Pathology Week 6 p36-49

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

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

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.

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. – 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. Dressler’s syndrome C. Metastatic carcinoma D. Ruptured LV E. Viral infection Friction rub – pericarditis – autoimmune reaction  Dressler’s 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.

Psamomma bodies

The following two test q’s 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.

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 (Barrett’s) 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, Paget’s Disease Paget’s 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 Paget’s 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 (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

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