HER2 Patient Outcome Data: If negative HER2 Protein Overexpression Br Ca: HER2 FISH Overexpression:

for HER2, survival for breast cancer is a

lot higher.

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. Targeted therapy wants to eliminate the drugs that
genetically will not work on your tumor and only give
Metabolomics 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 Above: If you have high COX2 in the tumor, poor
not spread yet. Using markers to predict who should get survival. Low COX2  survival rate is better.
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.

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?
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:
• 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.
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 EGFR-
TK 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 patient’s 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)
Using Skin Biopsies as Biomarkers to predict clinical efficacy:
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.
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.
Figure:
• K Ras Mutation
 poor survival.
• Colorectal Cancer
• Found in Blood
• Survival Curves
• ASCO 2008
 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 4. (E) Phosphorylated mitogen- Disease-free survival (DFS) by age -
activated protein kinase (pMAPK): AYA Tumors
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.
Above: FYI. If younger people (less than 30-
40) 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 • 80% specificity
• 90% of 1000 or 900 would be the true positives • 80% of 1000 or 800 would be the true negatives
• 10% of 1000 or 100 would be the false 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. EM lymphocytes look like this ^

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.

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 (Barrett’s)  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
Hashimoto’s D.  Lymphoma

• Helicobacter – gram-negative organism that causes stomach ulcers  more susceptible to adenocarcinoma or gastric
lymphoma.
• Hashimoto’s – 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…) Test q: A 49y/o man experiences an episode of hemoptysis.
Small Cell, Med. CA  ACTH/Cushings On phys exam, he has puffiness of the face, pedal edema,
ChorioCA/testis  HCG/gynecomastia and systolic hypertension. A chest radiograph shows a 5cm
SC CA/lung  PTH/hyperCa++ mass of the right upper lobe of the lung. A fine-needle
aspiration biopsy of this mass yields cells consistent w/small-
Med CA/thyroid  Calcitonin/hypoCa+ cell anaplastic carcinoma. A bone scan shows no
Islet cell  Insulin/hypoglycemia metastases. Immunohistochemical staining of the tumor cells
Small Cell  ADH/hypoNa+ is most likely to be positive for which of the following? ACTH
Renal Cell, Hepatocellular CA  Erythropeitin/>Hct

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) Glioblastomas of the brain are graded I-IV.
- Important for some tumors: breast, prostate, endometrium, astocytomas Grades III & IV are called “glioblastoma
- Dysplasias of the cervix are “graded” multiforme” – most malignant, aggressive
- Based on microscopic features form of a glioblastoma.
 Above: Adenocarcinoma is characterized by Above: Two squamous cell carcinoma (SCC) examples with “squamous pearls”
gland formation or evidence of glandular (SP). What’s the difference between a squamous pearl and an intra-epidermal
differentiation. 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, it’s a squamous cancer.
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
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 ½ 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.
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 adenomatous
from this patient. change

Which of the following best

describes this disease?
A. Crohn’s Disease
B. Ulcerative colitis
C. Inactivation of a supressor
gene
D. X-linked recessive inheritance
pattern
E. Autosomal recessive
inheritance pattern

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) Lymph Nodes (N) Distant Metastases (M)
Tis- in situ; not through the muscularis mucosa N0- no nodes involved M0- no distant metastasis
T1- invades submucosa N1- 1-3 regional LNs M1- distant mets present
T2- into but not through the muscularis propria N2- 4+ regional LNs *note: Tx, Nx, Mx – cannot be
T3- through muscularis propria assessed
T4- invades adjacent organs

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 surgery-
tumor monitoring
- Deeply infiltrating tumors cause desmoplasia and “apple core/napkin-
ring” 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.) Test q: CEA is used to follow patients w/cancer of the: colon.
- AFP- hepatocellular, germ cell (>500ng/ml) Test q: Cancer antigen 125 (CA-125) is used to follow patients w/cancer of
- CA 125- 80% non-mucinous ovarian CA the: ovary. REPEATED x2
- CA 19-9- pancreatic CA (80%)
- PSA- (0-4 ng/ml normal) (>10 ng/ml highly Test q (shown above): How are tumor markers useful in management of
colon cancer? CEA is used to monitor tumor recurrence
suspicious); also AlkPhos elevation in prostate
CA assoc. with bone metastasis (osteoblastic) Test q: Which of the following tumor markers can be used clinically to screen
- HCG- gestational trophoblastic tumors, testicular populations for presence of malignancy? PSA.
tumors

Benign breast ducts and lobules: Fibroadenoma:

 Intraductal carcinoma with cribbiforming (C)
Fibroadenoma of breast: 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 ½ 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 Test q: A Pap smear reveals the presence of severe cervical dysplasia
• Dysplasia in a 35y/o female. Which of the following viruses binds to pRb to
• CIS increase the risk for this lesion? HPV DNA type 16 or 18.
• Microinvasive cancer (<5mm below BM)
Test q: A 30y/o woman who has had multiple sexual partners sees her
• Invasive cancer (>5mm below BM physician because she has had vaginal bleeding and discharge for the
• Stage I: 5-year is 90% past 5 days. Pelvic exam shows an ulcerated lesion arising from the
• Stage II: 5-year is 70% squamocolumnar junction of the uterine cervix. A cervical biopsy is
performed. Microscopic exam reveals an invasive tumor containing
• Stage IV: 5-year is 10%
areas of squamous epithelium, with pearls of keratin. In situ
hybridization shows the presence of human papillomavirus type 16
HPV and Cervical Cancer (HPV-16) DNA within the tumor cells. Which of the following molecular
• HPV DNA types 6 and 11: condyloma abnormalities in this tumor is most likely related to infection with HPV-
16? Functional inactivation of the RB1 protein.
• HPV 16, 18, 13 others: carcinoma
• Viral protein E7 acts via retinoblastoma gene protein Test q: A 25y/o female presents w/an exophytic condyloma on her
• Viral protein E6 acts via to P53 (TP53). cervix. What HPV DNA types would you expect? HPV 6, 11
• Proliferation is stimulated and apoptosis is inhibited

Squamous metaplasia :