoplasm with components of more than one germ cell layer, usually all three (ecto, meso, endoderm)
49
What is the AL protein in amyloidosis?
- _Amyloid light chain protein_: complete immunoglobulin light chains, amino-terminal fragments of light chains, or both
- Most are _lambda_ light chains, or their fragments, but kappa chains present in some cases
- Produced from free Ig light chains secreted by _monoclonal population of plasma cells_ -\> deposition associated with certain types of plasma cell tumors
50
What is going on here?
- Carcinoma in situ in squamous epithelium with cells throughout with basal layer features and loss of orderly progression to flattened cells on surface
- _Carcinoma in situ_: tissue with all the cytologic (individual cell) features of malignancy without visible invasion
51
What is a hamartoma?
Mass of mature, but disorganized tissue indigenous to its site (developmental anomaly)
52
What is the chemical nature of amyloid?
- 95% fibril proteins
- 5% the P component and other glycoproteins
54
How is amyloidosis clinically recognized?
- Depends on the morphologic identification of amyloid in appropriate _biopsy_ specimens
- Under light microscope and H&E, amyloid looks like an amorphous, eosinophilic, hyaline, EC substance
- Most widely used stain to differentiate from hyaline is Congo Red, which imparts pink/red color to tissue under normal light, but shows _green birefringence_ of stained amyloid when visualized by polarizing microscopy
54
What is the major fibril protein and associated precursor in isolated atrial amyloidosis?
AANF from atrial natriuretic factor prescursor
56
What is this?
- Pedunculated colon polyp
- Polyp: macroscopic projection above a mucosal surface, or a bump/nodule on a stalk
1. Pedunculated: on a stalk
2. Sessile: flat, like a plateau
57
What is going on here?
- Gastric cancer white with desmoplasia
- _Desmoplasia_: formation of abundant fibrous stroma by some carcinomas (reactive)
57
What type of tumor is most associated with a EML4-ALK fusion gene?
Lung primary adenocarcinoma
58
What is the AA protein in amyloidosis?
- _Amyloid-associated_ type of amyloid fibril protein, derived from unique _non-Ig protein made by liver_
- Molecular weight around 8500, consisting of 76 AA residues -\> fibrils from proteolysis of larger (12,000 D) precursor in serum called _serum amyloid- associated protein (SAA)_ (syn in liver, circulates bound to HDL
- Production of SAA increased in inflammatory states as part of acute phase response -\> _secondary amyloidosis (associated with chronic inflammation) _
59
What is primary amyloidosis?
- Systemic, AL -\> most common form of amyloidosis
- _Clonal proliferation of plasma cells that syn Ig prone to form amyloid_ due to intrinsic physiochemical properties
- Some cases have classic multiple myeloma or o/overt B-cell neoplasm, but most do not -\> in virtually all of these cases, monoclonal Ig, free light chains, or both found in urine or serum (also have modest INC in # of plasma cells in bone marrow that secrete AL precursors)
1. These pts have underlying monoclonal proliferation of plasma cells (**monoclonal gammopathy**) in which production of abnormal protein, rather than production of tumor masses, is predominant manifestation
60
What is Rb?
- _Retinoblastoma protein_: tumor suppressor protein that is dysfunctional in several major cancers –\> inhibits cell cycle progression until cell is ready to divide
1. When cell ready to divide, Rb phosphorylated to pRb and inactive, allowing cell cycle progression
2. Recruiter of chromatin remodeling enzymes
3. Can be inactivated by oncogenic proteins, leading to cancer
4. Prevents progression from G1 to S phase by binding and inhibiting transcription factors of E2F family (E2F + dimerization partner (DP) –\> S phase); Rb – E2F/DP complex attracts histone deacetylase, DEC transcription of S phase promoting factors
61
What is the targeted therapy for the EML4-ALK fusion gene? What is the associated cancer?
- Lung primary adenocarcinoma
1. EML4-ALK fusion gene present in
- _Crizotinib_: nowhere near as impressive as Imatinib for CML, but lung cancer is much more rapidly fatal than CML
62
Does amyloid have a constant/distinctive pattern of organ or tissue distribution?
No, but a few generalization can be made (noted in other cards)
64
What type of tumor is most associated with a BCR-ABL fusion gene?
Chronic myelogenous lukemia
65
Describe how amyloid can be associated with aging.
- _Senile systemic amyloidosis_: 70-80 y/o with systemic _normal TTR_ amyloid, chieflly involving heart -\> present with restrictive arrhythmias and cardiomyopathy
- Another form affecting mainly the heart results from deposition of _mutant TTR_ (about 4% of AA US pop)
1. Cardiomyopathy in both homo and heterozygous patients, but precise prevalence of patients with this mutation who develop clinically manifest cardiac disease is unknown
66
What are the two possible *distributions* of amyloid? One of these has 2 subcategories - what are they?
- _Systemic_ (generalized): involving several organ systems
1. Primary: associated w/some plasma cell disorder
2. Secondary: complication of an underlying chronic inflammatory or tissue-destructive state
NOTE: hereditary, or familial, amyloidosis constitutes separate, heterogeneous grp, w/several distinct patterns of organ involvement
- _Localized_: deposits limited to single organ, i.e., heart
67
What is the most frequently mutated oncogenic pathway in human neoplasms?
- The receptor tyrosine kinase pathway
- However, the GPCR, Hedgehog, TGF-beta/SMAD, and NFKB pathways are also implicated in the devo and progression of various cancers
68
What is going on here. Name the organ, and describe the gross pathology.
- Spleen amyloidosis
- Distinct white spots are amyloid infiltrates in the white pulp. Larger deposits are seen in the area of reflection at the lower right.
69
Describe the Wnt signaling pathway.
1. Wnt protein binds N-terminal EC cysteine of Frizzled (Fz) family receptor
2. Fz receptors span membrane 7 times (distinct family of G-protein coupled receptors)
3. May also require co-stimulation from: lipoprotein receptor-related protein (LRP), receptor tyrosine kinase (Ryk), or ROR2
4. Activated Fz receptor signals to phosphoprotein, Disheveled (Dsh), located in the cytoplasm
5. Dsh has different domains, each leading down different pathways
70
In amyloidosis secondary to chronic inflammatory disorders, which organs/tissues are typically affected?
- Kidneys
- Liver
- Spleen
- Lymph nodes
- Adrenals
- Thyroid
- Many other tissues
72
What is going on here? How do you know?
- _Anaplasia_: no gland formation or other differentiation
1. Large cells (compare size to red cells in lower left)
2. Large nuclei
3. Abnormal tripolar mitosis (center)
4, Multinucleated giant cells (top left corner)
74
How is receptor tyrosine kinase therapy affected by an activating mutation of RAS?
- Downstream activating mutations of RAS _make targeted therapy of receptor tyrosine kinases useless_
- When RAS mutations are present in a tumor, activating mutations in receptor tyrosine kinases almost always absent, at least in dominant tumor clone, suggesting activated RAS can completely substitute for tyrosine kinase activity, driving malignant cell proliferation as, or more, effectively than receptor tyrosine kinase activity.
- _NOTE_: lung adenocarcinomas in mutually exclusive molecular subtypes associated with mutations involving RAS or various tyrosine kinase genes
76
What type of tumor is most associated with a Fli-EWS fusion gene?
Ewing sarcoma
77
What is reactive systemic amyloidosis?
- Systemic, AA, aka secondary amyloidosis
**WHAT **
- SAA syn by liver cells stimulated by cytokines (esp. IL-1 and 6) produced via inflammation -\> increased SAA itself not sufficient for amyloid deposition, so also:
1. Monocyte-derived enzyme defect resulting in incomplete breakdown of SAA, or
2. Genetically determined structural abnormality in SAA molecule so not degradable by macros
**WHO**
- Complicates _RA_ (3% of pts; clinically sig in 1/2 of those), other CT disorders like ankylosing spondilitis, and IBS, esp. Chron disease and ulcerative colitis (TB pre-AB)
- _Heroin abusers_ who inject drug sub-Q also have high incidence (skin-popping)
- May also occur in association w/_solid tumors_, i.e., renal cell carcinoma or Hodgkin lymphoma
79
What are the 2 downstream signaling pathways of the receptor tyrosine kinases? Describe 2 tumor suppressor genes associated with these.
- Signal transducer _RAS_ (a GTPase activated by growth factor receptor, aka receptor tyrosine kinase) operates immediately downstream from RTKs, & has 2 signaling arms (that are particularly important in cancer):
1. Mitogen-activated protein kinase (MAPK) pathway: RAS -\> RAF -\> MAPK -\> transcription activation -\> _MYC_ (pro-growth metabolism and increased protein syn) and _D-cyclins_ (cell-cycle progression)
A. _GAP_ (GTPase activating protein): a tumor suppressor gene responsible for turning off RAS by hydrolizing GTP
2. Phosphoinositidyl-3-kinase (P13K)/AKT pathway: P13K -\> AKT (pro-growth metabolism) -\> _mTOR_ (increased protein syn)
A. _PTEN_ (phosphatase and tensin homolog): tumor suppressor gene responsible for regulating P13K
- Most (possibly all) cancers have molecular defects that affect these pathways
80
Does amyloidosis elicit an inflammatory response?
NO
81
Briefly compare benign vs. malgnant tumors.
- Benign: cohesive, expansile local growth
1. Commonly with fibrous capsule
- Malignant: progressively infiltrative, invasive, local growth
1. Commonly with destruction of surrounding tissue
82
What is this?
- Chondrosarcoma showing gray cartilage formation (2 left yellow lines), hemorrhage (bottom right), and invasion through the periosteum (top right)
83
Is this tumor benign or malignant? Why or why not?
- Tan-white tumor of breast with features of malignancy:
1. Infiltrative, invasive local growth (invading surrounding adipose tissue), and
2. Making it difficult to see the margins of the tumor
84
Is this colon biopsy benign or malignant?
- Trick question: its BOTH (dividing line at the top right of the image)
1. Adenocarcinoma (left): abnormal gland architecture and basophilic glands due to crowding of nuclei and loss of most cytoplasmic mucin production arising in...
2. Adenoma (bottom right): excess cells, but near normal architecture and retained mucin production
86
Is this pancreatic cancer biopsy benign or malignant?
- High power image of an _adenocarcinoma_:
1. VERY crummy gland formation
2. Fibrous tissue response (desmoplasia)
87
Describe liver amyloidosis.
- Deposits may be inapparent grossly or may cause moderate to marked hepatomegaly
- Amyloid first in space of Disse (perisinusoidal space), then encroaches on adjacent hepatic parenchymal cells and sinusoids
- In time, deformity, pressure atrophy, and hepatocyte disappearance occurs, causing total replacement of lg areas of liver parenchyma -\> vascular involvement and deposits in Kupffer cells are frequent
- Normal liver function usually preserved even if quite severe liver involvement
89
Describe the mechanism of the BCR-ABL fusion gene in CML.
- In chronic myelogenous leukemia (CML), the ABL gene is translocated from chrom 9 to chrom 22, where it fuses with the BCR gene -\> resultant chimeric gene encodes a _constitutively active, oncogenic BCR-ABL tyrosine kinase_
- Most important contribution of the BCR moiety is that it promotes self-association of BCR-ABL, sufficient to unleash the (_nonreceptor_) tyrosine kinase activity of ABL
- **RECURRENT MECHANISM** in cancer: many different oncogenic tyrosine kinases consist of fusion proteins in which non-tyrosine kinase partner drives self-association, making the kinase constitutively active
90
What types of genetic mutations can constitutively activate receptor tyrosine kinases? Provide some examples (3).
- Multiple mechanisms, including point mutations, gene amplifications, and gene rearrangements:
1. **ERBB1**: encodes epidermal growth factor receptor (EGFR) -\> several different ERBB1 _point mutations_ in subset of lung adenocarcinomas result in constitutive activation of the EGFR tyrosine kinase
* **ERBB2**: encodes different member of the receptor tyrosine kinase family, HER2 -\> _amplified_ in some breast carcinomas, leading to overexpression of the HER2 receptor and constitutive tyrosine kinase activity
* _Gene rearrangements_ activate other receptor tyrosine kinases, like ALK. Deletion on chrom 5 fuses part of ALK with part of EML4 gene in some lung adenocarcinomas -\> **EML4-ALK fusion** gene encodes a chimeric EML4-ALK protein, with constitutive tyrosine kinase activity.
91
Briefly describe the pathogenesis of amyloidosis, and its two categories.
- Normally, misfolded proteins are degraded IC in proteosomes, or EC by macros, but in amyloidosis, these quality control mechs fail, leading to _accumulation of misfolded protein outside cells_ -\> become insoluble, aggregate, and deposit as fibrils
- Proteins that form amyloid fall into two categories:
1. _Normal proteins_ w/inherent tendency to misfold, associate, and form fibrils, and do so when produced in increased amounts
2. _Mutant proteins_ prone to misfolding and subsequent aggregation
92
How is MYC deregulated in cancer (4)?
1. Genetic alterations of MYC itself
2. Translocations in Burkitt lymphoma and other B and T cell tumors
3. Amplifications in neuroblastomas (NMYC), small cell cancers of lung (LMYC), some breast, colon, and many other carcinomas
4. Oncogenic muts in upstream signaling pathways, elevating MYC protein levels by increasing MYC transcription, enhancing MYC mRNA translation, and/or stabilizing MYC protein:
A. Constitutive RAS/MAPK signals (many cancers)
B. Notch signaling (several hematologic cancers)
C. Wnt signaling (colon carcinoma)
D. Hedgehog signaling (medulloblastoma)
94
What is going on in the middle of this image?
- Dysplasia, or disordered growth, w/two types:
1. Congenital, embryonically abnormal organization of cells
2. Acquired cellular atypia, usually premalignant, +/- reversible
96
How can Abs or drugs that block HER2 activity be used to treat breast cancer?
- Breast cancers w/_ERBB2_ amplification & overexpression of _HER2_ generally respond to tx with antibodies or drugs that block HER2 activity
- These inhibitors cause _cessation of tumor growth, and also induce apoptosis and tumor regression_, reflecting the ability of receptor tyrosine kinase signaling to augment cell survival as well as proliferation
97
Describe the gross and microscopic appearance of amyloidosis in the kidneys.
- _GROSS_: may be normal size and color, or may shrink via ischemia caused by vascular narrowing induced by amyloid in arterial and arteriolar walls if advanced
- _MICRO_: amyloid chiefly in glomeruli, but the interstitial peritubular tissue, arteries, and arterioles also affected
1. Glomerular deposits 1st subtle thickenings of mesangial matrix w/uneven widening o/basement membranes and glomerular capillaries
2. In time, mesangial and basement membrane deposits cause capillary narrowing and distortion of glomerular vascular tuft
3. With progression of glomerular amyloidosis,
capillary lumens obliterated, and dying glomerulus flooded by masses or ribbons of amyloid
98
What is an adenocarcinoma?
Malignant epithelial neoplasm forming or derived from glands
99
What is amyloidosis?
- A condition associated with a number of inherited and inflammatory disorders in which _EC deposits of fibrillar proteins_ are responsible for tissue damage and functional compromise
- Abnormal fibrils are produced by aggregation of _misfolded proteins_ (soluble in their normal folded conformation) -\> deposits bind a variety of proteoglycans and glycosaminoglycans, incl. heparan sulfate and dermatan sulfate, and plasma proteins, notably serum amyloid P
100
How is multiple myeloma implicated in primary amyloidosis?
- Occurrence of systemic amyloidosis in _5 to 15% of ppl with multiple myeloma_, a plasma cell tumor characterized by multiple osteolytic lesions throughout skeletal sytem
- Malignant plasma cells syn abnormal amts of single Ig (_monoclonal gammopathy_), producing M (myeloma) protein spike on serum electrophoresis (often also secrete free light chains, called _Bence-Jones protein_)
- Bence-Jones found in serum, and due to small size, are secreted in urine and deposited in tissues as amyloid (_vast majority_ of myeloma patients with light chain in serum and urine _DO NOT devo amyloidosis_)
- Not all free light chains are equally likely to produce amyloid -\> _amyloidogenic potential_ largely determined by AA sequence
101
What is erlotinib (Tarceva)?
- Targeted therapy to blockade mutated EGFR tyrosine kinase, resulting in G1 phase arrest, and blocking the P13K/AKT pathway
102
Why is p16 an important tumor suppressor gene?
- Germline mutations of p16 ( CDKN2A ) present in 25% of melanoma-prone kindreds
- Somatically acquired deletion/inactivation of p16 in 75% of pancreatic carcinomas, 40% to 70% of glioblastomas, 50% of esophageal cancers, 20% to 70% of acute lymphoblastic leukemias, and 20% of non–small-cell lung carcinomas, soft tissue sarcomas, and bladder cancers
- Loss-of-function mutations in tumor suppressor genes, CDKIs that inhibit cyclin D/CDK complexes and G1/S progression, are frequent.
104
What is the A-Beta protein in amyloidosis?
- _Beta-amyloid protein_ constitutes core of cerebral plaques found in _Alzheimer_ disease and amyloid deposits in walls of cerebral blood vessels in pts w/this disease
- AB protein is 4,000 D peptide derived by proteolysis from much larger transmembrane glycoprotein, called _amyloid precursor protein _
106
What are the 5 qualities for description of a gross pathologic lesion?
1. Size
2. Shape
3. Color
4. Consistency
5. Relationships
107
What are the clinical manifestations of amyloidosis?
- Range from no clinical symptoms to serious clinical problems, and even death
- Symptoms depend on magnitude of deposits and sites or organs affected
- _Early manifestations_: often entirely nonspecific, such as weakness, weight loss, light-headedness, or syncope
- _Later_: somewhat more specific symptoms, often related to renal, cardiac, and GI involvement
108
What are familial amyloidotic polyneuropathies?
- Group of _autosomal dominant_ familial disorders characterized by deposition of amyloid predominantly in peripheral and autonomic nerves
- Different parts of the world
- Fibrils made up of mutant _TTRs_ -\> genetically determined structural alterations render them prone to misfolding and aggregation, resistant to proteolysis
109
What does the localization of amyloid deposits in Mediterranean fever amyloidosis look like?
- May be widespread, involving the kidneys, blood vessels, spleen, respiratory tract, and (rarely) liver
- The localization of amyloid in the remaining hereditary syndromes can be inferred from the designation of these
entities
110
What is a leiomyoma? Where might you see one?
- A benign smooth muscle neoplasm (leiomyosarcoma would be the malignant version)
- You might see one in the uterus or heart
111
What is an autocrine loop in cancer devo? Provide 2 examples.
- The acquired ability of some cancers to synthesize the growth factors to which they are responsive:
1. Many brain tumors (glioblastomas) express both platelet-derived growth factor (PDGF) & PDGF receptor tyrosine kinases
2. Many sarcomas overexpress transforming growth factor α (TGF-α) and its cognate receptor, epidermal growth factor receptor (EGFR), another member of the receptor tyrosine kinase family
112
Does this look benign or malignant? How can you tell? Describe some of the features.
- Thyroid adenoma
- Benign: grow autonomously, but tend to grow slowly
1. Gradually compress surrounding tissue, causing pressure atrophy, and slowly progressive necrosis with fibrous tissue replacement creating a capsule
- _A fibrous capsule is more characteristic of a benign tumor than a malignant one_
113
How is amyloidosis manifested in the tongue and respiratory tract?
- Nodular deposits in the tongue may cause macroglossia, giving rise to the designation, tumor-forming amyloid of the tongue
- The respiratory tract may also be involved focally or diffusely from larynx down to the smallest bronchioles
114
Does this look benign or malignant? Why? Describe. I know... There are way too many of these, but at least you won't miss it on the test.
- Thyroid adenoma
- Benign: grow autonomously, but tend to grow slowly
1. Gradually compress surrounding tissue, causing pressure atrophy, and slowly progressive necrosis with fibrous tissue replacement creating a capsule
- _A fibrous capsule is more characteristic of a benign tumor than a malignant one_
115
What is imatinib?
- Tyrosine kinase inhibitor that transformed chronic myelogenous leukemia (CML) from a disease usually fatal in 5 years to a chronic condition w/indefinitely prolonged survival for most patients (80-90% of pts)
- MOA: binds close to the ATP binding site of BCR-ABL, locking it in a closed or self-inhibited conformation, inhibiting the enzyme activity of the protein semi-competitively. Explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation
117
Why is MYC considered a master transcriptional regulator of cell growth? Describe its many activities.
- **MYC** activates expression of genes involved in cell growth and _cell cycle progression_, e.g., D cyclins
- Upregulates _rRNA gene expression_ and processing, enhancing ribosome assembly for protein syn
- Upregulates _Warburg effect_ (via glycolytic enzymes and factors involved in glutamine metabolism, both of which supply metabolic intermediates needed for syn of macromolecules like DNA, proteins, and lipids)
- In some contexts, MYC upregulates _telomerase_, one of several factors enabling endless replicative capacity (the immortalization) of cancer cells
- One of a handful of transcription factors that can act together to reprogram somatic cells into pluripotent stem cells, so may also contribute to cancer cell “_stemness_,” an important aspect of cancer immortality
118
Where are depositions of amyloid most common in pts on long-term hemodialysis?
- Most prominent in carpal ligament of the wrist, causing compression of median nerve (carpal tunnel syndrome)
- These patients may have extensive amyloid deposits
in the joints too
119
What is hemodialysis-associated amyloidosis?
- Deposition of beta-2 microglobulin in pts on long-term hemodialysis for renal failure
- Beta-2 microglobulin can present in high concentrations in serum of people with renal disease and, in past, was retained in circulation b/c not filtered through dialysis membranes (pts sometimes presented with carpal tunnel)
- Substantially decreased incidence b/c new dialysis filters
121
What is the prognosis for people with reactive systemic amyloidosis?
- Somewhat better (than generalized) and depends to some extent on control of the underlying condition
- Resorption of amyloid after tx of the associated condition has been reported, but this is a rare occurrence
- New therapeutic strategies aimed at correcting protein
misfolding and inhibiting fibrillogenesis are in devo
122
Name the organ and describe the microscopic pathology.
- AA amyloidosis of the splenic vessels in Rhuematoid Arthritis
123
The receptor tyrosine kinase pathway appears to be the most frequently mutated oncogenic pathway in human neoplasms. Name some tyrosine kinase pathways.
GPCR pathway, JAK/STAT, WNT, Notch, Hedgehog, TGF-B/SMAD, and NF-kB
