56 y/o white female with 4 hours of neck pain, SOB and diaphoresis Figure: Crystal = where lipid/cholesterol used

d to be. Wall inflammatory repair plus deposition of lipids (cannot be removed because patient does not have enough HDL).

Myocardial Infarction Markers - Cardiac specific enzymes and proteins in 2 hours - Morphologic (light microscopic) changes in 4-12 hours What drug therapy should the patient receive in the ER? A. t-PA B. Aspirin C. Heparin D. Nitric oxide E. Vitamin K t-PA can break up the clot quickly and actively. Aspirin is helpful, but hopefully patient took it beforehand.
Test q: When is a patient who has suffered an acute MI at greatest risk for fatal arrhythmias? Days 1-3. Test q: When is a MI patient at greatest risk for fatal arrhythmias? Days 1-3. Test q: A 76y/o man presents to the ER w/progressive substernal chest pain over the past 4 hr. He is short of breath and reports pain in his left jaw and shoulder area. An initial ECG demonstrates ST elevation changes and a baseline troponin I level of 2.8ng/mL. Which of the following complications are you most concerned about occurring in this patient within the next 24hr? Ventricular arrhythmia.

When is the patient at greatest risk for fatal arrhythmias? A. Days 1-3 B. Days 5-7 C. After 2 weeks D. After 4 weeks E. After 1 year

Coagulative necrosis: 4-5hr muscle is gone, no acute inflammation:

Presence of neutrophils: 12-24 hours or longer

When is the patient at greatest risk for perforation (rupture) of the left ventricle? A. Days 1-3 B. Days 5-10 C. 2 weeks D. 4 weeks E. 1 year Day 7, so B. All the muscle is gone, no collagen scar heart is at its weakest. Figure: MI Day 7. Can see spindle-shaped cells, fibroblasts, lots of plasma cells and macrophages, few PMNs, early capillaries growing in. Extremely weak apt to form aneurysm or perforate.

More on Markers: Troponin I Is a specific indicator of MI Appears 4-6 hours post infarction, maybe not until 12 hours Peaks at 16 hours and decrease in 9-10 days. CK-MB MB fraction is specific for cardiac muscle, esp when there is no skeletal muscle damage in patient's history Appears to rise 4-6 hours post MI Not elevated in all patients until 12 hours post MI Level returns to baseline in 36-48 hours Myoglobin Elevates within 1-4 hours, most sensitive during early time period Lacks specificity BNP (marker for CHF) Beta natriuretic peptide is the active product of a split prohormone in response to atrial or ventricular wall stretch. In this case it is a response to the acute congestive heart failure secondary to acute myocardial infarction. <100 pg/mL CHF very unlikely 100-400 pg/mL indeterminate >400 CHF likely (MI survivors are likely to develop heart failure) Six weeks post-MI, this 56-y.o. male has chest pain, SOB, precordial friction rub. He dies within days. The cause of the pathology (photo) is? A. Granulomatous inflammation B. Dresslers syndrome C. Metastatic carcinoma D. Ruptured LV E. Viral infection Friction rub pericarditis autoimmune reaction Dresslers syndrome. Can see bread-and-butter appearance

Apoptosis: Cells activate enzymes that degrade DNA and proteins (ATP/energy-dependent); cell membrane remains intact; organelles are intact; NO INFLAMMATION. Necrosis: Cell membrane ruptures; organelles rupture; enzymatic digestion of the cell; inflammation Apoptosis is important in neoplasia and infectious disease. If apoptosis is intact, tumor cells die. If you have things that prevent apoptosis from occurring, will promote neoplasia and favor infection.

Apoptosis is common in neutrophils usually die after several hours. Also seen in Lichen Planus.

Above: intrinsic and extrinsic pathways of apoptosis. Sometimes receptors on the cell can trigger apoptosis Defective Apoptosis: Tumors with p53 mutations Follicular lymphomas express high levels of bcl-2 (translocation of bcl-2 gene) HPV- protein E6 binds and inactivates p53 EBV- proteins that mimic or increase production of bcl-2 Autoimmune disorders Sensitivity, specificity and predictive value: Screening tests Confirmatory tests Prevalence and predictive value

Given the photo, what enzyme abnormality would you expect? A. Increased alkaline phosphatase B. Decreased alkaline phosphatase C. Decreased gamma GT D. Markedly increased AST and ALT E. Decreased direct bilirubin Answer: A, increased AP: The photos show a gallbladder with stones and a large stone in the common bile duct. AP is made by the cells lining the bile canaliculi. During obstruction bile enters the lining cells and damages cell membranes, releasing AP. The yellow area represents galbladder adenocarcinoma

The PAP smear labeled B suggests: A. Herpes virus infection B. Human papillomavirus infection C. CMV infection D. Carcinoma insitu E. Invasive cervical cancer Answer: B, HPV infection. Koilocytes are present c/w a low grade dysplasia (LGSIL) Dysplasia: Atypical proliferative changes due to chronic irritation or inflammation; PREMALIGNANT CHANGE Metaplasia: A REVERSIBLE change in which one ADULT cell type is replaced by another ADULT cell type.

Above: Pap smear. B will be HPV and probably low-grade lesion because nucleus is not very big. C moderate dysplasia. D severe dysplasia. Note nucleus:cell ratio to help tell them apart

Above: Cervical dysplasia. Normal the only dark blue cells are down at the bottom. Low-grade dysplasia: goes up halfway. As it gets higher and higher, dysplastic cells fill more and more of the epithelium. CIN III carcinoma in situ.

The architecture of this bladder tumor can be described as: A. Mucinous B. Squamous C. Sarcomatous D. Papillary E. Signet ring cell Papillary tumor = finger-like or Hawaiian island-like (if cross section).
Here, can see finger-like projections

Answer: D, papillary Finger-like. In this case a papillary transitional cell carcinoma.

These endocervical biopsies show: A. Glandular metaplasia B. Squamous metaplasia C. CIS D. Invasive squamous cell carcinoma E. Invasive adenocarcinoma Answer: B, squamous metaplasia The endocervical glands have columnar epithelium. At early ages the female endocervix also has a columnar surface. With age, sexual activity, childbirth etc a mature squamous epithelium replaces the glandular epithelium.

This brain tumor superficially invades bone, but not brain tissue. Name the tumor. A. Glioblastoma multiforme/astrocytoma grade IV B. Meningioma C. Metastatic lung CA D. Metastatic breast CA E. Metastatic melanoma Psamomma bodies = dystrophic calcification (pictured in stained section below). Meningiomas, although benign, could grow into the bone. Will not spread to brain, etc. only invades via expansion. Answer: B, meningioma. There is no invasion of the brain parenchyma. The tumor is well demarcated but can kill by compression of the brain. It can locally invade bone, but does not metastasize.
The following two test qs can be answered using the lab manual Neoplasia III session: Test q: Meningiomas are differentiated from Schwannomas by the presence of: Psammoma bodies Test q: A 45y/o male is seen by an ear, nose, and throat specialist for unilateral tinnitus and hearing loss. A neoplasm associated w/this clinical history is: Schwannoma.

Psamomma bodies

This cut-section of liver is c/w: A. Congestionn B. Cirrhosis C. Hepatitis D. Metastasis Answer: D, metastases The tumor nodules are diffuse (not a primary) and are too big to be cirrhotic nodules- there is also an absence of white connective tissue. Multiple nodules of variable sizes metastatic disease.

Big and yellow or orange. If fixed, may be pale.

Triglycerides push nucleus off to the side in fatty change.

Oil Red O Stain for fatty change

Brick red liver answer will either be hemosiderosis (iron in Kuppfer cells) or hemochromatosis (iron in hepatocytes).

Iron in parenchymal cells of pancreas. Patient may be diabetic.

Bile looks brown in H&E like iron except smudgy rather than granular.

CONSISTENCY: Organs become stiff, hard, soft, waxy or greasy in disease Alcoholism or hepatitis cause extensive fibrosis (scar tissue) in the liver and the liver is pale, shrunken and firm with round NODULES (firm, circumscribed areas) These photos of uterus are c/w: A. Leiomyoma B. Leiomyosarcoma C. Endometrial adenocarcinoma D. Squamous cell carcinoma of cervix Answer: A, leiomyoma Leiomyosarcomas are bigger, necrotic and often have areas of hemorrhage- and they are rare. The tumor arises in the myometrium (smooth muscle) This H & E section of colon is c/w A. Adenoma B. Fibroadenoma C. Cyst D. Bulla Answer: A, adenoma. POLYP = precursor for adenocarcinoma. Tubular adenoma and adenomatous polyp are synonyms. Well-circumscribed nodular tumors:

Cancer Precursor Lesions Adenomatous polyp Actinic keratosis Hyperpl./breast Ulcerative Colitis Endom. Hyperplasia Esoph. Metaplasia (Barretts) Gastric metaplasia (Helicobacter) Cirrhosis

Colon AdenoCA SC SA Ductal CA Adeno CA colon Adeno CA endom. Esoph. Adeno CA Gastric Adeno CA/lymphoma Adeno CA liver

Below: TNM Staging System.

METASTASIS: LIVER: (portal circulation) GI tract and pancreas; lung, breast, melanomas LUNG: breast, stomach, sarcomas, renal cell carcinoma (vena caval system) rd BONE: 3 most frequent site for metastases; lung, breast, prostate, kidney, thyroid; PROSTATE to bone gives osteoblastic lesions on Xray (more dense) and high serum alkaline phosphatase ADRENAL: most common endocrine site Metastasis #1 marker of malignancy. If that is not an option, look for invasiveness. Exceptions: gliomas (astrocytomas) of the brain and basal cell carcinomas of the skin RARELY metastasize; also, meningiomas LOCALLY invade skull bone, but do not metastasize and are considered benign. Venous Drainage Portal: liver Caval: lungs Paravertebral plexus: thyroid and prostate carcinomas metastasize to the vertebrae. Colon cancer can present as brain met w/no mets in liver or lung. Renal Cell CA: invades renal vein and grows in the vena cava

Steps in Metastasis: Cell must break apart break through basement membrane and ECM through wall of blood vessel must survive in blood vessel must exit the blood vessel, attach, reenter the ECM. Once there, must establish a new blood supply. Difficult. So out of every 100,000 tumor cells that are potentially metastatic, only 1 or 2 actually make it. If a tumor has an overexpression of cadherins, it will be less likely to metastasize because the cells cannot break apart. If cadherin is underexpressed, will be more likely to metastasize. If there are increased laminin receptors, also more likely to metastasize.

Different kinds of lung carcinoma:

If making keratin pearls SCC. If making glands adenoCA. If there are large cells w/no differentiation = large cell CA. If there are small cells w/no differentiation = small cell CA. All are treated differently Small cell chemo ALWAYS, no surgical option. For the others, staging is critical. Could do surgery, radiation, chemo.

Well-differentiated if exhibition of squamous pearls and/or intercellular bridges. These H&E sections of breast nipple suggest: A. Melanoma B. Underlying adenocarcinoma C. Underlying squamous cell carcinoma D. HPV infection E. Marked epithelial dysplasia Answer: B, Pagets Disease Pagets disease of nipple (usually crusty or scaly on clinical exam) represents an adenocarcinoma in the breast tissue that has grown up the lactiferous ducts. The underlying carcinoma may be intraductal or invasive. How do you know it is NOT a melanoma? It is the nipple, so first choice will always be Pagets disease. Can do special stains if deciding between melanoma and adenocarcinoma, can do mucin stain adenocarcinoma is mucin +, melanoma is mucin -. Can also do melanoma stain. Most of the change that occurs in the breast occurs in terminal ducts. Lobule is a collection of ducts (only in female breast).

Above: Poorly differentiated.

Above: Proliferation of fibrous tissue (see fibroblasts) also shows proliferation of benign ducts (so adenoma). Fibroadenomas are benign.

Gland-in-gland appearance: cribbiforming.

What is the grade of this breast adenocarcinoma: A. I B. II C. III D. T1 E. T2 A, Grade I. T1 and T2 are staging, so not D or E. Grading is what it looks like staging is how far it has spread. Can see that most of the tumor exists as well-formed glands, no mitoses evident. No nuclear atypia. Welldifferentiated adenocarcinoma. Remember: Architecture (glands) 1-3. Mitoses 1-3. Nuclear pleomorphism 1-3. For this one, glands = 1. Mitoses = 1. Nuclear atypia/nucleoli = 1. Stage the tumor: The word tumor tells us that it is invasive. A. T0N0M0 Tumor is 1.1cm in diameter (<2cm, so T1) B. T0N1M0 1 of 4 sentinel lymph nodes are positive, so N1 C. T1N1M0 No evidence of liver or bone mets, so M0. D. T1N1M1 Answer: C, T1N1M0. E. T2N1Mx T0 = in situ, would not see lymph node involvement Inflammatory carcinomas of the breast show: A. Neutrophils in malignant ducts B. Lymphocytes in malignant ducts C. Pagets Disease D. Lymphatic invasion E. Liver metastases Figure: Can see lots of fibrosis. Fibrosis accompanying invasive tumor = desmoplasia.

In inflammatory carcinomas of the breast, tumor invades and blocks the lymphatics. Test q: Inflammatory carcinomas of the breast exhibit: lymphatic invasion by tumor How do we test for HER-2-neu overexpression? A. Mucin stain B. counting mitoses C. FISH D. Flow cytometry E. Gene sequencing C, fluorescence in situ hybridization. FISH is more accurate than immunohistochemistry. Testing at IU is in Medical Genetics Normal patient

Above: immunohistochemistry for HER2/neu. Usually used in conjunction w/FISH. Note in FISH picture above that the red = overexpression.

Which of the following breast cancers has the WORST prognosis? A. Invasive ductal carcinoma B. Tubular carcinoma C. Medullary carcinoma D. Mucinous (colloid) carcinoma
(This was a test q!)

Answer: A. Tubular is aka well-differentiated adenocarcinoma. Medullary and mucinous carcinomas tend to grow rapidly, have more volume, diagnosed sooner. All have a better prognosis than invasive ductal carcinoma.

Above: INDIAN FILING. If you see a picture of cell lining up w/nucleoli think breast cancer, and more specifically lobular.

Targeted Therapy: Signal-transduction Inhibitors Block enzymes and Growth Factor Receptors GLEEVEC - GIST and CML (abnormal tumor enzymes); IRESSAnon-small-cell lung cancer (EGFR) C-kit is the abnormal protein in GIST Target: Monoclonal Antibodies Herceptin - invasive breast carcinomas (that show overexpression of HER-2-neu) Generic names: Gleevec = Imantinib. Herceptin = Trastuzumab.

What is a diagnostic test for amyloid? A. Prussian blue B. Oil Red O C. Sudan black D. Congo red E. Congo red with polarization E will see apple green birefringence (pictured) Amyloid: 15 types- 3 major AL (light chain); Ig light chains AA (amyloid associated); liver product A-beta (amyloid in Alzheimer) And beta-2-microglobulin (dialysis) All are beta-pleated sheet proteins and all stain with Congo Red

What type of hypersensitivity reaction is acute rheumatic fever? A. I B. II C. III D. IV E. II and IV

The original insult (cross-reacting antibodies) is a type II, but what we see is a granuloma in tissue (seems like IV). WILL NOT BE ASKED because its controversial.

Rheumatic Heart Disease Acute rheumatic fever follows Streptococcus pyogenes pharyngitis Antibodies vs. M-protein of the bacterium cross-react with glycoprotein antigens in the heart Pancarditis involves all 3 layers of the heart. Esp. mitral, then aortic Fibrinous pericarditis Deformed valves subject to endocarditis due to alpha-streptococci (streptococcus viridans) endocarditis is NOT during the rheumatic fever appears later in life when the patient gets infected by other organisms. Will see Aschoff bodies in the myocardium collection of macrophages, sometimes called granulomas. Will get fibrinous pericarditis (bread-and-butter)

Aschoff bodies.

Malformed heart valves (mitral most common, then aortic)

Endocarditis.

What tumor markers are useful in management of colon cancer? A. CEA is used to monitor tumor recurrence B. CEA is used as a screening test for colon cancer C. CEA is used as a confirmation test if the test for occult blood is positive D. High PSA in serum is diagnostic E. High AFP in serum is diagnostic
(This was a test q!)

Answer: A, used to monitor tumor recurrence. CEA is not specific for colon cancer and not a sensitive test. CEA levels are determined pre- and post-surgery. The CEA level should fall to near zero. If the level falls and then increases, the patient may receive chemotherapy for the recurrence. NOT used as a diagnostic test. Tumor Markers: Management Detection (staging) Diagnosis (screening) PSA (prostate-specific antigen specificity is really bad lots of false negatives) CA 125 (marker for ovarian cancer, even worse than PSA) Markers CEA- colon, pancreas, stomach, lung, breast, (19% smokers, 3% gen. pop.) AFP- hepatocellular, germ cell (>500ng/ml) CA 125- 80% non-mucinous ovarian CA CA 19-9- pancreatic CA (80%) PSA- (0-4 ng/ml normal) (>10 ng/ml highly suspicious); also AlkPhos elevation in prostate CA assoc. with bone metastasis (osteoblastic) HCG- gestational trophoblastic tumors, testicular tumors

A 31y/o AIDS patient in the crisis phase has a BAL (bronchoalveolar lavage). The Giemsa and GMS stains are c/w: A. Blastomyces dermatitidis B. Candida albicans C. Coccidioides immitis D. Histoplasma capsulatum E. Mycobacterium avium On Giemsa stain, can see macrophage, nucleus of the macrophage, and budding yeast. On silver stain, can see tiny budding yeast.

Giemsa stain.

Silver stain

Answer: D, Histoplasma Capsulatum. The Giemsa and GMS show small, intracellular yeasts. If you look at the Giemsa, you can see that the yeasts are smaller than RBCs and thus about 2-3 microns in diameter. 25-50% of the AIDS patients in Indy get H. capsulatum infections

Biopsy and BAL from an AIDS patient: Diagnosis? Pneumocystis Pneumonia. H&E stain of tissue shows glassy pink alveolar contents. GMS (silver) stain of tissue shows cysts can see dots/grooves in them, but they are not budding. BAL fluid shows 8 trophozoites on Giemsa stain

Giemsa stain

H&E

GMS (silver) stain

HIV Remember that in the beginning of HIV infection, CD4 count is high and RNA viral load is also high. For several years, the viral load will drop down to very low levels, the CD4 count will progressively drop, and when you get to have a CD4 count of <200, that defines the patient as having AIDS. It also defines them as being in the crisis phase of AIDS at this point, they are susceptible to opportunistic infections. We follow the CD4 count, but it is more important to follow the viral load (better predictor than CD4 count). Count the number of virus copies, and when it gets up to 50-100k, they are also in the crisis phase. Typically, in crisis phase, they have a CD4 count <200 and a viral load approaching 100,000 can get very sick. Can be prevented w/HAART therapy keep CD4 count higher and viral load lower. Result Interpretation: Rapid test. 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. Sensitivity very good, specificity not. Not diagnosed until confirmed w/Western Blot.

Early HIV: Virus has affinity for macrophages and dendritic cells (APCs). Middle HIV: macrophages and lymphocytes Crisis/Late: Affinity for CD4 lymphocytes Macrophages and HIV: - Provide a site to maintain the infection when the CD4 count is very low. - Provide a route of infection for the brain.

Which of the following is poorly differentiated? Answer: C&D. C is small cell undifferentiated carcinoma (oat cell). D is large cell undifferentiated (either a squamous or adeno carcinoma)

Small cell, undifferentiated always metastatic, always treated w/chemotherapy. Large cell stage it. Three treatment options: surgery, chemo, radiation.

D
Anaplastic rhabdomyosarcoma. No resemblance to cell of origin. Large cells, bizarre nuclei, mitoses present.

The Rest Here are all of the leftover test questions that I couldnt find the right spot for Some of them may not be relevant anymore (since the tests date back to 2005), but some of them are probably still valid (and I just missed the spot where they should go).
Which of the following groups of patients would be most likely to develop the symptoms of aluminum toxicity: renal failure, Aluminum toxicity is most likely to develop in patient w/which of the following conditions: dialysis patients. If a motor vehicle accident victim w/a breathalyzer ethanol result of 0.24% is transported to a hospital, you would expect the hospital lab ethanol result to be approximately: 240 mg/dL. A 57y/o chronic alcoholic male was diagnosed w/a seizure disorder as a child. He takes the recommended dose of his Phenobarbital but does not stop drinking. Upon multiple repeat trips to his neurologist, the man is always subtherapeutic in his Phenobarbital levels and continues to seize. What hepatocellular organelle has adapted to the excess levels of alcohol and is responsible for the overmetabolism of the seizure medication? Smooth endoplasmic reticulum. A 21y/o female is found unconscious in her bed w/an empty bottle of analgesic pills beside her. She is rushed to the hospital where her stomach is pumped, revealing numerous pill fragments. She regains consciousness and seeks counseling. Three days later she becomes acutely ill w/nausea, vomiting, and scleral icterus. Which molecule has been exhausted allowing for extensive liver damage? Glutathione. A 25y/o female presents w/diarrhea, dysphagia, jaundice, and white transverse lines on the fingernails (Mees lines). What is the most likely diagnosis? Arsenic poisoning. A 52y/o male presents at urology clinic w/hematuria and what appears to be a flank mass. Further workup reveals an elevated hematocrit and hemoglobin. You suspect? Renal cell carcinoma A 68y/o male presents w/weight loss, anorexia, nausea, and constipation. Mucous membranes and sclera are icteric. A 5cm mass is palpated in the RUQ. Bili (tot) = 7.1 mg/dL (<1.0) ALT = 88 U/L (<40 U/L) Bili (d) = 3.4 mg/dL (<.2) AlkPhos = 506 U/L (115 U/L) AST = 102U/L (<40 U/L) gammaGT = 258 U/L (35 U/L) The most likely diagnosis is: Pancreatic adenocarcinoma Test q: A 55y/o man has developed bilateral breast enlargement over the last year. On phys exam, the enlargement is symmetric and is not painful to palpation. There are no masses. The patient is not obese and is not taking any meds. Which of the following underlying conditions best accounts for these findings? Micronodular cirrhosis. Individuals w/xeroderma pigmentosum are at increased risk for melanoma and basal cell carcinoma, but are at greatest risk for which skin tumor? Squamous cell carcinoma A 1y/o female child undergoes treatment of a stage IV S neuroblastoma. The primary tumor is only 1.5cm in diameter. Stage IV S has a very good prognosis and this clinical presentation includes metastases to: liver, skin, bone marrow Which of the following clinical stages of neuroblastoma have the best prognosis: Stage IV S An abdominal mass is discovered when undergoing an appendectomy. The tumor shows ganglia and a few neuroblastoma cells. Identify this tumor: Ganglioneuroblastoma A 2y/o female presents w/a large abdominal mass involving the left kidney. Age is critical in determining the prognosis for this malignant tumor. Histology shows small blue cells and neuropil. What molecular abnormality is associated with this tumor? N-Myc amplification Malignant tumors w/the highest incidence in men and women in the US as of 2009 are __ and __, respectively. Prostate and breast In the US in 2009, the most common malignant tumors in children younger than 15y/o are: leukemia, brain tumors, sarcomas The most common malignancies in children are: hematologic and brain tumors. A 3y/o female is noted to have an abdominal mass by her mother. The child is anemic. Hematuria is NOT present. The surgically resected tumor shows small, round blue cells, primitive tubules, and spindled stroma. This description is most consistent with: Wilms tumor. Which of the following benign tumors represents maturation of a neuroblastoma: ganglioneuroma. Two-thirds of all childhood deaths secondary to cancer are due to tumors of: brain and white blood cells A group of moms have a pox party to expose their children to chicken pox. Based on current literature, these children will be at increased risk when they are adults for: diabetes mellitus. A 14y/o male develops insulin dependent diabetes mellitus. His family reports that he received a vaccination for measles and rubella but acquired chickenpox naturally at a pox party. He currently has a cold and had strep throat last year. Which exposure is most likely associated w/development of insulin dependent diabetes mellitus? Varicella Anti-tRNA-synthetase (Jo-1) antibodies are most often associated with: Polymyositis/dermatomyositis

GOOD LUCK!