histology Flashcards
Small Cell Lung Cancer (SCLC)
15% of all Lung Cancers. Most aggressive Lung Cancer type. Poor 5-year survival rate of 6% vs.16% for Lung Cancer overall.Responsive to initial chemotherapy. Targeted therapies not currently recommended
Non-Small Cell Lung Cancer (NSCLC)
85% of all Lung Cancers. Various molecular aberrations identified. Standard treatment is platinum-based chemotherapy. Approved targeted treatment options available. Heterogeneous, with 3 major histologic subtypes: adenocarcinoma, squamous, and large cell carcinoma.
molecular targets for therapy in lung cancer
Epidermal Growth Factor Receptor (mutations): Drugs: Erlotinib, Gefitinib, Afatinib. Anaplastic Lymphoma Kinase (ALK) (gene rearrangements): Drugs: Crizotinib, Ceritinib
EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS
- Tyrosine Kinase Inhibitors (EGFRTKIs). These attack the internal domain and inhibit. 2. Monoclonal Antibodies. These attach the extracellular domain of EGFR. Patients with EGFR Mutations have superior effect on EGFRTKIs compared to chemotherapy.
Anaplastic lymphoma kinase (ALK)
Is a receptor tyrosine kinase. The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer(NSCLC). The vast majority of cases are adenocarcinomas. The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana has got the approval of Chinese FDA and European FDA to test mutation by IHC. Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended. ALK lung cancers are found in patients of all ages, although on average these patients may be somewhat younger. ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors. BIOMARKERS: Fluorescent in situ Hybridzation ALK-Protein Expression, Fusion gene demonstrated by PCR. ALK fusion gene results in formation of cytoplasmic chimeric proteins with constitutive kinase activity. Rarer fusion partners for ALK such as KIF5B and TFG have also been reported in NSCLC. The ALK fusion gene appears to be a distinct NSCLC molecular subset susceptible to targeted inhibition
Regulation of T-cell Function by Cell Surface Markers
the immune response is regulated by an array of molecules. This is achieved in part by the regulation of T cell activation, which requires two signals: activation through the t-cell receptor (TCR) by recognition of antigen presented by MHC on antigen-presenting cells (APCs). Then, the ligation of costimulatory and coinhibitory molecules expressed on T cells and APCs.
Programmed death-ligand 1 (PD-L1)
Is highly expressed in lung cancer. transmembrane protein that has been speculated to play a major role in suppressing the immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens where there is some accumulation in the lymph nodes or spleen which triggers a proliferation of antigen-specific CD8+ T cell. The formation of PD-1 receptor / PD-L1 complex transmits an inhibitory signal which reduces the proliferation of these CD8+ T cells at the lymph nodes and supplementary to that PD-1 is also able to control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis which is further mediated by a lower regulation of the gene Bcl-2. Engagement of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. PD-L1 Is Broadly Expressed in Human Cancer. Cell membrane localization is induced by IFN alpha, beta, and gamma; LPS; GMCF, VEGF, IL-4, 10. The hope is to treat with PD1 or PDL1 antibodies.
Nivolumab
Nivolumab acts as an immunomodulator by blocking ligand activation of the programmed cell death 1 (PD-1) receptor on activated T cells.
tunica intima
comprises the inner layer of the ves- sel and contains a layer of endothelial cells in intimate contact with the blood, in addition (in larger arteries) to a layer of elastic and loose collagenous tissues containing intimal cells.
tunica media
a layer in the middle of the vessel, which may be comprised of multiple layers of elastic laminae, smooth muscle cells, or collagen.
tunica adventitia
The outer supporting layer is the tunica adventitia and is comprised of collagenous tissue. In larger vessels, the adventitia contains blood vessels (the vasa vasorum, (vessels of vessels)) that actually supply oxygen and nutrients to the adventitia and outer part of the media, as they cannot diffuse to these regions from the blood inside the vessel.
Arteries
Arteries are quite thick-walled as compared to veins, and have approximately the same wall thickness as the lumen of the vessel itself. The largest arteries have a thick media with multiple elastic layers, but the elastic layers gradually decrease proceeding from the heart to the arterioles. Smooth muscle is found in the media from the aorta to the arterioles. The elastic layers are crucial to permit expansion of the vessels after systolic contraction of the heart, dampening the systolic blood pressure. Smooth muscle, particularly in the arterioles, permits control of blood flow to capillary beds.
Elastic arteries
The aorta and larger arteries branching from it are referred to as elastic arteries. The intima has a thin layer of endothelial cells and an under- lying layer of collagen/elastin-rich fibers and contains fibroblasts and myointimal cells which have similar structural features to smooth muscle cells. The media contains multiple elastic lay- ers (about 30-40 in the aorta, with some collagenous fibers and smooth muscle cells sandwiched in between. Their adventitia contains vasa vasorum.
myointimal cells
the smooth muscle cells of the intima of a blood vessel
vasa vasorum
a network of small blood vessels that supply the walls of large blood vessels.
Muscular arteries
medium-sized vessels known as distributing arteries. The multiple elastic layers in elastic arteries become restricted to two well-defined elastic layers in muscular arteries, the inner elastic lamina between the intima and the media and an outer elastic lamina that defines the boundary between the media and adventitia. The intima is thin and contains endothelial cells and a relatively thin layer of connective tissue. The media is primarily comprised of smooth muscle cells. The adventitia is com- paratively thick and contains collagen and elastin.
Smaller muscular arteries
These lose the outer elastic lamina, but retain the inner. The intima is comprised of the endothelial cell layer and a thin layer of collagenous material. They have a relatively large layer of smooth muscle in the media which can control vessel diameter. The adventia is about the same width as the media, and usually merges with surrounding con- nective tissue.
Arterioles
Arterioles contain an inner lining of endothelial cells on a thin basement mem- brane. This is immediately surrounded by 1-2 layers of smooth muscle cells, and outer colla- genous tissue which typically blends in with surrounding connective tissue. Arterioles are the gatekeepers to local capillary beds and can greatly restrict, if need be, the flow of blood through them. Metarterioles and arteriole-venule shunts can connect larger arterioles and venules and their vasoconstriction/ vasodilation can direct blood flow through, or permit bypass of capillary beds.
Capillaries
Capillaries are the smallest vessels (about 5-15 μm inner diameter) and have 1-2 endothelial cells surrounding the lumen. There is no muscular layer, but the endothelial cells are often surrounded by cells called pericytes, which are relatively unspecialized cells that can give rise to smooth muscle cells during vessel growth and wound healing, and may be contractile in nature. These are surrounded by collagenous fibrils which connect the capillary to adjacent connective tissue. Most of the molecular traffic between the vascular system and tissues occurs through the capillary endothelium, much of the exchange by diffusion. Two main types of capillaries are recognized, continuous and fenestrated.
pericytes
contractile cells that wrap around the endothelial cells of capillaries and venules throughout the body.
continuous capillaries
In continuous capillaries the endothelial cells form an uninterrupted lining, although transfer across the lining can occur via pinocytotic vesi- cles.
fenestrated capillaries
In fenestrated capillaries there are pores or fenestrations in the endothelial cells. In some fenestrated endothelia the pores are covered by a thin diaphragm. A good example of fenestrated endothelium is found in the glomerulus of the kidney. Fenestrations permit bulk flow of plasma past the endothelial boundary. In some places, such as in sinusoidal capillaries, the en- dothelial cells are separated by wide pores (discontinuous) that are large enough to permit red blood cells to pass, as in the spleen. Fenestrations (discontinuities) in the liver sinusoids permit blood plasma to directly contact the liver cells.
Post-capillary venules
Capillaries empty into these vessels which initially are similar structurally, but have a larger diameter. They also have surrounding pericytes. Blood flow is slow and leukocytes tend to primarily diapedese through vessel walls at these sites. The endothelium is responsive to vasoregulatory substances such as serotonin and histamine, making these regions more sensitive to controlled permeability. Larger venules begin to get 1-2 layers of smooth muscle in their media (muscular venules), with thin layers of connective adventitia often merging with surrounding connective tissues.
Veins
Veins differ from arteries in being relatively thin-walled, and are often seen as collapsed structures in ordinary histological specimens. Although blood pressure is low in veins, the wall thickness increases with their diameter. Small veins have an intimal layer of endothelial cells and no inner elastic lamina. The media is primarily smooth muscle of 2-4 layers. Adventitia is collagenous and again often seen to blend in with surrounding connective tissue. Medium-sized veins have a similar endothelial lining and muscle layer, with an increasing thickening of the tunica adventitia which is the thickest layer. Large veins contain a thin intima of endothelial cells and a media of interlayered smooth muscle and collagen fibers (about 5-7 layers), with very small amounts of elastin fibers. The tunica adventitia is thick and in larger veins contain vasa vasorum. Circulation in veins is by hydrostatic pressure and is aided by contraction of smooth muscle and and the compression of surrounding skeletal muscles. This is particulary important in veins of the legs in helping to overcome gravity. Veins often contain one-way flap valves to prevent backflow. Loss of function of flap valves can lead to expansion of veins, which is particulary evident in veins of the leg (varicose veins).
Pulmonary vasculature
The pulmonary arteries function under lower pressure (about 15-25 mm Hg) and hence their structure is different from systemic arteries in being less thick walled.
Lymphatics
Lymphatics flow only one way, from tissues to empty into the blood on the right and left side near the junction of the internal jugular and subclavian veins. They actually begin as nothing more than small spaces in connective tissues which connect to larger spaces lined by a very thin layer of squamous endothelium. At the size of small veins, they are immediately discernable, having only a single, very thin endothelial layer and little discernable outer layers, other than their direct connectivity to interstitial connective tissue. Lymphocytes are often visible, but red cells are absent. The lymph itself often stains a light color, which is not observed with the plasma of blood vessels. Larger lymphatics show a loosely-defined connective tissue structure outside the endothelium. Flap-like valves are abundant, and lymphatics have on-line filters (lymph nodes) where leukocytes are detained and undergo interactions.
arteriovenous shunts
the diversion of blood from an artery directly to a vein.
Anastomoses
Anastomoses are defined as connections between arteries and veins that permit collateral circulation to occur within tissues. Should a vessel become occluded or if pressure prevents flow of blood to an area, then that area can be alternatively supplied by flow from an anastomosing artery.
End arteries
End arteries supply a section of a tissue that cannot have an alternate arterial supply hence occlusion of a vessel prevents blood flow in that area. This is found, for example, in the arterial supply to sections of the kidney and segments of the lung.
Portal systems
Portal systems begin in a capillary bed and end in a capillary bed. These are found, for example, in the hypothalamic-anterior pituitary portal system and the hepatic portal system.
Pampiniform plexus
A countercurrent arrangement between an artery and venous net- work. This arrangement is found in the spermatic cord for optimal heat exchange.
How do you determine patient’s prognosis with lung cancer?
Look at genes that do DNA repair (ERCC and RMM). These increase prognosis but decrease chance of response to platinum based chemotherapy. Also look at stage of the cancer, Small cell vs. large cell, and type of tumor and tissue.
To determine criteria predicting patient’s sensitivity to the therapies.
Look at the patient’s cell type, molecular markers, histology. Clinical information is used as well.
To explain what “targeted therapy” means for cancer therapy.
To design and develop targeted therapies, specifically designed to “attack” the molecular targets that are tumor specific. Find agents that work against specific biologic pathways. Ex: Non-small cell lung cancer: can choose bevacizumab or pemetrexed, blocks VEGF pathway or the formation of purine and pyridimine precursors.
demonstrate that exact histological classification matters.
Certain tissue types will make the patient susceptible to toxicity or will confer specificity and effectiveness to a given treatment.
What does biomarkers mean and how can they be used for therapy decision.
Two types of biomarkers: Prognostic: reflect natural history of disease independent of therapy- based on the tumor and the patient themselves. Predictive: reflects the impact of a therapeutic intervention (predicts response to treatment).
lung caner
is diagonesed at a very late stage, kills more ppl than colorectal, breast, pancreas, and prostate combined. 220,000 new cases per year in US, 160,000 deaths per year. Is very heterogeneous disease (probably the most in cancers). It is not only based on morophology but also based on molecular profiling. Only a few of these mutations are drivers, most are just passengers. Screening with low dose CY led to 20% reduction in lung cncer mortalty 6.7% better survival in all cause mortality reduction. It is now recommended by US prevention task force and is now covered by medicare/medicaid. a problem is that there is a 95% false positive rate. we need better imaging and biomarkers in order to reduce the false positive rate
immunotherapy
the “treatment of disease by inducing, enhancing, or suppressing an immune response”. Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors. I
skeletal muscle
are long cylindrical cells also called muscle fibers or myofibers. They are 50-100 μm in diameter and several cm long. They contain hundreds of nuclei, all on the periphery of the cell (a centrally located nucleus in skeletal muscle is indicative of a fiber that has been damaged and repaired). One of the most striking aspects of skeletal and cardiac muscle is the precise and repeating alignment of the myofilaments that creates the striated appearance. Skeletal muscle cells come in several types: slow twitch and two types of fast twitch. Stains can be used to show the random distribution of fiber types in a muscle. This distribution has been referred to as a “checkerboard” pattern, and this pattern can change if a muscle is partially denervated and later reinnervated. nucleus is on periphery. no gap junctions
Cardiac muscle
cells have a single nucleus and are much smaller in diameter and shorter than skeletal muscle fibers. One of the distinguishing features of cardiac muscle is the intercalated disc, which serves two functions. First, it physically ties together adjacent cells so that they don’t pull apart when contracting. Second, it contains gap junctions (within interculated discs, sep the myocytes) for the transmission of electrical current from one cell to the next (for propagation of the action potential) in order for the heart to contract synchronously.