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1. Describe neoplasia and cancer
Neoplasia – “new growth”. Unregulated growth of cells whose proliferations cannot be
adequately controlled by normal regulatory mechanisms. The proliferation of normal cells can be
autonomous (independent of growth factors and stimuli that promote growth of normal cells,
excessive (unceasing in response to normal regulators of cellular proliferation), and disorganized
(do not follow rules governing formation of normal tissues).
Cancer – Tumors invade tissues like crawling crabs.
Tumors – proliferation of neoplastic cells that lead to masses. Synonymous with neoplasm.
○ Classify tumors on the basis of their clinical behavior and histopathology
Benign tumors – Limited growth potential and good outcome. Sharply
demarcated from normal tissue and are often encapsulated. Capsule made of connective tissue.
Expansive growth and compress the adjacent normal tissue, which undergoes atrophy and
fibrosis, forming a pseudocapsule. Composed of cells that resemble the tissue from which they
have arisen. Show high degree of differentiation. Made of a uniform cell population with
approximately the same features. Have a normal number of chromosomes. Slow, expansive
growth. No metastases. Smooth external surface. Encapsulated. No necrosis, no hemorrhage.
Few mitoses, well differentiated cells, normal shape and size nuclei.
Malignant tumors – Grow uncontrollably and eventually kill the host. Tumors
lack a capsule and are not clearly separated from normal tissue. Invade surrounding tissue.
Tumors are undifferentiated. Exhibit new features that are not related to the tissue of origin.
Have a heterogeneous cell population. Chromosomes are abnormal. Fast and invasive. Exhibit
metastases. Irregular external surface. No capsule. Necrosis and hemorrhage. Irregular mitoses.
○ Describe typical features of benign and malignant cells
Benign cells – Nuclei resemble those of their normal progenitor cells. Nuclei are
uniform (of the same size and shape). Cells have a well-developed cytoplasm and well-
developed cytoplasmic organelles. The nucleus accounts for a small part of the total cell
volume. Nuclei have a regular, even distribution of chromatin. Nucleoli are not overly
prominent. Benign cells maintain normal function of the normal cells in the tissue of origin.
Malignant cells – Cells show anaplasia (exhibit new features not like those of
their origin). Malignant cells show nuclear pleomorphism (variation in size and shape of nuclei).
Heterogeneous cell population. Cell nuclei are pleomorphic. Malignant cells have very little
cytoplasm and contain a reduced number of cytoplasmic organelles. Undifferentiated cells.
Nucleus is larger, and they have a high nuclear/cytoplasmic ratio. Larger, irregularly shaped
nuclei surrounded by narrow cytoplasm. Nuclei are hyperchromatic (more dark staining
chromatin) and the chromatin is distributed unevenly. Malignant cells have no specialized
functions. Their metabolism is geared toward supporting rapid growth and replication. Have a
modified basic metabolism and function that gives them a growth advantage over normal cells.
Malignant cells are often aneuploid (they do not have a normal diploid, 46, XX or 46, XY,
number of chromosomes. Chromosomes are abnormal due to deletions or translocations due to
7) new tumor formation at site of metastasis. Not all cells can metastasize. Some
are capable, and their descendants form distinct subpopulation (clone) that will expand until it
can disseminate. These cells are transported from the primary site to other locations, where the
cells attach and begin forming secondary, or new, tumors. To survive, these cells need their own
blood supply (angiogenesis).
○ Describe the avenues for metastatic spread
1.Through the lymphatics. 2.Via blood (hematogenous spread), and 3.by seeding
surfaces of body cavities.
○ Describe angiogenesis
Angiogenesis is the formation of new blood vessels. Tumors can initiate angiogenesis to facilitate nutrient and oxygen delivery.
● Explain the TNM system
TNM is the major staging system. The staging of solid cancers is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases. T for
primary tumor (t 0-4) , N for regional lymph node involvement (n 0-3), and M for metastases (0-2). Numbers increase based on involvement. Important for defining the prognosis, chances of cure, tx
● Describe the evidence for viral carcinogenesis with
○ Human papillomavirus
Linked to human lesions, such as common warts, genital warts, laryngeal papillomas, dysplasia of cervical epithelium, and cervical carcinoma. HPV type 16 has been found in 60% of cases of cervical carcinoma.
○ Epstein-Barr virus and
A herpesvirus that has a predilection for B lymphocytes. EBV is related to Burkitt’s lymphoma (a B cell neoplasia that occurs most often in Africa and typically affects children). Nasopharyngeal cancer is related to EBV is prevalent in China. EBV causes chromosomal breaks that result in activation of endogenous cancer genes (oncogenes).
○ Hepatitis B virus
Viral hepatitis B is linked to liver cancer. Not clearly understood how. HBV is integrated into the DNA of neoplastic cells.
● Describe oncogenes and tumor suppressor genes and explain their clinical
significance
○ Oncogenes are Genes that have undergone mutation that direct the synthesis of protein to accelerate the rate of tissue proliferation ○ Tumor suppressor (aka anti-oncogenes) are normal cells which have regulatory mechanisms to
protect against oncogenes
■ Retinoblastoma gene (Rb-1) ● Retinoblastoma tumor has a portion of the chromosome deleted which carries Rb-
→ thus tumor may form in retina (bilateral) or in another place later in life
○ This shows that rb-1 is not limited to just protecting the eye ○ In sporadic retinoblastoma, child is born with Rb-1, but exogenous factors affect Rb-1 and eye tumors develop (usually one-sided) ■ Tumor protein p53 (TP53) acts as both tumor suppressor and oncogene. It can transform normal
cells into neoplastic cells by transfection
● A loss/or mutation of TP53 may lead to tumor formation (most commonly colon or breast)
● Describe anemia and list the major forms
Anemia: reduction of the total circulating red cell mass below normal limits
○ Iron deficiency anemia: most common form of anemia ■ Associated with deletion of Fe stores by chronic blood loss ■ Without Fe, hemoglobin synthesis is impeded and new RBCs are small and contain less Hb than normal ■ Classifications ● Increased Fe loss (chronic bleeding) ● Inadequate Fe intake or absorption (diet or GI disease) ● Increased Fe requirement (childhood growth, metorrhagia and pregnancy) ■ Causes: hypochromic microcytic anemia ● Total body Fe stores are reduced (RBCs have less hemoglobin than usual) ● Bone marrow shows normal hematopoiesis but contains a reduced number of hemosiderin-laden macrophages ■ Clinical ● Women>Men ● Responds well to Fe intake ● If symptoms are related to other etiology, that disease should be treated appropriately ○ Megalobastic anemia: deficiency of vitamin B12 and/or folic acid
■ This delays normal maturation of blood cells and negatively affects hematopoiesis ■ Megaloblasts are formed because RBC precursors do not mature ● Nucleus remains large in these cells and they are usually destroyed before they reach maturity ■ Reduced erythropoiesis and defective RBC maturation lead to anemia ■ Patho ● Pernicious Anemia: most severe form of vit B12 deficiency ○ Results from a lack of gastric intrinsic factor ○ These patients have atrophic gastritis ○ They do not produce enough gastric parietal cells and therefore do not have sufficient amounts of IF ■ Clinical ● Fatigue, pallor, SOB, weakness ● Destruction of spinal posterior and lateral columns (pernicious anemia)= loss of senses of vibration and proprioception and DTRs ● Folic acid can be taken orally ● B12 must be administered IV
■ Thalassemia alpha: reduced synthesis of the alpha chain of hemoglobin ■ Thalassemia beta: reduced synthesis of the beta chain ■ Heterozygotes have thalassemia trait but only experience mild anemia ■ Homozygotes develop thalassemia major which is severe and usually lethal ■ If all 4 genes for alpha chain are deleted you have intrauterine death ■ Beta is more common and minor is more common than major ■ Clinical ● Minor: mild non-specific symptoms ○ Must distinguish from other forms of anemia ○ Thalassemia will not respond to iron supplementation like other types of anemia ○ This form requires no treatment ● Major : severe often fatal disease ○ Erythrocytes are not produced in sufficient numbers and many are hemolyzed ○ You will also have hemosiderosis and hepatosplenomegaly ○ Hyperbilirubinemia, jaundice and gallstone formation ○ Bone marrow hyperplasia recognizable by “crew-cut” hair on newly formed bone spicules ○ These children are: short of breath, tired constantly, have impaired brain development and cardiorespiratory insufficiency that leads to heart failure ○ Aplastic anemia: anemia is accompanied by leukopenia and thrombocytopenia (=pancytopenia). The body stops producing enough new blood cells (bone marrow failure) ■ Idiopathic: without an identifiable cause, most common ● Less favorable outcome ■ Secondary: related to bone marrow suppression that is caused by cytotoxic drugs, radiation therapy or viral infection ● May be reversible ■ Clinical ● Uncontrollable infection secondary to leukopenia ● Bleeding tendencies ● Chronic fatigue, pallor and weakness ● Bone marrow transplant is the only cure if hematopoiesis does not recover spontaneously ○ Hemolytic anemia: ■ All forms share common features ● Anemia and a shortened red cell life span below the normal 120 days ● Elevated erythropoietin levels and a compensatory increase in erythropoiesis ● Hyperbilirubinemia and jaundice ○ Excess serum bilirubin is unconjugated ■ Sickle Cell Anemia ● Caused by genetic defect in the -chain of hemoglobin that results in the formation of an abnormal hemoglobin S (HbS) ● HbS undergoes polymerization when oxygen levels are decreased and the RBC becomes deformed/sickled ● The sickled aggregates occlude small BVs and cause ischemia ● The abnormal RBCs are also hemolyzed at a faster rate and the bone marrow undergoes compensatory erythroid hyperplasia ● Pathology ○ Repeated sickling attacks cause infarcts in various organs ○ Brain: neurologic defects ○ Bones, spleen and extremities: sharp pain ○ Retina: visual disturbances ○ Spleen: becomes fibrotic and shrinks (autosplenectomy) = dysfunctional spleen
● Clinical Features ○ Retarded intellectual development and neurologic deficits
Tx: bloodletting fr. veins; cytotoxic drugs
● Describe leukemia, lymphoma and multiple myeloma
○ Explain common pathologic findings in leukemia and lymphoma and relate them to clinical syndromes
Leukemia
Means “white blood”, blood becomes milky white after so many white blood cells (rarely happens, but a helpful visual). All leukemias have common features:
- Bone marrow infiltrated with malignant cells
- Peripheral blood has increased number of immature blood cells. (may be first indication of Leukemia)
- Clonal diseases with neoplastic stem cells that show genetic changes specific to each disease - this is good to know when choosing diagnosis and what kinds of treatment to choose.
- Common complications: anemia, recurrent infections, uncontrollable bleeding. (this is d/t fact that malginant cells replace precursors for erythrocytes, WBC, and platelets → this kind of disturbance in hematopoiesis has pts looking anoxic, bruising easily, unable to fight infections, and develop bleeding tendency. (overwhelming infection is most common cause of death in leukemia).
- Can affect any age, most common are childhood ● Acute Lymphoblastic Leukemia (ALL) : kids <5 yrs, then elderly population. Most common form of Leukemia in children. Massive infiltration of blast cells (lymphoid). These kids will have recurrent infections, generalized weakness, and bleeding into skin and major organs. Lymph nodes and spleen enlarged. ● Acute Myelogenous Leukemia (AML) : the most common leukemia overall (40%), all age groups but mostly older people. Clonal prolif and malignant myeloblasts (little leukocyte precursor cells) in the bone marrow, blood, and other tissues. There are multiple kinds of AML, but the “non-specified” kind is most common. Disease has an acute course, pts will die within 6 months of onset if not treated. High dose radiation and chemo-therapy help. ● Chronic Myelogenous Leukemia (CML): 15% of all Leukemias, rarely in adolescence, usually an adult’s disease. Slow onset with nonspecific symptoms like mild anemia and s/s hypermetabolism, tired, lack endurance, prone to infections, splenomegaly, thrombosis (secondary to accelerated clotting). Chronic phase is 2-3 yrs with bone marrow containing <10% blasts, 20% basophils in peripheral blood, and increasing unresponsiveness to therapy. Phase ends in a blast crisis that looks like acute leukemia and char by blasts in bone marrow increasing to >20%. Regular chemo doesn’t really work. Bone marrow transplant and radiation
- tyrosine kinase inhibitors works pretty well. ● Chronic Lymphocytic Leukemia (CLL) : 25% of all leukemias. Rarely ever happens in pts younger than 40 years but incidence rises after. (most are around 50 yrs). CLL cells are indistinguishable from mature lymphocytes. Slowly progressive, usually asymptomatic other than peripheral lymphocytosis or lymph node enlargement. Unresponsive to chemotherapy.
Lymphoma
Lymphomas are a spectrum of malignant disease involving lymphocytes and their precursors. ALL LYMPHOMAS ARE MALIGNANT. They can occur in any age group. Often infiltrate lymph nodes, spleen, thymus, or bone marrow. Divided into NHL and Hodgkin’s. See below
Multiple Myeloma
Malignant disease of plasma cells. Clonal expansion from a single plasma cell. Plasma cells secrete immunoglobulins that can be identified biochemically in the serum. After an infection causes polyclonal activation of plasma cells, there will be a hump in the serum electrophoresis pattern. Chemo is ineffective, prognosis is grim. Most pts die in 3-4 yrs d/t kidney failure or infection.
trauma. Other clinical manifestations include bruising, hematomas, & hemarthrosis. These individuals have a prolonged aPTT. These patients need frequent blood transfusions.
● Explain the Coagulation Cascade (Robbins and Cotran, pages 118-120 ) ● Clotting cascade is the third step in normal hemostasis (1.vasoconstriction, 2. platelet plug) ● A stepwise series of reactions via three pathways during thrombus formation where each step uses a proenzyme or procoagulation factor to activate the next step. ● Coagulation factors are made in the liver and platelets and circulate INACTIVATED in blood plasma ● Liver dependent on fat-soluble vitamin K to produce them. ● Must be activated in order to participate in the clotting process. ● Circulating Ca++ very important as a cofactor to help with membrane binding and activation (from diet and bone) ● Factors are numbered 1-12 (I-XII) ● In diagrams the a means activation
● Activation and primary platelet plug (within seconds)
● During tissue injury, circulating platelets come into contact with exposed subendothelial layer that contains von Willebrand factor and collagen. vWf acts as a bridge between the collagen and the platelets setting off adhesion, activation and aggregation. This changes the shape of the platelets making them spikey to attach to circulating fibrinogen and causes them to release granules containing clotting proteins leading to the primary platelet plug.
● Blood Coagulation (approx 30 secs post injury)
● Proenzymes and enzymes interact to set off the Intrinsic, Extrinsic pathway that then merge into the Common pathway leading to the fibrin clot ○ Intrinsic Pathway: begins in the bloodstream after INternal damage to vessel wall. (factors 12, 11, 9, 8, 10, 5, 2,1) ■ activates circulating factor XII (12) Hageman factor withIN the circulation. Arteriole Plaque. ○ Extrinsic Pathway: triggered by trauma when platelets come into contact with the EXterior of the circulation (perivascular tissue) Broken vessel wall. (7, 10, 5, 2, 1) ○ Common Pathway: The intersection of the intrinsic and extrinsic with factor X (10). ■ Leads to activation of Prothrombin into Thrombin which converts fibrinogen into the insoluble fibrin hemostatic clot. ● All three are in play during coagulation. ● For example: after a cut on your arm or a mechanical injury leading to a bruise then the platelets are activated and trigger the cascade. A= the activated cofactor ○ The Extrinsic pathway releases Tissue Factor III (3) that combines with factor VII (7) to activate VIIa (7a) ○ VIIa (7a) uses Ca++ to bind with factor X (10) to activate Xa (10a). ○ The Intrinsic pathway is initiated with factor XII (12) Hageman factor then XI (11) then IX (9) then helpmate VIII (8) then merge with the Common pathway at X (10). ○ Common Pathway begins at X (10) combines with Ca++ to become 10a which leads to the activation of Prothrombin into Thrombin which converts fibrinogen into the insoluble fibrin hemostatic clot ● Thrombin (a protease) is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa) ● Thrombin ○ directly converts soluble fibrinogen to insoluble fibrin ○ Induces platelet activation and aggregation ○ Links clotting to inflammation and repair ○ In presence of normal endothelial cells it acts as an anticoagulant
Clot dissolution or Lysis: two systems
● Natural anticoagulants reduce production of or limit activity of Thrombin ○ Heparin, antithrombin, plasminogen and vitamin K-dependent proteins ○ Cirrhosis, nephrotic syndrome, sepsis, burns, DIC impair this system
■ Plasminogen trapped inside as clot is formed. The injured tissue and endothelium release plasminogen activator (t-PA) converting plasminogen to plasmin which digests the fibrin strands and dissolves the clot. ○ Anticoagulant: Antithrombin. Limits activity of thrombin ■ Antithrombin (a protease inhibitor) inactivates Thrombin and its effects on fibrinogen - is not vitamin K dependent ● Within minutes myocin in platelets begin to contract causing clot to retract ●
Images above are two different representations of the same thing.
● Lysis begins soon after formation
Clinical Importance
● PT (prothrombin time) measures function of the clotting factors of the EXTRINSIC and common pathway. ○ Factors 7, 10, 5, 2, 1 (fibrinogen) ○ Causes of prolonged PT: ■ deficiency or inhibition of any of the factors in this pathway ■ DIC ■ Warfarin/Coumadin ○ in lab tissue factor, phospholip, and calcium added to initiate reaction
○ Is monitored when patients are on Warfarin/Coumadin. ■ Shorter, faster pathway – gun shaped in image above on right- Warfarin ● aPTT measures function of the clotting factors of the INTRINSIC pathway ○ 12,11, 9, 8, 10, 5, 2, 1 ○ In lab ground glass, phospholipid, and Ca++ then measure time to fibrin clot ○ Causes of prolonged aPTT: ■ vWF, deficiency or inhibition of any of the factors in this pathway, heparin use. DIC
