Diseases of Immunity 2 SYSTEMIC AUTOIMMUNE DISEASES:

Tues. 09/07/10

Mechanisms of Autoimmune Diseases: Genetics (DR3/4, B27) & Environment play a role A. Failure of peripheral tolerance. B. Molecular mimicry -- cross reacting antibody (Rheumatic fever) C. Release of sequestered antigens (sperm and ocular antigens) D. Epitope spreading: Epitope = specific site on Ag recognized by Ab, BCR or TCR. Immune response against initial self Ag induces cell damage or alteration of macromolecules that reveals additional epitopic sites that can be recognized thus epitope spreading: 1. Release of hidden intracellular proteins 2. Enzymatic modification in response to infection/inflammatory response (e.g. addition or removal of lipids, sugar groups) that alters normal structure). 3. Hidden epitopes protected by binding to other macromolecule(s) (e.g. multi-protein complexes, lipids, etc) are revealed. 4. Proteins that exhibit exposure of buried Ags due to proteolysis or denaturation that alter secondary or tertiary structure. Immune Mediated Inflammatory Diseases 1. Antibody or Immune Complex Mediated Organ-specific (Covered in organ-specific chapters) Autoimmune hemolytic anemias Autoimmune thrombocytopenia Myasthenia gravis Graves disease Goodpasture syndrome Systemic autoimmune diseases Systemic lupus erythematosus (SLE) 2. Primarily T-cell mediated diseases Organ-specific Type I diabetes Multiple sclerosis Systemic autoimmune diseases Rheumatoid arthritis Systemic sclerosis (Scleroderma) Sjogren syndrome 3. Chronic inflammatory disease / overly robust T-cell immune responses see neutrophils involved. Inflammatory bowel diseases Crohns disease Ulcerative colitis Psoriasis IBD/Psoriasis: Anti-TNFa therapy (i.e. remicade) useful. Also useful for Rheumatoid Arthritis
Test q: A 23y/o female develops ulcers and fistulas associated with her underlying Crohns disease. She is treated with Rimicade (Imixaflab) infusions w/resolution of her symptoms. This drug inhibits apoptosis and acute and chronic inflammation. The target of action of this drug is: TNF-.

Ab vs T-cell mediated AI disease not absolute As expected, B-cell depletion therapy (anti-CD20; i.e. rituximab) is useful in treating Ab-mediated diseases (i.e., SLE) However, B-cell depletion therapy has also been shown to be useful in treating T-cell dependent AI disease (i.e. Rheumatoid arthritis, Sjogrens Syndrome). Thus, autoantibodies may play an important role in these diseases. Systemic AI Diseases: Systemic Lupus Erythematosis Scleroderma: Systemic Sclerosis Sjogrens Syndrome Mixed Connective Tissue Disease (MCTD)

Systemic Lupus Erythematosus (Systemic Disease): Immune Complex Disease Skin: butterfly malar rash / discoid rash / photosensitivity Joints: Arthritis - nonerosive, nondeforming synovitis CNS: cerebral vasculitis / Seizures / Psychosis CVS: pericarditis, Libman-Sacks non-bacterial verrucous endocarditis Spleen: splenomegaly Lungs: pleuritis, pulmonary interstitial fibrosis\ Hematologic: Hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia, thrombosis Renal: Glomerulonephritis
Test q: A 52y/o female dies after a prolonged chronic autoimmune disease. At autopsy, multiple heart valves show small-to-medium-sized vegetations. The disease most likely associated with these valvular changes is: SLE. Test q: Six weeks post MI, a 56y/o male has chest pain, shortness of breath, and precordial friction rub. He dies within days. The cause of the pathology is: autoimmune pericarditis.

SLE: 1.

Systemic inflammatory disease mediated by immune complex deposition. Chronic, remitting and relapsing, febrile illness. 2. Numerous Antibodies (over 120 described): Pathology largely dependent on immune complex deposition in vascularized tissues. Characteristic antinuclear antibodies identified by the ANA test: dsDNA, RNA, ribonuleoprotein, histone proteins. a. Anti-dsDNA or Smith (Sm) Ag is virtually diagnostic of SLE. 1. Other non-nuclear autoantibodies, so tests for syphilis and HIV may be false positive. b. Lupus Anticoagulant: Antiphospholipid Syndrome (PROTHROMBOTIC STATE) 2. There is some genetic predisposition (e.g. twin studies, HLA association) and environmental factors appear to be involved in disease onset (e.g. viral syndromes, UV exposure, drugs, female sex hormones (F:M ratio = 9:1) or act as triggers for flare-ups of disease.

Test q: A 34y/o woman has had increasing lethargy for the past 8 months. During this time, she has experienced increased sensitivity to sunlight. She has pain in her hands, elbows, knees, and feet and muscle aches in her arms and legs. She has had increasing dyspnea for the past week. Physical exam shows no joint deformities, swelling, or redness. On auscultation of the chest, a friction rub is audible. A chest radiograph shows bilateral pleural effusions. Lab findings show hemoglobin of 11.6mg/dl, hematocrit 34.3%, MCV 84m3, platelet count 133,400/mm3, WBC count 4610/mm3, Na+ 140mmol/L, K+ 4.0mmol/L, Cl- 99mmol/L, CO2 25mmol/L, glucose 80mg/dl, creatinine 2.4mg/dl, and calcium 7.9mg/dl. Which of the following additional lab tests is most helpful to diagnose her underlying condition? Antinuclear antibody. Test q: Which of the following antibodies is diagnostic (most specific) for SLE? Anti-dsDNA.

Indirect IF (ANA): Detects Circulating Serum Antibodies Use indirect immunofluorescence to detect circulating serum antibodies against ANA. Take patients serum and show that serum antibodies will bind to other tissues (can use monkey kidney, see if it binds to nucleus).
Test q: In the indirect fluorescence antibody test for SLE, the patient specimen being tested is: serum.

ANA: Key Points Antinuclear Abs are directed against nuclear Ags (as seen by indirect IF) Very sensitive for detecting antinuclear Abs Poor specificity. Seen in variety of AI diseases, but nearly always positive in SLE. Pos ANAs seen in 5-15% of normal individuals and increase with age. ANA tests are also subjective and have variability due to cells used, technician training. Semi-quantitative (titers only). Four subtypes ANAs: 1. Anti-DNA (anti-double stranded DNA): very specific for SLE. 2. Anti-histone 3. Anti-non-histone ribonuclear: anti-Sm, anti-U1-ribonucleoprotein (U1-RNP), anti-Ro (also known as anti-SS-A), and anti-La (anti-SSB) 4. Anti-nucleolar Ags: anti-PM-Scl, fibrillarin (U3-RNP), Th/To, and RNA polymerase I-III. Highly suggestive of systemic sclerosis or overlap syndromes with scleroderma features.

ANA patterns: homogenous/diffuse; Rim/peripheral; speckled; or nucleolar lack specificity and are more of academic interest. Positive ANAs are generally followed by specific autoantibody (e.g. anti-dsDNA, anti-Smith, anti-histone) testing by immunoassay-based methods (e.g. ELISA, immunoprecipitation) Non-nuclear ANA patterns are also seen: Anti-centromere and anti-cytoplasmic pattern.

Test q: The ANA test for SLE is best described as: excellent sensitivity, poor specificity. Test q: Because you suspect a patient has an autoimmune disease, you request an antinuclear antibody (ANA) test. The lab ANA report shows a rim pattern w/results positive at a 1:5000 dilution. This result would most likely be consistent with which of the following diseases? SLE.

Mainly of Historical Interest: Thus good fodder for Boards Lupus Erythematosis (LE) cell: Mature phagocytes engulfing denatured nucleus (light purple stained ball filling up cytoplasm of PMN (arrow)) of injured cells. They suggest SLE but are found in many diseases. Can be found incidentally in blood that has sat around for awhile or in pericardial or pleural effusions of SLE patients. LE Cell test: Blood is mechanically disrupted and then incubated to allow phagocytosis of nuclear material. Phagocytosis is prompted by Anti-nuclear Ab binding (opsonization). Systemic Lupus Erythematosus Visceral lesions are caused by DNA-anti-DNA complex deposits. High titer anti-dsDNA = nephritis (titers used to monitor therapy & disease progression) Anti-SS-B (usually associated with Sicca Syndrome): Low risk of nephritis Anti-SS-B: Maternal - fetal transfer = present in 90% of mothers of infants with neonatal lupus (heart block) Key Points: Lupus Anticoagulant & Anti-phospholipid Syndrome Secondary anti-phopholipid syndrome: Common in SLE (40-50%) & other AI diseases. Primary antiphospholipid syndrome ( 50%): Not associated with other AI disease. Lupus Anticoagulant (LA) testing: LA most common cause of unexplained prolongation of the aPTT and some other phospholipid-dependent coagulation tests (Kaolin clotting time). LA Test: prolonged APTT that does not correct in an 80:20 mixture with normal human plasma. Addition of phospholipid corrects the coagulation test. Other clotting tests may be used (Dilute Russel Viper Venom Test). Anti-cardiolipin Ab: Enzyme-immunoassay based assay. Clinically a prothrombotic state: History of multiple miscarriages, recurring or unexplained thrombotic episode(s), positive syphilis testing. Key Points: Lupus Anticoagulant & Anti-phospholipid Syndrome (APS) Anti-Phospholipid Syndrome Testing 1. Lupus anticoagulant: Based on clotting tests 2. Anti-cardiolipin Ab Assay: ELISA assay for Abs against cardiolipin preparation (Cardiolipin = the phospholipid diphosphatidyl glycerol). The autoantibodies that cause anti-phospholipid syndrome have actually been found to target not the phospholipids themselves, but rather anticoagulant proteins that are complexed with phospholipids in the lipid preps (i.e. prothrombin, b2-glycoprotein I, annexin V, protein S, protein C). Patients with treponemal infections (e.g. syphilis) can have positive anti-Cardiolipin Ab tests. In syphilis the Abs are to the phospholipid, rather than the proteins. In APS, positive testing is seen for non-treponemal syphilis serological testing (Venereal Disease Research Laboratory (VDRL), and Rapid Plasma Reagin (RPR) Assay. This is due to auto-Ab reaction with crude prep from bovine heart enriched for cardiolipin and the associated APS Ags (b2-glycoprotein I, prothrombin, etc). Anticardiolipin antibody and lupus anticoagulant tests are discordant in approximately 30% of patients. Positive results with either of these assays should be regarded as independent risk factors for a thrombotic tendency. Positive results with both tests do not connote a greater risk of thrombosis than a single positive test.

LUPUS NEPHRITIS: (Classification) Class I. Minimal Mesangial Notes Normal Glomeruli - Light microscopy (LM). Mesangial (M) Immune complex (IC) deposits- electron microscopy & immunofluorescence Matrix expansion with mesangial hypercellularity by LM. Mild: Corticosteroids highly effective Glomerulonephritis in < 50% of glomeruli (May involve all or portions of each glomerulus). Crescents & fibrinoid necrosis may be present. Hypercellular (mesangial, endothelial, leukocytes) Active: Acute hypercellular / Active & Chronic: Some sclerosed glomeruli / Chronic: sclerosed glomeruli Early advanced: High dose corticosteroids effective As in class III, but involvement of 50% of glomeruli. Advanced and often rapidly progressive to ESRD Corticosteroids with immunosuppressive therapy (B-cell depletion now also being used). Subepithelial IC deposition. Thickened glomerular basement membrane without a hypercellular glomerulus (nonproliferative). High rate of nephrotic syndrome (protein loss & edema). Tends to be more indolent: Corticosteroids with or without immunosuppressive therapy 90% of glomeruli sclerosed. No evidence of active glomerular disease. End-stage renal disease

II. Mesangial Proliferative III. Focal Proliferative

IV. Diffuse Proliferative

V.Membranous

VI. Advanced Sclerotic

DNA:anti-DNA Deposition in Lupus Glomerulonephritis 1&2. Subepithelial deposition w/humps (1) & spikes (2) 3. Subendothelial deposition 4. Mesangial deposition 5. Basement membrane I. Minimal Mesangial: Mesangial immune complex (IC) deposits by electron microscopy (EM) or direct immunofluorescence (DIF), not light microscopy (LM) II. Mesangial: Granular mesangial IC deposits by LM; few isolated subendothelial (Endo) or subepithelial (Epi) deposits by EM or DIF III. Focal Proliferative (FP): Mesangial/subendothelial IC deposits IV. Diffuse proliferative (DP): Extensive Mesangial/subendothelial/subepithelial IC deposits by LM (wire loops may be seen). If subepithelial extensive = combined class IV & V. V. Membranous (ME):Subepithelial +/- Mesangial. Scattered subendothelial IC deposits by DIF or EM. If subendothelial IC deposition noted by LM = combined Dx of class III & V or IV & V, depending on distribution. Wire loops may be seen.

V happens on the other side of the BM. Do not see a lot of inflammatory cell activity.

Pathophysiology of Lupus IC Deposition: Additional Notes Glomerular patterns of IC-mediated injury depend on the site of accumulation of immunoglobulins, their antigen specificity, their capacity to bind and activate complement and other serine proteases, and their ability to evoke a cellular inflammatory response. Mesangial pattern: In the mesangial pattern, mesangial hypercellularity and matrix accumulation result from mesangial immune complex accumulation. Endothelial pattern (Focal & Diffuse Proliferative): Exudative component with leukocyte accumulation, endothelial cell injury, and endocapillary proliferation (lots of cells inside capillary loops). Associated with capillary wall destruction, mild to marked immune complex deposition, and varying degrees of mesangial proliferation and crescent formation. Immune complexes in the subendothelial space. These endocapillary changes usually occur in association with mesangial pathology because the mesangium is in direct continuity with the subendothelial space and is accessible to circulating immune complexes. This combined mesangiocapillary or membranoproliferative pattern of injury is particularly common in the chronic phase of lupus nephritis. Epithelial pattern (Membranous Non-proliferative pattern): IC & complement inflict cytotoxic injury on the podocyte & or basement membrane, resulting in a nonexudative, nonproliferative capillary wall lesion with marked protein loss (proteinurea). Pathophysiology of Lupus IC Deposition: Additional Notes Clinical manifestations of these three major morphologic patterns can be predicted based on the topography and character of the glomerular lesions: Mesangial pattern: Leads to a syndrome of microscopic hematuria and subnephrotic proteinuria with wellpreserved or minimally reduced glomerular filtration rate (GFR). Endocapillary proliferative pattern (Focal & Diffuse): Characterized by an acute reduction in GFR, hematuria, and mild to moderate proteinuria. Membranous pattern: Associated with significant proteinuria, often with nephrotic syndrome (> 3.5 grams/day protein in urine). However, since there is limited inflammatory infiltrate, glomerular structure is maintained with preservation and more gradual reduction in GFR. In lupus glomerulonephritis, as in other glomerular diseases, it is not uncommon for several different morphologic patterns to coexist, leading to a more complex clinical expression of disease. Proliferative GN: (remember the other type III glomerular disease: Post-streptococcal GN)

Above: Two areas of focal necrotizing lesions

Above: Crescents represent proliferating epithelial cells and infiltrating leukocytes (red arrow) along inside edge of Bowmans capsule: Occurs following immune/ inflammatory injury.

Below: SLE Glomerulonephritis with wire loop thickening of the glomerular capillary basement membrane. (Extensive subendothelial IC deposits) .

Below: Advanced lupus membranous nephropathy with massive subepithelial accumulation of immune deposits and interdigitating spike formation (methenamine silver).

Above: Membranous GN Normal Cellularity. Silver stain best for detecting subepithelial deposition: Silver stains BM, but not IC deposits. Interdigitating spikes (arrow) represent BM staining as the BM that wraps around IC deposits. Over time, BM will completely cover the deposits with domes and markedly thickened, irregular BM. Below: Glomerular Sclerosis Entire Bowmans capsule space is scarred over

Disorders Related to SLE (anti-dsDNA rare): Discoid Lupus - affects skin only-erythematous, scaly plaques with follicular plugging, alopecia leading to scar formation (characteristic dermoepidermal Ig). Systemic symptoms uncommon except for minority with long-standing disease. Subacute Cutaneous Lupus Skin only tends to be more widespread, superficial and non-scarring. Most have mild systemic symptoms. Anti-SS-A Abs & HLA-DR3 genotype common. Drug-induced lupus -- drug causes positive ANA, but symptoms are mild and remit with drug withdrawal (anti-histone Abs). HLA-DR4 associated with Hydralazine-induced SLE. Discoid rash: Red, scaly patches on skin that cause atrophic scarring & alopecia. Can also manifest as urticaria (dark red, raised, itchy bumps or hives), bullous lesions (blisters), hypertrophic growths resembling warts, and ulcers (usually mucous membranes around mouth, nose, and throat). Discoid Lupus: Predominantly affects the cheeks, nose and ears, but sometimes involves the upper back, V of neck, and backs of hands. Characteristic Malar butterfly rash of SLE
Test q: A 25y/o woman has had increasing malaise, a skin rash on her face exacerbated by sunlight exposure, and arthralgias and myalgias. On auscultation, a friction rub is audible over the chest. Lab findings include pancytopenia and serum creatinine 3 mg/dL. Urinalysis shows hematuria and proteinuria. A serologic test for syphilis yields a false-positive result. A renal biopsy shows a slight increase in mesangial cells and granular deposits of IgG and complement in the mesangium and along the basement membrane. Which of the following mechanisms is most likely involved in the pathogenesis of her disease? Defective clearance of apoptotic nuclei. Test q: A 25y/o woman has had increasing malaise, a slight fever, and arthralgias/myalgias for the past month. On auscultation, a friction rub is audible over the chest. There is no joint deformity or swelling. Lab findings include hemoglobin 10.8g/dl, hematocrit 32.5%, platelet count 106,700/mm3, and WBC count 3420/mm3. Urinalysis shows 2+ proteinuria. A serologic test for syphilis yields a false-positive result. A chest radiograph shows bilateral pleural effusions. Which of the following problems is most likely to occur as a result of the patients underlying disease? Photosensitivity. Test q: A 25y/o woman w/a family history of autoimmune disease present w/a butterfly rash over the face, pleuritic chest pain, photosensitivity, and persistent proteinuria. Which of the following immunologic abnormalities is most characteristic of the disorder manifested by this patient? Antibodies against native double stranded DNA.

Cutaneous Lupus Inflammation necrosis; Edema Avoid UV light! Note + stained nuclei in epidermis (ANAs)

Junctional IgG (Direct IF) (aka: Lupus Band Test) Discoid Lupus: Only seen underlying rash SLE: Also seen underlying uninvolved skin
Test q: A 25y/o male presents w/bullous lesions on his abdomen, arms, and legs. You wish to submit tissue for both routine histologic exam (H&E) and for immunofluorescence studies (IgG and IgA). The specimens that you should collect are: A lesional biopsy for H&E stain and a peri-lesional biopsy for immunofluorescence.

Scleroderma: Systemic Sclerosis Scleroderma or Progressive Systemic Sclerosis: Systemic inflammatory disease marked by progressive interstitial and perivascular fibrosis (collagen deposition) of skin and viscera. Intimal proliferation (100% of digital arteries): Proliferation of intimal cells, endothelial cells, and smooth muscle cells with perivascular fibrosis. Perivascular lymphocytic cuffing (CD4+ T-cells) is seen. Fibrosis leads to: Peripheral vascular disease Renal hypertension / failure Pulmonary HTN/fibrosis Dysmotility syndromes (esophageal/gut no peristaltic action) Lose elasticity of vessels, so severe hypertension develops. Figure: CD4+ T-cell activation (unknown Ag trigger) with production of repair or fibrogenic cytokines (e.g. TGFb). Alternatively, abnormal FB responses may be involved: FB hyper-responsiveness to fibrogenic cytokines or abnormal FB collagen production. Subtypes of systemic sclerosis: Diffuse cutaneous systemic sclerosis: Skin involvement in trunk, upper arms, and legs Raynaud phenomenon Gastrointestinal involvement Renal involvement (about 30%): Acute renal failure-Renal arterial intimal fibrosis leading to malignant hypertension and renal infarcts. Frequently occurs with rapid onset leading to ESRD & death Interstitial lung disease (30%40%): Most common cause of death Pulmonary hypertension - may be primary arterial hypertension (small percentage) or secondary to interstitial lung disease Myositis Cardiac involvement Autoantibodies in diffuse disease: Scl 70 antibodies (10-20%)increased risk of interstitial pulmonary fibrosis RNA polymerases I, IIIincreased risk of renal disease, probably cardiac disease
Test q: A 45y/o woman has experienced difficulty in swallowing that has increased in severity over the past year. She has also experienced malabsorption, demonstrated by a 5-kg weight loss in the past 6mo. She reports increasing dyspnea during this time. On phys exam, her temp is 36.9*C, pulse 66/min, respirations 18/min, and BP 145/90mmHg. Echocardiography shows a large pericardial effusion. The ANA test result is positive at 1:512 w/a nucleolar pattern. Which of the following serious complications of the patients underlying autoimmune disease is most likely to occur? Malignant hypertension. (other choices were Meningitis, Glomerulonephritis, Perforated duodenal ulcer, and Adrenal failure.)

Limited cutaneous systemic sclerosis: Skin involvement of fingers, later hands, face, and feet Raynaud phenomenon Visceral disease less common and occurs late Gastrointestinal involvement Primary pulmonary hypertension (25%50%) Interstitial pulmonary fibrosis (10%) Anticentromere antibodies (20-30%)indicates increased risk for pulmonary hypertension & CREST

CREST syndrome common: Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangietasia. (anti-centromere Ab: Also seen in primary biliary cirrhosis) Microvascular intimal fibrosis and subepithelial/submucosal fibrosis:

Raynauds Phenomenon: Brief cold exposure: Exaggerated microvessel response: white: blue: red

Calcinosis cutis: Sub-epidermal calcium deposition.

Sclerodactyly: cannot extend fingers, get shiny skin b/c of collagen.

crest Telangiectasia:

Above: Skin Increased dermal collagen. Chronic inflammatory cells are sparse with systemic sclerosis, unlike SLE.

Above: At high magnification, the dermis is expanded by dense collagenous fibrosis. Immunofluorescence is not helpful with scleroderma.

Systemic Sclerosis: Pulmonary Alveolitis: Inflammatory "alveolitis" of scleroderma lung. Note the irregular thickening of alveolar walls by inflammatory cells (arrows), sometimes making lymphoid aggregates (LA).

Below: Pulmonary Interstitial Fibrosis. Alveolar walls are distended by collagen (arrows), fibroblasts, and some chronic inflammation (blue cells here).

Pulmonary HTN: Primarily vascular fibrosis. Below: B = Pulmonary artery in a scleroderma patient with pulmonary hypertension. A = Normal Pulmonary Artery

Sjogrens (Sicca) Syndrome: Symptoms: keratoconjunctivitis & siccaxerostomia. Dry eyes, dry mouth. Laboratory: anti-SS-A / anti-SS-B. anti-SS-A and B are not specific for Sjogrens b/c it could mean lupus. Physical Exam: Mikulicz syndrome: lacrimal and salivary gland enlargement
Test q: A 35y/o female complains of chronic dry eyes and dry mouth. Her neck is irregularly enlarged. A workup for autoimmune disease is ordered. You expect to find: Anti-SS-A. (Other choices were Anti-dsDNA, Anti-Sm, Anti-centromere, and giant cell arteritis) Test q: A 45y/o female presents w/chronic dry eyes and dry mouth. Lacrimal salivary glands are identified. The lab reports anti-SS-A and anti-SS-B. She suffers from: Sjogrens syndrome.

Salivary Gland: Sjogrens Syndrome

- Extraglandular involvement (approx 30%): Pleuritis & pulmonary interstitial fibrosis, synovitis, tubulointerstitial nephritis, skin, peripheral neuropathy. - Approx 40 x increased rate of B-cell marginal zone lymphomas

Mixed Connective Tissue Disease A mixture of SLE, RA, scleroderma, and polymyositis. Anti-snRNP U1 ribonucleoprotein (U1-RNP) Polymyositis: Inflammatory Myopathy (Covered in Ch 27)

Note: If anti-dsDNA or -Sm Ag is present, regardless of other antibodies present = most likely SLE

PRIMARY IMMUNODEFICIENCY SYNDROMES: (very rare to relatively common genetic disorders) Defect of humoral immunity: X-linked agammaglobulinemia of Bruton (tyrosine kinase deficiency) Common variable immunodeficiency Isolated IgA deficiency (related to CVI) X-linked Hyper IgM Defect of Cell mediated immunity: DiGeorges syndrome (thymic hypoplasia) SCID (defect of both humoral and CMI)

Types of Infection Associated with Immunodeficiencies Pathogen Type Bacteria T-Cell Defect Bacterial Sepsis B-Cell Defect Pyogenic bacteria Streptococci Staphylococci Haemophilus Enteroviral encephalitis Granulocyte Defect Staphylococci Pseudomonas Complement Defect Neisserial infections Other pyogenic bacteria infections

Viruses

Cytomegalovirus Epstein-Barr Virus Severe Varicella Chronic Infections with respiratory & enteroviruses Candida Pneumocystis Aggressive disease with opportunistic pathogens Failure to clear infecions

Fungi & Parasites Special Features

Severe intestinal giardiasis

Candida Nocardia Aspergillus

Recurrent sinopulmonary infections Sepsis Chronic meningitis

Test q: Recurrent infection w/yeasts, fungi, or mycobacteria, and inability to confine viral infections are associated w/a deficiency of: cellular immunity.

X-linked Agammaglobulinemia of Bruton (tyrosine kinase deficiency(Btk)): Tyrosine kinase deficiency = defect in B-cell maturation and light chain rearrangement (cytoplasmic heavy chain is produced, but no light chain) thus unable to be activated by Ag and produce secreted IgM or undergo class switch and produce secreted IgG, IgA, etc. Immature B-cells are present normally in BM but largely absent in blood/LNs. Underdeveloped lymph node germinal centers Onset after maternal IgG titer drops: Recurring sinopulmonary infections (almost always Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus. Prone to meningoencephalitis with enteroviruses (No live polio vaccine) and persistant Giardia protozoan infections also seen. High frequency of Autoimmune Disease
Test q: A 19-y/o man suffers from a B-cell deficiency. He receives oral polio vaccine. He develops gastroenteritis and diarrhea. He apparently suffers from: poliovirus infection. Test q: An 8month old infant who had an uneventful birth and normal development has developed recurrent otitis, pneumonia, and meningitis caused by Haemophilus influenzae and Streptococcus pneumoniae over the past month. Biopsy of lymph nodes would be expected to show: Absent germinal centers.

Test q: You order quantitative immunoglobulin measurements on a patient as part of your workup for an immunodeficiency disease. Results from the lab show no detectable IgG, IgA, or IgM. Which of the following is the most likely diagnosis? Brutons agammaglobulinemia. Test q: A 12mo old boy w/a 6mo history of repeated infections has had a fever and cough for the past 3 days. A gram stain of sputum shows many gram-positive cocci in chains. CBC shows neutrophils. Lab studies show that the patients neutrophils phagocytose and kill organisms normally in the presence of normal human serum, but not in his own serum. The neutrophils migrate normally in a chemotaxis assay. A lymph node biopsy shows rare and very small germinal centers. Which of the following is the most likely cause of the childs increased susceptibility to infection? Immunoglobulin deficiency.

Common Variable Immunodeficiency Relatively common (Sporadic & Inherited forms). Males = Females Inefficient immunoglobulin synthesis: plasma cell differentiation: Hypogammaglobulinemia (variable loss of Ig classes (can be only IgG). B-cell rich lymphoid follicles (e.g. spleen, gut) are hyperplastic Symptoms similar, but usually less severe than those observed in Brutons agammaglobulinemia. Defects in T-cell mediated activation of B-cells and B-cell function have been detected in a small subset of inherited form of CVI: BAFF cytokine receptor mutation (B-cell survival & differentiation. ICOS: Protein homologous to CD28 and involved in T-cell activation and B-cell interaction. Relatives have high frequency of selective IgA deficiency High frequency of AI disease and lymphoma Isolated IgA Deficiency: Most common primary immunodeficiency disease (1:600 of European descent). Familial and acquired (e.g. post-viral syndrome) Like CVI, defect in B-cell maturation to IgA-producing cells (e.g. BAFF cytokine mutation also seen in CVI). Associated with mucosal infections (sinopulmonary, GI, UTI) and high rates of atopy (i.e. allergic bronchitis) and autoimmune disease. Anaphylactic reaction during transfusions (whole blood, plasma containing IgA). Common Board question.
Test q: A 35y/o man has a history of mild infections of the upper respiratory tract. He also has had diarrhea for most of his life, although it was not severe enough to cause malabsorption and weight loss. After an episode of trauma w/blood loss, he receives a blood transfusion and has an anaphylactic reaction. Which of the following underlying conditions best explains these findings? Selective IgA deficiency. (should it be isolated?) REPEATED TWICE.

Hyper IgM Syndrome Defect of B-cell class switching and maturation: Pyogenic infections / pneumonia from intracellular pathogen: Pneumocystis jiroveci 70%: X-linked loss of CD40 ligand (CD154) on T-cells Remaining: Autosomal recessive Mutations encoding CD40 or the enzyme activation-induced deaminase (Enzyme required for class switching) DiGeorge Syndrome: Thymic Hypoplasia Chromosomal deletion syndrome (22q11 deletion syndrome (Ch 5): Aplasia or rd th hypoplasia of 3 and 4 pharyngeal pouch (Thyroid and parathyroid) during embryogenesis. Other associated abnormalities of aorta, congenital heart disease and facial anomalies Failure of T-cell maturation (absent thymus) and hypocalcemic seizures/tetany (absent parathyroid) Usually cause for diagnosis in newborns Both Cellular & Humoral: Severe Combined Immunodeficiency (SCID) bubble baby. Severe bacterial, viral, fungal infections. Thymus small and devoid of lymphocytes. X-linked (most common): Genetic loss of common gc-chain for cytokine receptors (IL-2, IL-4, IL-7 etc). IL-7: Lymphoid progenitor proliferation Autosomal Recessive: Adenosine Deaminase (ADA) JAK3 (gc chain signaling) IL-7a receptor MHC class II deficiency (bare lymphocyte syndrome)
Test q: Which of the following would be expected with SCID? This disease results in dysfunction of both B- and Tcells secondary to one of several known mutations of cytokine receptors (e.g. common gamma chain) or a component of cytokine receptor intracellular signaling pathways.

IMMUNODEFICIENCY SYNDROMES (Wiskott-Aldrich) Immunodef. with thrombocytopenia & eczema (X-linked) (WASP protein) Defect in actin polymerization & receptor/cytoskeletal interaction in B/T-cells and platelets (eczema, thrombocytopenia purpura and recurring infections). Genetic deficiencies of the complement system: Alternate pathway (properdin, factor D): pyogenic infections Classic pathway (C2, C1, C4): AI diseases Alternate & Classic pathway (C3): Severe pyogenic infections. Deficiency of complement inhibitors: C1 inhibitor: hereditary angioedema = elevated bradykinin Prone to respiratory/mucosal edema (asphyxia, N/V, diarrhea) Glycophophatidyl Inositol (GPI) deficiency: CD59 & Decay accelerating factor (Paroxysmal nocturnal hemoglobinuria) ACQUIRED SECONDARY IMMUNO- DEFICIENCY SYNDROMES (very common conditions) AIDS Cancer treatment: (Bone marrow transplant) radiation, chemotherapy Aging: Most common immunodeficiency syndrome. Decreased T-cell proliferative responses, blunted cytokine response (IL-2), decreased circulating naive T-cells (ThP). B and T-cell anergy AMYLOIDOSIS: One of the extracellular hyaline accumulations Amyloidosis is a distinct pathologic entity from immune complex disease and fibrin or plasma protein deposition (e.g. fibrinoid reaction). Amyloid deposition results from deposition of distinct proteins (e.g. lambda light chains, b-amyloid protein) which aggregate as b-pleated sheets secondary to altered protein secondary or tertiary structure and are resistant to proteolytic degradation. Congo Red Birefringence SYSTEMIC DISEASE PRIMARY AMYLOIDOSIS: Amyloid (AL) Ig light chain fragments Bence Jones protein, synthesized in copious excess by simply dysfunctional, or overtly malignant (multiple myeloma) monoclonal plasma cells. SECONDARY REACTIVE SYSTEMIC (AA): Amyloid (AA) from serum amyloid associated (SAA) protein synthesized by liver in response to inflammatory cytokines (e.g. IL-1). Associated with chronic inflammatory diseases (e.g. Rheum. Arthritis)(Heroin skin poppers)(Also Heriditary Familial Mediterranean Fever). SECONDARY HEMODIALYSIS-ASSOCIATED (Ab2m): Amyloid from b2 microglobulin (component of MHC class I receptor) HEREDITARY AMYLOIDOSIS: Transthyretin (ATTR): Neuropathic disease with pre-albumin (transthyretin) amyloid Kidney: Nephrotic syndrome-End stage kidney disease - Congo-Red birefringence in glomeruli. Spleen (Splenomegaly): Splenic follicle deposition (Sago)/Sinus deposition (lardaceous) Liver (hepatomegaly) Heart: CHF, conduction defects, restrictive cardiomyopathy Adrenals, thyroid, pituitary, GI tract Congo Red stain of kidney biopsy:

Localized Amyloidosis: Alzheimers: Amyloid beta (A) plaques from Amyloid precursor protein (APP). Senile systemic amyloidosis: Systemic deposition of transthyretin (ATTR)-biggest issue is restrictive cardiomyopathy and conduction abnormalities. o Inherited: Mutant transthyretin (ATTR amyloid) o (4% African-Americans carriers) Cardiac mainly Endocrine amyloid (tumors, IDDM): Polypeptide protein (e.g. calcitonin) or unique proteins that produce microscopic lesions

Cardiac Amyloidosis:

Liver:

AIDS EPIDEMIOLOGY AND PATHOLOGY Acquired Immunodeficiency Syndrome:

Fri. 09/10/10

Above: New cases are down. Deaths are down.

Above: Prevalence continues to increase.

Above: We have greatly reduced the # of annual deaths. Focusing on persons 25 to 44 years old emphasizes the importance of HIV disease among causes of death. Compared with rates among other age groups, the rate of death due to HIV disease is relatively high in this age group, but rates of death due to other causes are relatively low. HIV disease was the leading cause of death among persons 25 to 44 years old in 1994 and 1995. In 1995, HIV disease caused about 32,000 deaths, or 20% of all deaths in this age group (based on ICD-10 rules for selecting the underlying cause of death). The rank of HIV disease fell to 5th place from 1997 through 2000, and to 6th place from 2001 through 2005. In 2005, HIV disease caused about 6,000 deaths, or 5% of all deaths in this age group.

AIDS Risk increased by other STDs (that cause ulcerations) Syphilis Herpes Chancroid Trichomonas Epidemiology of AIDS in the U.S. AIDS is present in all 50 states The midwest has relatively few AIDS patients In the U.S.Over 1,000,000 infected and over 50% of those had died as of 2001. Worldwide, >60,000,000 people are living and are infected by HIV/AIDS

Late teens-early 40s at greatest risk (coincides w/sexual activity).

White males decreased, African American citizens increased.

This slide (yellow/green bar graph, above) shows the distribution of AIDS cases, by age at diagnosis and sex. From 1981 through 2005, a total of 956,019 cases of AIDS have been reported to CDC: 81% were in males and 19% in females. Most of the cases were diagnosed when the men and women were 2544 years of age.

The proportional distribution of AIDS cases among racial/ethnic groups has changed since the beginning of the epidemic. The proportion of AIDS cases in non-Hispanic whites has decreased while the proportions in non-Hispanic blacks and Hispanics have increased. The proportion of AIDS cases among Asians/Pacific Islanders and American Indians/Alaska Natives has remained relatively constant, at approximately 1% of all cases. Of persons diagnosed with AIDS in 2005, 49% are non-Hispanic black, 28% are non-Hispanic white, 21% are Hispanic, 1% are Asian/Pacific Islander, and less than 1% are American Indian/Alaska Native.

50% in African Americans, but they only make up 13% of population. NOT equal distribution.
The pie chart on the left illustrates the distribution of AIDS cases reported in 2005 among racial/ethnic groups. The pie chart on the right shows the distribution of the U.S. population (excluding U.S. dependent areas) in 2005. Non-Hispanic blacks and Hispanics are disproportionately affected by the AIDS epidemic in comparison with their proportional distribution in the general population. In 2005, non-Hispanic blacks made up 13% of the population but accounted for 50% of reported AIDS cases in the 50 states and the District of Columbia. Hispanics made up 14% of the population but accounted for 18% of reported AIDS cases. Non-Hispanic whites made up 68% of the U.S. population but accounted for 30% of reported AIDS cases.

Through 2005, AIDS had been diagnosed for a cumulative total of 943,528 persons in the United States and District of Columbia. Most (81%) of all AIDS cases in adults and adolescents have been in males. Among males with AIDS, 59% reported male-to-male sexual contact. The proportion of AIDS cases among males reporting male-to-male sexual contact was even larger among those aged 13 to 24 years. During 2005, male-to-male sexual contact was the most frequently reported transmission categoryapplicable to 43% of all AIDS cases diagnosed that year.

Used to be mostly caucasian, but now is more equally distributed.

U.S. Women and AIDS IV drug use Sex with infected males Sex with infected males who are IV drug users

Expansion of disease in African American females. Children with AIDS Over 90% of children in the U.S. acquire AIDS perinatally from their mothers (may be closer to 98-99%) Transplacental, at birth, via breast milk Pediatric cases are decreasing in the U.S. because expectant mothers are treated with anti-AIDS drugs (eg. AZT)

The estimated number of AIDS cases diagnosed among persons perinatally exposed to HIV peaked in 1992 and has decreased in recent years. The decline in these cases is likely associated with the implementation of Public Health Service guidelines for the universal counseling and voluntary HIV testing of pregnant women and the use of antiretroviral therapy for pregnant women and newborn infants (MMWR 2002;51(No. RR-18)). Other contributing factors are the effective treatment of HIV infections that slow progression to AIDS and the use of prophylaxis to prevent AIDS opportunistic infections among children. In 2006, 86 children with AIDS were reported to CDC. Most (86%) of these children acquired HIV infection perinatally, that is, from their mother during pregnancy. Since the beginning of the AIDS epidemic, 9,522 children have been reported with AIDS. Again, most of these children (92%) were infected perinatally. Another 4% acquired HIV from a transfusion of blood or blood products, and another 2% acquired HIV from transfusion because of hemophilia.

AIDS Transmission: In heterosexual transmission of AIDS in the U.S. the male-to-female transmission is 20X more efficient than female-to-male transmission The risk of transmission by sexual contact may be as low as 1/300 The risk for transmission by superficial needle stick may be as low as 1/300; (1/3000 with AZT etc.) The risk for transmission by transfusion or IV drug use may be as high as 6/10 In females, AIDS transmission is overwhelmingly attributed to high risk heterosexual contact. Of AIDS cases diagnosed in 2005 for male adults and adolescents, 58% were attributed to male-tomale sexual contact and 18% were attributed to injection drug use. Approximately 16% of cases were attributed to high-risk heterosexual contact and 7% were attributed to male-to-male sexual contact and injection drug use. Most (71%) of the AIDS cases diagnosed in 2005 for female adults and adolescents were attributed to high-risk heterosexual contact, and 27% were attributed to injection drug use. The data have been adjusted for reporting delays and cases without risk factor information were proportionally redistributed.
Test q: In the US in 2005, 71% of females infected by HIV and developing AIDS acquired the infection via: high risk heterosexual contact.

Definition of AIDS Positive HIV Test (confirmed) plus: 1. CD4 lymphocyte count less than 200 cells/mm3 and/or 2. Opportunistic infection or neoplasm; esp. Pneumocystis jirovecii (carinii) pneumonia
Test q: An AIDS patient exhibits shortness of breath, fever, and diffuse infiltrates on chest x-ray. A Giemsa stain shows several cysts that contain up to 8 trophozoites. No buds are identified. The cause of the infection is: Pneumocystic jirovecii.

Most are classified by their CD4 count. AIDS Treatment Drug treatment of opportunistic infections has improved Drugs exist to inhibit the AIDS virus and they are directed against 3 enzymes: reverse transcriptase, protease and integrase Highly Active Anti-Retroviral Therapy (HAART) Increased the length of time to onset of AIDS in the HIVinfected Decreased symptoms in AIDS patients Delayed onset of opportunistic infections Decreased HIV Viral Load in blood this is #1 predictor of how HIV pt will do. More important than CD4 count. Increased survival time for AIDS patients Cost is >$20,000.00 per year No cure HAART helps people go longer w/o having CD4 count <200 or getting opportunistic infections.
Test q: The overall death rate in US AIDS patients has declined since 1995 primarily due to: Wide use of HAART in HIV-infected patients.

ANTIRETROVIRAL RESISTANCE TESTING GENOTYPING (figuring out whether the virus will be resistant to certain drugs) Examine the HIV genome for resistance associated mutations in the PR and RT* regions For example: Zidovudine T215P- Resistance PHENOTYPING Test HIV isolates against PR and RT drugs for 50% inhibition of replication For bacteria, grow it in the lab and test antibiotics to see which one works. Does not work very well w/HIV because it can mutate. Genotyping is more useful.
Test q: A 25y/o HIV positive female has demonstrated an increasing viral load and a decreasing CD4 lymphocyte count. The RNA from the viral strain infecting her lymphocytes is isolated and characterized for resistance mutations in the PR and RT regions. This procedure is called: Genotyping. Test q: Selection of successful anti-retroviral therapy has been largely due to genotyping. Basically, genotyping can be described as: Gene sequencing of the retrovirus. Test q: A 40y/o HIV infected female has been receiving highly active antiretroviral therapy (HAART) for the past 2yr. HIV-1 RNA level initially decreased below 50 copies/L after initiation of therapy; the current level is >10,000 copies/L. A mutation in the gene for which of the following substances is most likely to have occurred? Reverse transcriptase (Other choices: CD40 ligand, Chemokine receptor, Cytokine receptor chain, p24 antigen.) Test q: A 25y/o male 2 yr med student at Harvard was found to have a positive screening test for HIV-1 when he attempted to donate blood. He has been well except for minor cervical lymphadenopathy and an occasional upper respiratory infection. He admitted to occasional IV drug use as a college freshman. The confirmatory Western Blot was also positive for HIV-1. His CD4+ T cell count is 202/mL and his HIV-1 RNA viral load is 35,000 copies/mL. You have decided to begin combination antiretroviral therapy. Selection of the proper drug combo can BEST be guided by: Submitting a patient blood sample for HIV-1 genotyping. (Other choices- submitting a blood sample for: HIV-1 phenotyping, HIV-2 screening, CBC, and cell culture of HIV-1 and in vitro retroviral susceptibility testing.) Exactly 1yr after your diagnosis of AIDS in this patient, he develops a bilateral pneumonia and is extremely short-of-breath. A BAL (bronchoalveolar lavage) is performed and sent to the microbiology lab. A Giemsa stain shows cyst forms that each contain several trophozoites and a GMS (silver) stain shows round bodies w/folds, grooves, and central dots. Budding forms are not seen on either stain. The most reasonable diagnosis is: Pneumocystic pneumonia.
nd

If you genotype a virus and predict its resistance, you can have better outcomes, as shown above. ^ The HIV Virus 2 copies of RNA *reverse transcriptase, integrase, *protease (*common targets of antiviral drugs) many proteins; p24 is easiest to detect (most antigenic) lipid envelope (target of vaccines and screening tests) HIV-1 is common in U.S., Europe and central Africa HIV-2 is more common in western Africa Screening tests are for HIV-1 AND 2.

p24 most antigenic part of the virus

Above: When you sequence the genome of the virus, the 3 most important groups are gag (capsid p24), pol (enzymes involved in replication), and env (outside, attach to cells). Need to know. Pathogenesis: 1. The primary targets of HIV-1 are CD4+ T cells, macrophages and dendritic cells. Macrophages and dendritic cells are the most important targets in the early stages. 2. CD4+ cells have receptors for HIV-1, but cell penetration requires coreceptors (chemokine receptors) 3. R5 strains (M-tropic) use CCR5; X4 strains (T-tropic) use CXCR4 M-tropic = more likely to infect macrophages and dendritic cells T-tropic = more likely to infect T cells 4. M-tropic strains predominate early (dendritic cells have only CCR5); Ttropic late- in the aggressive phase of AIDS 5. *CCR5-deficient individuals (1%), (homozygous), are resistant to infection by R5 strains of HIV-1
Test q: In epidemiologic studies of HIV infection and AIDS, investigators noticed that certain individuals did not develop HIV infection despite known exposure to the virus under conditions that cause HIV disease in all other individuals similarly exposed. When CD4+ lymphocytes from resistant individuals are incubated with HIV-1, they fail to become infected. Such resistance to infection by HIV is most likely caused by a mutation affecting genes for which of the following cellular components? Chemokine receptor. REPEATED x3! Test q: In the acute phase of HIV infection, macrophages and dendritic cells are the primary targets. These cells share in common: CCR5 co-receptor.

Figure: Proliferation of AIDS virus either in T cells or dendritic cells (could have macrophages pictured w/dendritic cells, too). Processing and replication in lymphatic tissues integration into genome death of T cells.

 Figure: Early T cells not likely to be infected. Mainly macrophages and dendritic cells. Middle: Macrophages, dendritic cells, and T cells. Late: T cells

Macrophages and Dendritic Cells as Gatekeepers: 90% of early infections are by M-tropic strains Macrophages offer a protected environment Macrophages transport HIV (eg. to the brain) Both are sites of HIV replication when CD4+ T cells are depleted; dendritic cells (Langerhans cells) utilize Fc receptor to capture Ab-coated HIV-1 HIV Replication 1. Reverse transcription of HIV DNA (timing is variable) 2. Integration into the host genome where the latent period may last for years 3. Transcription of more viral DNA and viral particles that bud from the cell membrane and the infected cell dies

Figure: Virus attaches via envelope attaches to CD4 receptor, then also attaches to chemokine receptor (coreceptor). If that receptor is absent, patient will be very resistant to infection. Cytokine receptors are involved in activation of the virus. People get infected w/AIDS AIDS integrates into host genome sits there until stimulated to replicate (because of other infections). Other infections stimulate TNF-, etc. via cytokine receptor reactivation of AIDS virus. Need to limit exposure to other STDs so they dont activate replication of the virus. Need to keep HIV-1 viral load as low as possible.

Release from Latency 1. Latently infected CD4+ T cell encounters an environmental antigen stimulation via cytokine receptor active replication of the virus. 2. NF-KB released (I-KB phosphorylation) activates replication of proviral HIV DNA; TNF can also activate replication. 3. In summary, when macrophages and T cells are activated HIV replication occurs. 4. Many viruses and STDs can serve as the stimulus.
Test q: A 28y/o HIV-infected male has been diagnosed w/the retrovirus infection for 4 years, but has not yet had an opportunistic infection. After a genital herpes infection, his CD4 count drops, his HIV RNA viral load increases, and he develops Pneumocystis pneumonia. Release from the latent phase was due to: Interaction of cytokine and cytokine receptors.

Loss of CD4 T-cells 1. Death of HIV-infected cells 2. Death of non-HIV-infected cells Figure: Most T cells are not infected w/AIDS. AIDS does not infect all T helper cells and kill them. Only 1 in 1000-10,000 T helper cells are infected the others are killed by apoptosis or cytotoxic T lymphocyte activation not actually infected w/HIV-1. Other Immune Abnormalities Lymphopenia Decreased T cells in vivo: opportunistic infections and neoplasms; anergic to skin tests (loss of DTH/IV) Decreased T cell activity in vitro: IL-2 and TNF-gamma, response to other antigens Polyclonal B cell activation Macrophage dysfunction: phagocytosis CNS Pathology Macrophages and microglial cells infected M-tropic strains almost entirely M-tropic strains use macrophages to access the CNS. Do not see T-tropic strains in the brain. Pathology is probably due to neurotoxins since necrosis of neurons is rare, but neurologic symptoms are severe 90% have evidence of HIV-related neuropathology at autopsy
Test q: A 30y/o man infected w/HIV begins to have difficulty w/activities of daily living. He has memory problems and decreased ability to perform functions that require fine motor control such as writing and painting. His CD4+ lymphocyte count currently is 150/L. Which of the following cell types is most important for the dissemination of the infection into the CNS? Macrophages. REPEATED x4!!

Natural History of HIV-1 Early phase- viremia, fever, fatigue Latent phase- 7-10 years with minor lymphadenopathy and minor infections such as Candida and Herpes Zoster Final (crisis) phase- persistent lymphadenopathy, fever, rash, opportunistic infections, neoplasms, CNS disorders Figure: Most important chart to commit to memory: shows CD4 cells vs. how many virus copies are in the blood (viral load). In early infection, both counts are high. Over the next few months/years, viral load drops down and CD4 count slowly comes down. When CD4 count is below 200, you definitely have AIDS. If you have a high viral load and get an opportunistic infection, you have AIDS. If CD4 count is below 200 and viral load is above 100,000, you are in the crisis phase. Will get opportunistic infections, will not live long. We use HAART to keep CD4 high and viral load down.
Test q: A 21y/o male thinks he was exposed to HIV-1 about 4wk ago. His CD4 count is 600/mm3 and his HIV-1 viral load is 100,000/mL. These findings are consistent with: Early (acute) phase.

Test q: A 35y/o man has had unprotected sex w/numerous partners during the past 18 years. He states that he has felt well except for tingling sensations in his lower legs, but has now developed a painful rash over the left side of his chest. On phys exam, you observe that the rash follows the T5 dermatome. This is most likely related to infection by: herpes. (Zoster shingles. Other choices: Cryptococcus, cryptosporidium, CMV, or pneumocystis)

Crisis Phase (AIDS) HIV-1 mRNA (aka HIV viral load) greater than 30,000/uL and the CD4+ T cell count is less than 200/uL Opportunistic infections occur and fever, rash etc. are constant *Oral Candidiasis is a major predictor of rapid disease progression
Test q: A 40y/o male has a CD4 T cell count of 25/mL and the HIV viral load is 10,000,000 copies/mL. He is in the __ phase of AIDS. Crisis. Test q: In the crisis phase of AIDS, the CD4 count is ___ and the HIV RNA viral load is ___. CD4 < 200cells/mm3; HIV RNA > 30,000 copies/mL

Detection of the AIDS Virus 1. ELISA screening test for Ab (p24 is most antigenic but can also be other) to HIV-1 (and HIV-2) OR rapid testing (OraQuick) 2. Confirmatory test- usually western blot 3. CD4 lymphocyte count is an indirect measurement 4. HIV-1 viral load (HIV-1 mRNA) best predicts patient prognosis- if the HIV Viral Load is less than 50/uL: observe patient
Test q: A 35y/o female had a sexual exposure w/an HIV-infected male 2wk ago. She comes to clinic and requests a rapid HIV test. The OraQuick test is performed and is positive. The appropriate next step is: Order a confirmatory test (Western blot). REPEATED TWICE

The OraQuick Rapid Antibody Test Only test approved by the FDA for use on oral fluid (NOT saliva). Can also be performed on whole blood (fingerstick or venipuncture) or plasma. Results in 20 40 minutes Screens for both HIV-1 and HIV-2 Stored at room temperature The Procedure: Patient being tested opens the pouch Patient swabs flat pad between teeth and gums (upper and lower) only Patient places swab in test vial so pad touches bottom Start timing must be read in 20 - 40 minutes For blood or serum, use included loop and mix in solution, then insert flat pad Result Interpretation Non-Reactive Line at C only Reactive Line at T and C Invalid No line at C, the background remains red/pink, or the line is outside of the triangle next to either letter Does it work? Whole Blood Plasma Oral Fluid Sensitivity 99.6% 99.6% 99.3% Specificity 100% (??) 99.9% 99.8%

Positive Predictive Value: 90% to 50% with 10% to 0.1% population disease prevalence, respectively. If you use this test in a population w/a low prevalence, will get a lot of false positives. PPV is 90% if you only test patients that exhibit a clue that makes you think HIV.

Western Blot Confirmation of HIV AIDS Associated Neoplasia Kaposis sarcoma (KS) is rare in the U.S. except in AIDS patients *Sexually acquired AIDs patients are 20X more likely to get KS than transfusion acquired HIV/Herpesvirus (KSHV or HHV8))/cytokines theory Hodgkins and especially non-Hodgkins B-cell Lymphomas are more common in AIDS patients Cervical carcinoma (HPV infections) HPV-associated oral cancers (squamous cell)
Test q: A 32y/o woman w/a 10yr history of IV drug use has developed a chronic watery diarrhea that has persisted for the past week. On phys exam, she is afebrile and has mild muscle wasting. Her BMI is 18. Lab studies of the stool show cysts of Cryptosporidium parvum. 1mo later, she develops cryptococcal meningitis, which is treated successfully. Oral candidiasis is diagnosed 1mo later. This patient is at greatest risk of developing which of the following neoplasms? Intestinal nonHodgkin lymphoma.

Figure: Progression of HIV Kaposis sarcoma. Dont exactly know how it works. AIDS Infections 80% of AIDS patients die due to opportunistic infections (and wasting) 90% have Candida; 50% have Pneumocystis; 40% have MAI; 30% have CMV; 10% have Cryptococcus In Indianapolis 25-50% of AIDS patients have active Histoplasmosis before they die Opportunistic Infections in AIDS Candida albicans CMV (Cytomegallovirus) Pneumocystis (jirovecii) carinii Cryptosporidium Toxoplasma gondii Histoplasma capsulatum Mycobacterium avium (MAI) multifocal leukoencephalopathy (JC Virus) Cryptococcus neoformans Coccidioides immitis (desert southwest) Human Papillomavirus Herpes virus Treponema pallidum Kaposi sarcoma HHV-8) Progressive

Above: Oral candidiasis (usually candida albicans): although CD4 count may look good, may need to increase HAART therapy because patient should not be getting thrush.

Above: Candida in the blood disseminated candida. Look like linksausages.

Above: Most common life-threatening infection that AIDS patients get. Candida is most common infection (non lifethreatening).

Test q: In Pneumocystis jirovecii infections of human lungs: macrophages undergo apoptosis

Cyst dot/groove in the middle. Can look all folded up like this.

Above: Spleen from HIV-infected patient. Disseminated mycobacterial infection gray/white nodules are colonies of mycobacterium avium.

Above: All macrophages stuffed full of acid-fast bacteria.

Above: Infection of eyes/lungs is common. Normal pneumocytes and much larger infected cells. Cytomegalic inclusion disease caused by CMV. Cells are big; dark spot in nucleus is the inclusion. Owls eye.

Above: Looks hypercellular not just filled w/inflammatory and mesangial cells. Also has dots surrounded by halos represents Cryptococcus neoformans.

Above: GMS Stain- Cryptococcus neoformans in a chest wall biopsy. Always has clear space encapsulated.

Above: India Ink preparation of Cryptococcus neoformans in CSF. Note halos.

Above: Coccidiodes immitis. California/Arizona more common. Spherule is 10x bigger than RBC.

Above: Silver Stain of H. capsulatum

Above: Disseminated histoplasmosis (in blood). Can see macrophage dark area is nucleus. All surrounding dots are the yeast.

Above: Parasitic infection common in AIDS patients tiny dots on surface of small intestine = cryptosporidium. AIDS patients also tend to get Giardia.

Above: Increased rate of infection w/toxoplasma in AIDS patients.

Above: Syphilis is more common in AIDS patients also can increase risk of contracting AIDS.

Above: Normal cervical epithelial cells around; giant purple cells are herpes-infected cells.

Above: Also increased risk for HPV. Nucleus much bigger in infected cell (koilocytes) also has halo. Above: White material = cervical cancer.

Above: Oral cancer in HIV-infected patient. Also co-infection w/HPV.

Above: Kaposis sarcoma of stomach Above: Kaposis sarcoma: proliferation of endothelial cells w/extravasation of RBCs.

Kaposis Sarcoma and Candida albicans Dark color = Kaposis sarcoma. White colonies on top = candida.
Test q: A 50y/o HIV-infected male has a history of infections by Pneumocystis and Histoplasma. He develops blue-purple nodules on his gingival and gastric mucosa. The patient has probably also been infected by: Human Herpesvirus type 8. Test q: A 37y/o man who is HIV-positive has noticed multiple 0.5-1.2cm plaquelike, reddish purple skin lesions on his face, trunk, and extremities. Some of the larger lesions appear to be nodular. These lesions have appeared over the past 6 months and have slowly enlarged. Molecular analysis of the spindle cells found in these skin lesions is likely to reveal the genome of which of the following viruses? Human herpesvirus-8 REPEATED x2! (In 2009, its #85 and the answer key is wrong. See #53 2006 Human Herpesvirus-8 is the correct answer.)

CONFERENCE: VOCABULARY OF NEOPLASIA Metaplasia METAPLASIA is a reversible change in which one adult cell type is replaced by another adult cell type. Note: the influence that predisposes to change, if persistent, may induce cancer transformation in the metaplastic epithelium. Examples: Columnar-to-squamous (lung, cervix) Squamous-to-columnar (esophagus) Endocervix with squamous metaplasia

Fri. 09/10/10

DYSPLASIA: pre-malignant change Term describing cells that have undergone proliferation and atypical cytologic alterations involving cell size, shape, and organization. In models of neoplasia in many organs dysplasia is an antecedent of malignancy (both in-situ cancers and invasive tumors).

Originally was glandular, but underwent metaplasia.

Above: Uterine cervix showing transition between dysplastic epithelium (right) and nondysplastic epithelium (left).

Above: moderate dysplasia

Carcinoma in-situ (CIS) A preinvasive stage of epithelial malignancy which exhibits the cytologic features of malignancy but has not yet invaded beyond the confines of the native basement membrane. Stage 0 cancer. When dysplasia involves the whole epithelium, it is CIS.
Test q: A 25y/o female is diagnosed w/squamous cell carcinoma in situ of the cervix. Her 5yr survival rate can be estimated at: 100% Test q: A patient is diagnosed as having squamous cell carcinoma in-situ (CIS) of the cervix. With standard treatment for this disease the cure rate is best estimated as: 100% Test q: Following an abnormal Pap smear, a 34y/o woman has a cervical biopsy. This demonstrated marked hyperchromatism and increased nuclear/cytoplasmic ratio of the epithelial cells. These changes involved the full thickness of the epithelium but did not penetrate the basement membrane. These changes are best described as: Carcinoma in situ (CIN III)

Test q: Pap smear from a 29y/o sexually active female shows carcinoma in situ (CIS). Which of the following is consistent w/a diagnosis of CIS? Neoplastic cells fill the entire thickness of the epithelium

Above: Carcinoma In Situ of cervix (CIN III)

Carcinoma In Situ- mitoses throughout the epithelium

Below: Early invasion by squamous cell carcinoma through the basement membrane. Once through the BM, can metastasize because it has access to vessels.

Definitions:

Above: Pap smears. Low grade nuclei are bigger. Moderate nuclei is half the cell size. Severe cells are almost entirely nucleus.

Neoplasia [G. neos, new + G. plasis, a molding]: The pathologic process that results in the formation and growth of a neoplasm. Abnormal growth that continues Neoplasm [neo- + G. plasma, thing formed]: A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change. Sir Rupert Willis
Test q: The most likely biologic course of an untreated benign neoplasm is: slow progressive growth.

-OMA(S) [Greek suffix -oma = tumor] Examples of benign tumors: lipoma, fibroma, angioma, leiomyoma, rhabdomyoma, Schwannoma, neuroma, hepatoma. Many neoplasms end in oma. Can be malignant or benign. Malignant can metastisize; invasive. Benign does not pass through BM, does not pass through lymphatics and spread to distant organs, just get bigger.
Test q: The most important single characteristic that distinguishes malignant neoplasms from benign neoplasm is: tendency to invade & metastasize.

Adenoma [G. aden, gland + -oma] A term applied to benign epithelial neoplasms that form glands, as well as to the tumors derived from glands but not necessarily reproducing glandular patterns. Examples: cystadenoma, papillary cystadenoma, fibroadenoma. Polyps in colon = adenoma. Malignant Neoplasms with oma: Carcinoma, sarcoma, lymphoma, melanoma, mesothelioma, glioma. (So oma does NOT = benign.) Teratoma: Tumor with components from 2 or 3 germ cell layers. (Some epithelial, some mesenchymal, some neural tumor all making up the same tumor.) Ovary- usually benign. Can contain hair. Testis- usually malignant (in adults) Ovarian
Test q: A 32y/o woman has experienced dull pelvic pain for the past 2mo. Phys exam shows a right adrenal mass. An abdominal ultrasound scan shows a 7.5cm cystic ovarian mass. The mass is surgically excised. The surface of the mass is smooth, and it is nonadherent to surrounding pelvic structures. On gross exam, the mass is cystic and filled with hair. Microscopically, there is squamous epithelium, tall columnar glandular epithelium, cartilage, and fibrous connective tissue present. Which of the following is the most likely diagnosis? Teratoma

Testicular

Tumors of Mesenchymal Origin: BENIGN MALIGNANT (sarcomas) Fibroma Fibrosarcoma Lipoma Liposarcoma Osteoma Osteosarcoma (osteogenic sarcoma) Figure: Malignant tumor of the small intestine mesenchymal tumor. Mesenchymal = connective tissue. These are grayish-white, just like scars. Golden-yellow tumors are usually glandular.

Above: Teratoma. Arrow indicates neural tissue; benign here, but sometimes malignant

Tumors of Muscle Origin: BENIGN Leiomyoma Rhabdomyoma

MALIGNANT Leiomyosarcoma Rhabdomyosarcoma

Smooth muscle and striated muscle both have benign and malignant counterparts.
Figure: Smooth muscle tumors of the myometrium Can have leiomyoma (benign) or leiomyosarcome (malignant). Malignant tumors big, rapidly growing, and very irregular. Irregular at the edges because they are invading. Benign small, welldemarcated, slow-growing.
Test q: Which of the following is a malignant neoplasm arising from smooth muscle? Leiomyosarcoma.

Below: Leiyomyoma. Smooth muscle tumor.

Above: Benign leiyomyoma occupies most of the wall

Above: Benign smooth muscle of a leiomyoma

Tumors of Epithelial Origin (Carcinomas): BENIGN Squamous cell papilloma Adenoma Tubular adenoma (adenomatous polyp) Fibroadenoma- breast

MALIGNANT Squamous cell carcinoma Adenocarcinoma Colon carcinoma (adenocarcinoma) Adenocarcinoma, (Ductal carcinoma)

Figure: Multiple adenomatous polyps. Seen in famlial polyposis. Each polyp is an adenoma, and each has the potential to become malignant. Some benign tumors have malignant potential (1/1000), some do not. In the wall of the uterus, they do not usually have this potential.

Above: Adenocarcinoma of colon

Above: Invasive adenocarcinoma of colon. Glands are back-to-back, grow into each other.

Anaplasia = MALIGNANT Anaplasia = Lack of differentiation = undifferentiated Atypical-looking. Anaplasia is considered a hallmark of malignant transformation. Anaplastic features include: - Cellular/nuclear pleomorphism - Increased nuclear-cytoplasmic (N/C) ratio - Nuclear hyperchromasia (increased DNA content) - Large nucleoli - Just interested in reproducing, so more nuclear material. Large, active, rapidly-replicating. - In contrast, benign tumors tend to look like cell of origin (ex: leiyomyoma). Above: Anaplastic rhabdomyosarcoma. Generally, all benign tumors are well-differentiated Malignant tumor of skeletal muscle. Does not Malignant neoplasms, in contrast, range from welllook like glands, squamous tissue just looks differentiated to undifferentiated anaplastic (poorly differentiated). High grade Well, moderately well, and undifferentiated (poorly tumor synonym. differentiated or anaplastic) Grade 1, 2, or 3 (or I, II, III) with 3 the least differentiated The more the tumor looks like the tissue of origin, the better it is (less invasive). Grade I tumor that is not very aggressive, looks like the cell of origin. Grade III anaplastic, more aggressive Grade II is in between.

Other Histologic Features of Malignant Neoplasms - Increased/atypical mitotic activity - Tumor giant cells - Abnormal architecture- sheets or masses of tumor cells growing in an anarchic, disorganized fashion with infiltration and destruction of normal tissues.
Figure: Anaplastic tumor with tripolar mitosis. Atypical. Never see tripolar mitosis in benign cell.
Test q: A 50y/o female undergoes an abdominal hysterectomy after 1yr of abnormal uterine bleeding. An irreg mass in the myometrium measuring 10cm in diameter is identified. Histopathology shows spindled cells w/large, bizarre nuclei, prominent nucleoli, and many mitoses. Tripolar mitoses are seen. The most likely diagnosis is: leiomyosarcoma.

Carcinoma - Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas. - Examples of modifiers include: Squamous cell carcinoma, Adenocarcinoma, Renal cell carcinoma
Figure: Bronchogenic carcinoma of the lung. Comes from the bronchus. Tend to be adenocarcinomas or squamous cell carcinomas. Sometimes small cell carcinoma. Do not see sarcomas here.

See pearls in the skin all the time squamous carcinoma (below)

Above: Arrow indicates keratin pearl

Above: Squamous cell carcinoma with squamous pearls (SP)

Above: intercellular bridges.

Above: Pap Stain on sputum cytology: keratinized squamous cell carcinoma. Huge nuclei, pink material is keratin.

Above: Metastatic adenocarcinoma: immunohistochemistry + for thyroid. Immunoperoxidase stain for thyroglobulin tells us its adenocarcinoma that originated in thyroid.

Sarcoma Cancers arising within mesenchymal tissue are called sarcomas. Examples of modifiers include: - leiomyosarcoma - osteosarcoma - fibrosarcoma Figures: Osteogenic Sarcoma (osteosarcoma) Tumors continue to make osteoid often not mineralized. In histological stain, can see malignant osteoblasts all around. All osteosarcomas are highgrade, aggressive lesions. Grading them is not useful. Differentiation: Differentiation refers to the extent to which parenchymal cells resemble comparable normal cells, both morphologically and functionally. (Opposite of anaplastic) Differentiation and Tissue of Origin - A general rule is that neoplasms differentiate in the direction of their parent tissue. - Consider: Transitional cell carcinoma of the urinary bladder is more common than squamous cell carcinoma and adenocarcinoma in this site. Conversely, transitional cell carcinoma arising in the ovary and uterine cervix is quite unusual, though may occur. Figure: Metastatic tumors do not always look the same as the primary tumor.

Additional Concepts Rate of Growth - In general, the growth rate of tumors correlates with their level of diffferentiation, and thus most malignant tumors grow more rapidly than do benign lesions. High grade malignant tumors (Grade 3) are more aggressive Local Invasion - Most benign tumors are well circumscribed, while cancers grow by progressive infiltration, invasion, and destruction of the surrounding tissue. GRADING TUMORS - Malignant tumors only - Degree of differentiation and mitotic rate - Grades I-IV (higher grades are more anaplastic) - Important for some tumors: breast, prostate, endometrium, astocytomas - Dysplasias of the cervix are graded - Grading is done by Pathologists - Stage is more important than grade. STAGING TUMORS - How far has the tumor spread? - Malignant tumors only - Based on tumor size (T), lymph node involvement (N), distant metastases (M) - Staging often involves: the Pathologist, radiology or other imaging, lab tests (tumor markers) - CIS is often referred to as Stage Zero

Pathways of Spread - Seeding of Body Cavities and Surfaces: carcinoma, mesothelioma, and thymoma - Lymphatic Spread: initial route of spread for carcinomas - Hematogenous Spread: utilized by sarcomas and carcinomas Fibroadenoma of Breast most common tumor of the breast - Benign - No invasion - No metastasis - Small, no irregular borders, well-circumscribed
Mammogram with carcinoma. Dense, white, fingers projecting out, locally invading.

Benign ducts of a fibroadenoma

Benign ducts of fibroadenoma

Sometimes ducts will get squeezed down classic look of a fibroadenoma.

Above: Invasive Ductal Carcinoma

Ductal Carcinoma In Situ Replicating inside the duct but havent broken through the basement membrane. 100% curable. Figure: Breast carcinoma CIS lesion w/breast cancer infiltrating through the stroma.

BREAST CARCINOMA GRADING Bloom and Richardson - Tubules present (1-3 points) - Nuclear atypia (1-3 points) - Mitoses (1-3 points) - Total score 3-5: Grade I - Total score 6,7: Grade II - Total score 8,9: Grade III

BREAST CARCINOMA STAGING - Stage 0 (in situ or CIS): 5-year 92% - Stage I. (<2 cm & LN-): 5-year 87% - Stage II. (2-5 cm & 0-3 LN+): 5-year 75% - *Stage III. (>5 cm & >4 LN+): 5-year 46% - Stage IV. Distant metastases: 5-year 13%

Grade 1 Well differentiated: Tubules; Small nuclei; No/few mitoses

Grade 2 Moderately differentiated. Rare tubules/ solid nests. Pleomorphic nuclei

Grade 3 Poorly differentiated: No tubules; pleomorphic. Many mitoses

BREAST CARCINOMA (OTHER) - Estrogen receptor (+): tumor is stimulated by estrogen and can be treated with the anti-estrogen tamoxifen. This is palliation. - HER-2 Neu amplification: by immunostaining or FISH. If HER-2 Neu is amplified in the tumor, the patient can be treated with Herceptin. This is very expensive and tends to be used in high grade/high stage lesions that are HER-2 Neu positive.

Vascular invasion by invasive ductal carcinoma

Above: ER (+). Estrogen receptors present. Can treat w/Tamoxifen.

Above: HER-2 Neu (+) Stains the cell membrane/cytoplasm. Can treat w/Herceptin.

Test q: A 50y/o woman saw her physician after noticing a mass in the right breast. Physical exam showed a 2cm mass fixed to the underlying tissues and three firm, nontender, lymph nodes palpable in the right axilla. There was no family history of cancer. An excisional breast biopsy was performed, and microscopic exam showed a well-differentiated ductal carcinoma. Over the next 6mo, additional lymph nodes became enlarged, and CT scans showed nodules in the lung, liver and brain. The patient died 9mo after diagnosis. Which of the following molecular abnormalities is most likely to be found in this setting? Amplification of the c-erb B2 (HER2) gene in breast cancer cells REPEATED x5!! (Once, answer was Amplification of the ERBB2 (HER2) gene) Test q: A 38y/o female has a left breast lumpectomy. A mass which measures cm in greatest diameter is excised as are two sentinel lymph nodes from the left axilla. The tumor consists of well-formed glands (tubules), exhibits no mitoses and has no nucleoli. The ductal adenocarcinoma is focally invasive and there is minimal desmoplasia. Both lymph nodes are negative for adenocarcinoma and there is no evidence of distant metastases in liver, lung, or bone. Special stains for Estrogen Receptor (ER) and Her-2 Neu are totally negative. The grade of this tumor is: I The treatment plan for this patient will include: neither tamoxifen nor herceptin Test q: A mass is biopsied from the left breast of a 42y/o female. Invasive ductal carcinoma is present. All tumor cells are present as round glands. Mitoses and nucleoli are absent. This tumor can be described as: low grade. (Other choices: anaplastic, undifferentiated, hamartoma, CIS) Test q: A mass was removed from the breast of a 46y/o female. The surgery performed was a lumpectomy w/axillary tail dissection (to look for metastatic disease in lymph nodes). The tumor measured 5.4cm in greatest diameter. Stromal invasion was extensive and desmoplasia was identified. 3-4 mitoses were present in every high-power field. Gland/tubule formation was not present and most of the tumor showed sheets and nests of undifferentiated malignant cells w/prominent nucleoli and irregular chromatin clumping. 15 lymph nodes were harvested from the axillary tail and 6/15 were positive for adenocarcinoma. 3 of the positive nodes were matted together and fixed (surrounded by fibrosis) to the surrounding soft tissue. Staining for estrogen receptors was entirely negative. Staining for Her2-Neu showed strongly positive cytoplasmic and membrane staining in 90% of the tumor cells. There was no clinical evidence of distant metastases. - An accurate grade for this tumor would be: Bloom and Richardson Grade III. - Additional treatment for this patient would include: Herceptin. Test q: A 42y/o female has a 5.0cm tumor removed (lumpectomy) from her right breast. 2 senitel lymph nodes are negative for tumor. Histologically, the tumor is anaplastic and shows no tubules or ducts, approx 25% of the tumor cells exhibit mitoses, and the nuclei are pleomorphic w/prominent nucleoli and irreg nuclear membranes. These features are consistent w/a Scarff Bloom Richardson grade of: III.

COLON CANCER - Grading is not very helpful - STAGING: predicts clinical outcome (TNM) - No penetration of the muscularis mucosa (Tis); 100% cure rate - Penetration of muscularis propria (and maybe serosa too) but lymph nodes negative (T3); 70% cure rate - 1-3 (+) lymph nodes (N1); 30% cure rate - Distant metastases (M1); rare cures - 50% of colorectal carcinomas show ras mutations; 50% of adenomas > 1cm also show ras mutations - CEA (carcinoembryonic Ag) can be used to follow patients after surgery Test q: CEA is used to follow patients w/cancer of
the: colon.

Deeply infiltrating tumors cause desmoplasia (fibrosis) and apple core/ napkin-ring appearance. Desmoplasia is also seen in breast carcinoma Polyp 1/1000 chance for malignancy. With FAP: have thousands of polyps = 100% chance of getting cancer.

Test q: A 50y/o man w/a history of colon cancer undergoes a segmental resection of a dysplastic polyp in the transverse colon. The polyp shows focal adenocarcinoma (<0.2cm diameter) in the tip but there is no invasion of the stalk nor penetration of the muscularis mucosa. 5 lymph nodes from the surrounding fat are free of tumor and the liver appears normal at surgery. The clinical stage of this neoplasm is: TisN0M0.

Adenoma: Crowded glands but no atypia. (Polyp in colon.)

Above: Polyp. Pre-malignant changes (nuclei darker, bigger, more hyperchromatic)

Adenomatous polyps

Molecular model for colorectal adenocarcinoma: Any time you have cancer, you have had multiple abnormal changes. Usually, at least four major molecular changes.

Metastisis can occur through direct contact or transport by vessels, nerves, lymphatics.

Above: TMN Staging System

Colon adenocarcinoma

Metastases: Metastases are tumor implants discontinuous with the primary tumor. *METASTASIS unequivocally marks a tumor as malignant because benign neoplasms do not metastasize.

Liver w/metastatic carcinoma

Metastatic melanoma in liver and bone marrow

Other Terms: - Choristoma: An ectopic rest of normal tissue. Normal tissue in an abnormal location. Examples include glial tissue in the tongue, breast tissue in the milk line, nodules of pancreas in the small bowel, and adrenal rests in the uterine broad ligament or spermatic cord. - Hamartoma: Mass of disorganized but mature specialized cells or tissue indigenous to the particular site. Hamartoma of lung is classically a mass of benign cartilage with or without, blood vessels, adipose tissue, etc. Hemangiomas are also called hamartomas. ex: birthmarks.