HER2 Patient Outcome Data: If negative

for HER2, survival for breast cancer is a lot higher.

HER2 Protein Overexpression Br Ca:

HER2 FISH Overexpression:

Located on cell membrane.

There is one area of Her2neu gene on chromosome 17 can see overexpression above.

Clinical Implications of HER-2/neu - Monoclonal antibody, Herceptin, recently approved for treatment of invasive breast cancer. - Clinical trials indicate that this antibody has a significant effect on survival. - Both FISH and IMC available at major medical centers to assess HER-2/neu gene or protein amplification in tumors. - Problem: increase in heart problems because of Herceptin. Predictive Medicine/Targeted Therapy - New clinical biomarkers will dictate clinical chemotherapy (eg. HER2/neu) - These biomarkers may predict patient survival and eliminate some of the current toxicities seen with standard chemotherapy. Biomarkers Conventional (one-size-fits-all) Chemotherapy:

Goal: to use biomarkers to move the diagnostic paradigm way over to the left. Metabolomics

Targeted therapy wants to eliminate the drugs that genetically will not work on your tumor and only give you the treatment that works.

Test q: Optimal use of most tumor markers in the US as of 2009 are for: monitoring response to chemotherapy

Trying to find a way to diagnose cancer earlier and treat it quicker.

Above: Women w/DCIS (ductal carcinoma in situ) that has not spread yet. Using markers to predict who should get chemotherapy and who should not. Followed patients over 10 years to look at survival curves big markers are p16 and Ki67. If you have high Ki67, survival is down. If you have high p16 AND Ki67, death occurs fairly quickly. These are the ones who should be aggressively treated.

Above: If you have high COX2 in the tumor, poor survival. Low COX2 survival rate is better.

New EGFR Inhibitors for Oncology Targeted Therapy (Most solid tumors) - Imclone - Iressa only ~8% of people saw improvement - Tarceva low toxicity - Approximately 170 new inhibitors in development

EGFR structure and distribution of types of mutation: Tremendous amount of mutations in EGFR some affect survival, some affect proliferation. (A) Ligand binding to EGFR stimulates autophosphorylation (B) and activation of signaling pathways, promoting both cell (C) proliferation (via MAPK/ERK) and survival (via AKT/STAT). (D) In addition to altering downstream signaling, EGFR mutations are within the tyrosine kinase inhibitor binding site and enhance inhibition of receptor activation. (E) Distribution of the types of EGFR mutations within the tyrosine kinase domain.

Graph showing the higher and lower % of EGFr in different tumor types:

Above: EGFR is highly expressed in a lot of different kinds of tumors. Not like Her2neu (which is very predictive). (See breast goes from 10 to 90%.)

Does EGFR expression predict response?

Caption from this slide: Tumor biopsies were taken between diagnosis and start of gefitinib treatment from 87/209 patients recruited into the IDEAL 1 trial. Forty-seven patients received 250 mg/day gefitinib and 40 patients received 500 mg/day; 18 of these patients experienced objective responses. Tumor EGFR expression levels did not predict response to gefitinib; indeed, some patients with partial response had undetectable levels of EGFR. Similar results were also observed for the IDEAL 2 analysis (data not shown). Comparable analyses using data from Phase II clinical trials of erlotinib and cetuximab in NSCLC have also found no correlation between EGFR expression and tumor response.

Genetic Mutations in EGFR receptor - Researchers found that patients who had dramatic responses to gefitinib (>50% tumor shrinkage) had lung tumors with EGFR-TK (tyrosine kinase receptor area) mutations - Paez also noted that the frequency of these mutations correlated with clinical factors identified as being associated with response to gefitinib (female, adenocarcinoma, no smoking, Japanese ethnicity) Prognostic biomarkers in tumors that may predict response to Cancer:

Caption from this slide:

In the study described by Lynch et al, EGFR gene sequencing identified EGFR-TK mutations in 8/9 patients who had responded to gefitinib. In contrast, no mutations were seen in 7 patients with NSCLC who had not responded to gefitinib. Furthermore, Paez et al correlated the frequency of these mutations with previous clinical demographic factors (female gender, adenocarcinoma histology, never having smoked and Japanese ethnicity) that have been associated with response to gefitinib. If confirmed, these correlations would explain the variability of response within these subsets of patients. A further analysis of 9 primary tumors from patients treated with gefitinib found that all 5 patients who had responded to gefitinib had EGFR-TK mutations. In contrast, none of the patients who progressed while receiving gefitinib had EGFR-TK mutations. Additional molecular analyses are required in order to clarify the frequency of these EGFRTK mutations in all patients who experience clinical benefit (stable disease or symptom improvement) with gefitinib.

Caption from this slide:

Identification of factors that are associated with response to epidermal growth factor receptor (EGFR)-targeted therapies may optimize the treatment of individual patients. Biologic markers that are associated with the EGFR signaling pathway (eg EGFR expression, MAPK, and pAkt levels), proliferation (eg Ki67 levels), and apoptosis (eg Bcl-2 or TUNEL levels) may predict whether some patients are more likely to respond to EGFR-targeted therapies. In addition, analysis of tumor gene expression may enable a treatment plan depending on each patients individual needs by identifying those patients with a resistant or susceptible phenotype to EGFR-targeted therapy. Clinical benefit using EGFR-targeted therapies may also be affected by baseline demographic factors such as disease characteristics (histology and metastasis), poor performance status, and weight loss. Surrogate markers (improvements in disease-related symptoms or quality of life, or the incidence of adverse events such as skin rash) may also identify patients who are more likely to gain clinical benefit.

Biomarkers - Biofluids & Tissues Tissue IHC, IMF & FISH of target pathway proteins Biofluids & Tissue Use metabolomics (DNA, RNA, protein) Blood CTC (circulating tumor cells) CEC (circulating endothelial cells) CEPC (endothelial progenitor cells) CPC (circulating Progenitor cells)

Figure: K Ras Mutation poor survival. Colorectal Cancer Found in Blood Survival Curves ASCO 2008

Using Skin Biopsies as Biomarkers to predict clinical efficacy:

Figures: If you do a punch biopsy before and after treatment, EGFR is knocked down. Map kinase is also knocked down. Stat3 (on inflammatory pathway) is up. P27 tumor suppressor gene is turned on and up.

Fig 3. Pharmacodynamic effects of EMD72000 punch biopsy of the skin. Pretreatment (left panel) and on-treatment (right panel) for (A) hematoxylin and eosin (HE); (B) epidermal growth factor receptor (EGFR): no changes in expression were observed after treatment; (C) transforming growth factor alpha (TGF-): no changes in TGF- were detected; (D) phosphorylated EGFR (pEGFR): activated EGFR was completely inhibited in basal keratinocytes of epidermis after drug administration.

Fig 4. (E) Phosphorylated mitogenactivated protein kinase (pMAPK): activated MAPK was inhibited in the basal layer of epidermis; (F) phosphorylated signal transducer and activator of transcription protein 3 (pSTAT-3): expressed in basal and suprabasal layers of epidermis after treatment; (G) Ki-67: exhibited in proliferating cells and decreased under treatment; and (H) p27kip1: staining increased in keratinocytes after treatment, preferentially in basal layers of epidermis.

Disease-free survival (DFS) by age AYA Tumors

AYA Tumors:

Above: mRNA expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and epidermal growth factor receptor (EGFR) among younger versus older women.

Above: FYI. If younger people (less than 3040) get a tumor that normally occurs in older people, it will be very aggressive and resistant to treatment.

Age Differences in Pathway Deregulation Seen in Breast Tumors Figure: Non-parametric T test evaluating pathway probability between tumors arising in younger versus older women. Red represents women aged 45 years. Blue represents women aged 65 years. The line represents the median. B catenin was up in younger women.

Cancer Is a Multi-Step Process: - Mutation of one oncogene or tumor suppressor gene does not lead to tumor formation - e.g. colon cancer --mutation of 4-6 critical genes (e.g. TSG, oncogenes, apoptosis genes) is required for tumor formation

Pathology Conference Neoplasia Review

Fri. 09/17/10

Note: This day, the lecture was only 30min long not sure where Dr. Davis stopped, but much of the material was not discussed in class.

1. A new test for prostate cancer (PC) is developed. 90% of men with PC test positive. 80% of men without PC test negative. 2. In a population of 1000 men, 30% (300 men) have the disease (the prevalence is 30%). Calculate sensitivity, specificity and PPV. Sensitivity and specificity: 90% sensitivity 90% of 1000 or 900 would be the true positives 10% of 1000 or 100 would be the false negatives 80% specificity 80% of 1000 or 800 would be the true negatives 20% of 1000 or 200 would be the false positives

PPV (predictive value of a +) with a prevalence of 30% 410 men have a positive test: 270 TP (90%x300) and 140 FP (20%x700) PPV= TP/FP+TP = 270 / (270 + 140) = 270/410 or about 66% Skin RR-1: 29 y.o. male with waxing and waning lesions like those pictured. Which of the following physical findings are most likely: A. Guiac-positive stool B. Friction rub C. Hyperreflexia D. Nail damage E. Hypertension D, psoriasis: Discolorization, pitting, separation from the nail bed Skin RR-10: What disorder produces the blister and immuno stain pictured? A. Impetigo B. Pemphigus vulgaris C. Bullous pemphigoid D. Eczematous dermatitis E. Urticaria Need to know if it is IgG or IgA pretty linear pattern, so go with IgG.
Above: (sub-epidermal blister)

C, Bullous pemphigoid: Subepidermal; linear IgG at hemidesmosomes of basal cell-basement membrane interface. Remember: The bull sees red. (red = eosinophils)

Above: If this was an IgA stain, it would be dermatitis herpetiformis. On the histopathology of dermatitis herpetiformis, see neutrophils (micro-abscesses).

Above: Intra-epidermal split = pemphigus vulgaris

Above: Pemphigus Vulgaris. Every cell is stained, but no stain associated w/basement membrane, dermal papillae, etc. is between each of the cells (desmosomes).

39 y.o. male has unusual rash on his trunk and atypical lymphocytes. A. Langerhans cell tumor B. Langhans cell granuloma C. Mycosis fungoides D. Maligmant melanoma E. Multiple myeloma Nuclei look like a brain Cerebriform nuclei = mycosis fungoides w/Sezary syndrome. C, Mycosis fungoides: Sezary cells = Sezary syndrome of mycosis fungoides; CD4+ cells. MF is a dermatologic condition w/CD4+ cells in the skin. In Sezary syndrome, these atypical T cells circulate in the blood. If you saw atypical bean-shaped cells w/CD1a and S100 positivity, tumor would be Langerhans.
EM lymphocytes look like this ^

Skin RR- 18 A 68 y.o. male has pearly nodule on his upper lip. Dx? A. Malignant melanoma B. Dermatofibtoma C. Actinic keratosis D. Nevocellular nevus E. Basal cell carcinoma E, BCC: Ulcerated, Pearly, Peripheral palisading

Skin RR 21 45 y.o. i.v dug user has scalp lesion. Diagnosis? A. Psoriasis B. Lichen planus C. Dermatofibroma D. Squamous cell carcinoma E. Erythema multiforme Think: IV drug user may have HIV immune suppressed squamous cell carcinoma (SCC IS RELATED TO IMMUNE SUPPRESSION!) Can see in scan that it has grown all the way through dermis and subcutaneous tissue into the skull. D, Squamous cell carcinoma: Aids patient (drug abuse); Immune supression

Cancer Precursor Lesions HAVE TO KNOW. MEMORIZE THIS LIST. Actinic keratosis Sq. Cell CA Atyp. Hyperplasia Breast Ductal CA Ulcerative Colitis Adeno CA colon Endom. Hyperplasia Adeno CA endom. Esoph. Metaplasia (Barretts) Esoph. Adeno CA Gastric metaplasia (Helicobacter) Gastric Adeno CA Cirrhosis Adeno CA liver Scar in lung Adeno CA Dysplasia/cervix, lung/larynx Sq. Cell CA Adenomatous polyp Adeno CA colon Hashimotos D. Lymphoma Helicobacter gram-negative organism that causes stomach ulcers more susceptible to adenocarcinoma or gastric lymphoma. Hashimotos overproliferation of lymphocytes. MUST be treated. If not, at high risk for lymphoma. If given Synthroid, not at increased risk (lifelong drug).

Malignant Tumors and Endocrinopathies (these tumors can produce these substances) Small Cell, Med. CA ACTH/Cushings ChorioCA/testis HCG/gynecomastia SC CA/lung PTH/hyperCa++ Med CA/thyroid Calcitonin/hypoCa+ Islet cell Insulin/hypoglycemia Small Cell ADH/hypoNa+ Renal Cell, Hepatocellular CA Erythropeitin/>Hct

Test q: A 49y/o man experiences an episode of hemoptysis. On phys exam, he has puffiness of the face, pedal edema, and systolic hypertension. A chest radiograph shows a 5cm mass of the right upper lobe of the lung. A fine-needle aspiration biopsy of this mass yields cells consistent w/smallcell anaplastic carcinoma. A bone scan shows no metastases. Immunohistochemical staining of the tumor cells is most likely to be positive for which of the following? ACTH

The following image is most c/w which malignancy: A. Medullary Carcinoma of Thyroid B. Small cell carcinoma of Lung C. Sq. Cell Carcinoma of Lung D. Metastatic melanoma E. Renal Cell Adenocarcinoma Figure: The walls are blue because they are filled w/calcium metastatic calcification. Squamous cell carcinoma of lung is most likely to make parathormone-like substance. Ans. C, SCC of Lung These tumors frequently make a parathormone-like substance.

Anaplasia = Lack of differentiation Anaplasia is considered a hallmark of malignant transformation. Anaplastic features include: - Cellular/nuclear pleomorphism - Increased nuclear-cytoplasmic ratio - Nuclear hyperchromasia (increased DNA content) - Large nucleoli - Undifferentiated, poorly differentiated, high grade - Small cell undifferentiated carcinoma of the lung = very aggressive, undifferentiated tumor. Not very successful in treating. GRADING TUMORS: Malignant tumors only - Differentiation and mitotic rate - Grades I-III/IV (higher grades are more anaplastic) - Important for some tumors: breast, prostate, endometrium, astocytomas - Dysplasias of the cervix are graded - Based on microscopic features

Glioblastomas of the brain are graded I-IV. Grades III & IV are called glioblastoma multiforme most malignant, aggressive form of a glioblastoma.

Above: Adenocarcinoma is characterized by gland formation or evidence of glandular differentiation.

Above: Two squamous cell carcinoma (SCC) examples with squamous pearls (SP). Whats the difference between a squamous pearl and an intra-epidermal pseudo-horn cyst (since they look similar)? The difference is the setting. Squamous pearl = SCC. Inclusion cyst in skin = normal finding (seen in nevi, etc)

Squamous pearls can sometimes have a lot of keratin, sometimes are swirls of malignant cells.

Above: * = intercellular bridges. SCCs also have intercellular bridges. Does not mean it is malignant normal skin has these. But if you look at a mass from the lung w/intercellular bridges, its a squamous cancer.

Above: Anaplastic rhabdomyosarcoma totally undifferentiated.

Test q: A malignant tumor is removed from the liver. Microscopically the tumor exhibits squamous pearls and intercellular bridges. The most likely origin of this neoplasm is: lung. (Other choices pancreas, liver, gallbladder, thyroid) REPEATED x2 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 stage of this tumor is: T1N0M0 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 are not seen and nucleoli are absent. This tumor can be described as: low grade. (Other choices: anaplastic, undifferentiated, hamartoma, or CIS) The tumor measures 1.1cm in diameter. Three sentinel lymph nodes are all negative for tumor. Distant metastases are not detected. The stage of this neoplasm is: T1N0M0 Test q: A 76y/o man has experienced lower back pain for the past year. On phys exam, the physician palpates a firm nodule in the prostate. Lab studies show an alkaline phosphatase level of 290 U/L and a serum prostate specific antigen level of 17 ng/mL. Both are elevated. A prostate needle biopsy specimen shows a moderately differentiated adenocarcinoma. Which of the following mechanisms best accounts for these findings? Osteoblastic metastases. Test q: Which of the following tumors commonly metastasize to bone? Renal cell carcinoma.

STAGING TUMORS: - How far has the tumor spread (has NOTHING to do w/what the tumor looks like) - Malignant tumors only - Tumor size (T), lymph node (LN) involvement, distant metastases (M big 3 are brain, lung, and liver.) - Staging often involves: the Pathologist, radiology or other imaging, lab tests (tumor markers) - CIS is referred to as Stage Zero is malignant, but has not gone through basement membrane. - T1N0M0 = very small tumor, no lymph node involvement, no distant metastases. T3N5M1 = large, 5 lymph nodes involved, 1 met could have gone to liver or brain, for example METASTASIS LIVER: (spreads through portal circulation) tumors from GI tract and pancreas; lung, breast, melanomas LUNG: breast, stomach, sarcomas rd BONE: 3 most frequent site for metastases; lung, breast, prostate, kidney, thyroid In bone, either break down the bone or cause bone to proliferate. Osteoblastic = proliferative, bone gets denser. Osteolytic lesions = break down bone, see holes in bone. PROSTATE bone gives osteoblastic lesions on X-ray and high serum alkaline phosphatase Breast bone is osteolytic, break down bone and get lytic lesions. ADRENAL: most common endocrine site

Neoplasia Case: A 38-y.o. male has a family history of colectomies performed between ages 30 and 40. The slide shows the total colectomy specimen from this patient. Which of the following best describes this disease? A. Crohns Disease B. Ulcerative colitis C. Inactivation of a supressor gene D. X-linked recessive inheritance pattern E. Autosomal recessive inheritance pattern

adenomatous change

Answer: C, inactivation of APC. This disorder is autosomal dominant with the APC suppressor gene on chromosome 5.

COLON CANCER - Grading is not very helpful - STAGING: predicts clinical outcome - TNM Tumor Size (T) Tis- in situ; not through the muscularis mucosa T1- invades submucosa T2- into but not through the muscularis propria T3- through muscularis propria T4- invades adjacent organs Lymph Nodes (N) N0- no nodes involved N1- 1-3 regional LNs N2- 4+ regional LNs Distant Metastases (M) M0- no distant metastasis M1- distant mets present *note: Tx, Nx, Mx cannot be assessed TNM Staging System:
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. Test q: A 73y/o man undergoes a left hemicolectomy for primary colorectal adenocarcinoma. The best prognostic indicator is: Absence of regional lymph node metastasis.

Colon cancer (OTHER): - 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 surgerytumor monitoring - Deeply infiltrating tumors cause desmoplasia and apple core/napkinring appearance

Above: Apple core/napkin ring appearance.

Name the most common human tumor supressor genes and protooncogene (RESPECTIVELY) A. P53 and RB B. P53 and RAS C. RB and RAS D. APC and P53 E. APC and RB Answer: B, P53 and RAS P53 is the tumor supressor gene mutated in over 50% of human tumors. The mutation prevents DNA repair and inhibits apoptosis. The point mutation in the proto-oncogene RAS allows cell proliferation (GTP signal transduction) and is seen 30+% of human tumors 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 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. Tumor Markers: - Management - Detection (staging) - Diagnosis (screening)- PSA and CA 125 - 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

Test q: CEA is used to follow patients w/cancer of the: colon. Test q: Cancer antigen 125 (CA-125) is used to follow patients w/cancer of the: ovary. REPEATED x2 Test q (shown above): How are tumor markers useful in management of colon cancer? CEA is used to monitor tumor recurrence Test q: Which of the following tumor markers can be used clinically to screen populations for presence of malignancy? PSA.

Benign breast ducts and lobules:

Fibroadenoma:

Fibroadenoma of breast:

Intraductal carcinoma with cribbiforming (C) and comedonecrosis (CN):

Breast Carcinoma:

BREAST CARCINOMA GRADING: Bloom and Richardson Tubules present (1-3) Nuclear atypia (1-3) Mitoses (1-3) 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 & 1-3 LN+): 5-year 75% *Stage III. (5 cm & >4 LN+): 5-year 46% Stage IV. Distant mets: 5-year 13% 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 (20%), 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. All of the following questions were already written into the week 4 study guide:
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.

Squamous Carcinoma of Cervix: Squamous metaplasia Dysplasia CIS Microinvasive cancer (<5mm below BM) Invasive cancer (>5mm below BM Stage I: 5-year is 90% Stage II: 5-year is 70% Stage IV: 5-year is 10% HPV and Cervical Cancer HPV DNA types 6 and 11: condyloma HPV 16, 18, 13 others: carcinoma Viral protein E7 acts via retinoblastoma gene protein Viral protein E6 acts via to P53 (TP53). Proliferation is stimulated and apoptosis is inhibited Squamous metaplasia :

Test q: A Pap smear reveals the presence of severe cervical dysplasia in a 35y/o female. Which of the following viruses binds to pRb to increase the risk for this lesion? HPV DNA type 16 or 18. Test q: A 30y/o woman who has had multiple sexual partners sees her physician because she has had vaginal bleeding and discharge for the past 5 days. Pelvic exam shows an ulcerated lesion arising from the squamocolumnar junction of the uterine cervix. A cervical biopsy is performed. Microscopic exam reveals an invasive tumor containing areas of squamous epithelium, with pearls of keratin. In situ hybridization shows the presence of human papillomavirus type 16 (HPV-16) DNA within the tumor cells. Which of the following molecular abnormalities in this tumor is most likely related to infection with HPV16? Functional inactivation of the RB1 protein. Test q: A 25y/o female presents w/an exophytic condyloma on her cervix. What HPV DNA types would you expect? HPV 6, 11