Transcript NEOPLASIA REVIEW

NEOPLASIA REVIEW
PLUS
9-16-2014
T. Davis
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
• PPV= 270 / 270 + 140
270/410 or about 66%
A 68 y.o. male farmer has an ulcerated, pearly
nodule on his upper lip. Dx?
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B.
C.
D.
E.
Malignant melanoma
Dermatofibtoma
Actinic keratosis
Nevocellular nevus
Basal cell carcinoma
E, BCC
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Ulcerated
Pearly
Peripheral palisading
Chronic solar damage
Malignant but rare to metastasize
45 y.o. i.v dug user has huge scalp lesion.
Diagnosis?
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A.
B.
C.
D.
E.
Basal cell carcinoma
Melanoma
Systemic lupus erythematosis
Squamous cell carcinoma
Ulcer
D, Squamous cell carcinoma
• Aids patient (drug abuse)
• Immune supression
• Deep invasion
Cancer Precursor Lesions
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Actinic keratosis
Atyp. Hyp. Breast
Ulcerative Colitis
Endom. Hyperplasia
Esoph. Metaplasia
(Barrett’s)
• Gastric metaplasia and
lymphocytosis
(Helicobacter)
• Cirrhosis
• Sq. Cell CA
• Ductal CA
• Adeno CA colon
• Adeno CA endom.
• Esoph. Adeno CA
• Gastric Adeno CA
(and low grade or MALT
Lymphoma)
• Adeno CA liver
Precursors (2)
• Scar in lung
• Adeno CA
• Sq. Dysplasia/cervix,
lung/larynx
• Sq. Cell CA
• Adenomatous polyp
• Adeno CA colon
Malignant Tumors and
Endocrinopathies
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Cushings;SIADH
HCG/gynecomastia
PTH/hyperCa++
Calcitonin/hypoCa++
Insulin/hypoglycemia
Erythropoetin/polycy
themia or HiHct
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Small Cell
ChorioCA/testis
SC CA/lung
Med CA/thyroid
Islet cell
Renal Cell CA
Hepatocellular CA
The following image is most c/w which
malignancy
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B.
C.
D.
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Medullary Carcinoma of Thyroid
Small cell carcinoma of Lung
Sq. Cell Carcinoma of Lung
Metastatic melanoma
Renal Cell Adenocarcinoma
Ans. C, SCC of Lung
• These tumors frequently make a
parathormone-like substance resulting in
hypercalcemia and metastatic calcifications in
lung and kidney.
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
- Also called: Undifferentiated, poorly differentiated, high
grade
Anaplastic rhabdomyosarcoma
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
SP
SP
Squamous cell carcinoma with “squamous pearls” (SP)
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Intercellular bridges (*)
STAGING TUMORS
• How far has the tumor spread
• Malignant tumors only
• Tumor size (T), lymph node (LN)
involvement, distant metastases (M)
• Staging often involves: the Pathologist,
radiology or other imaging, lab tests
(tumor markers)
• CIS is referred to as Stage Zero
METASTASIS
• LIVER: (portal circulation) GI tract and
pancreas; lung, breast, melanomas
• LUNG: breast, stomach, sarcomas
• BONE: 3rd most frequent site for
metastases; lung, breast, prostate, kidney,
thyroid; PROSTATE to bone gives
osteoblastic lesions on Xray and high
serum alkaline phosphatatse
• ADRENAL: most common endocrine site
COLON CANCER
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Grading is not very helpful
STAGING: predicts clinical outcome
TNM
Robbins Table 17-11
Tumor Size (T)
• Tis- insitu; not through the muscularis
mucosa
• T1- invades submucosa
• T2- into but not through the muscularis
propria
• T3- through muscularis propria
• T4- invades adjacent organs
TNM Staging System
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
Which of the following best describes colon
cancer?
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B.
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Grading is very important
Staging is not important
Inactivation of a supressor gene
X-linked recessive inheritance pattern
Autosomal recessive inheritance pattern
Answer: C, inactivation of APC
• This disorder is autosomal dominant with the
APC supressor gene on chromosome 5.
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 using a
tumor marker (CEA also done with PSA, HCG etc.
• Deeply infiltrating tumors cause desmoplasia and
cause “apple core/ napkin-ring” appearance
Name the most common human
tumor supressor genes and
protooncogene (RESPECTIVELY)
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B.
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P53 and RB
P53 and RAS
RB and RAS
APC and P53
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 preand 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.
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%)
Markers (2)
• 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
Fibroadenoma
Fibroadenoma of breast
C
C
CN
Intraductal carcinoma with cribbiforming (C) and comedonecrosis (CN)
Invasive CA
Stellate
tumor
Mammogram shows a mass and Ca**
BREAST CARCINOMA GRADING
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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- Grade I
BREAST CARCINOMA STAGING
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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%
Invasive (infiltrating) ductal carcinoma with lymphatic invasion
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.
ER (+)
HER-2 Neu (+)
Squamous Carcinoma of Cervix
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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
Carcinoma Insitu
Normal
Moderate
Low Grade
Severe/CIS
Microinvasive Squamous Cell CA
What is the most sensitive test for high
grade dysplasia of the cervix?
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B.
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Pap smear
HPV DNA or RNA test for high risk types
HPV culture for DNA type 16
HPV culture for DNA type 18
HPV serum antibodies to DNA type 16
HPV DNA or RNA test are more
sensitive tests for High Grade
dysplasia
• Pap smear 55%
• HPV DNA 95%
• **RNA test more specific- requires
integration into host DNA for expression
LUNG CANCER
• Large cell carcinomas, adenocarcinomas and
squamous cell carcinomas: can be cured by
surgery if caught early (<1/3); radiation may
offer palliation; chemotherapy and targeted
therapy improving for adenocarcinomas
• SMALL CELL carcinoma: “always” metastatic
at diagnosis, therefore, surgery usually not an
option; remains poorly controlled by
chemotherapy
Normal
Squamous CA
CIS
Squamous CA
Small cell undifferentiated carcinoma
Adeno CA
Large cell CA
keratin
Nuclear molding
Squamous Cell Carcinoma
Small Cell Carcinoma
Paraneoplastic Syndromes
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Acanthosis nigricans
Eaton-Lambert
Osteoarthropathy
Seborrheic keratosis
Migratory
thrombophlebitis
(Trousseau’s)
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Adeno CA (gastric)
Small Cell CA
Bronchogenic CA
Gastric CA
• Pancreatic CA
PARANEOPLASTIC SYNDROMES
• Small Cell CA
• Squamous cell CA
hypercalcemia
• Carcinoid tumor
(invasive in lung or liver
usually)
• ACTH (Cushings); ADH
(SIADH)
• PTH-like
(Hypercalcemia)
• Serotonin, bradykinin
(Carcinoid syndromediarrhea, flushing, high
output murmur)
Viruses and Cancer (RNA)
• HCV
• Hepatocellular
• HTLV-1
• T-cell leukemia/
lymphoma
Viruses and Cancer (DNA)
• EBV t(8;14)
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HBV (<p53)
HPV 16 (E6/p53)
HPV 18 (E7/RB)
HHSV-8
(HIV/cytokines)
• Burkitt L., NP CA, MC
Hodgkin
• Hepatocellular CA
• SC CA cervix, anus
• Same as HPV 16
• Kaposi’s sarcoma in
AIDS
Neoplasms
• Benign
• Malignant
• Non-invasive
• Non-metastatic
• Invasive
• Metastatic or nonmetastatic
Malignant Tumor Properties
• Penetration of the basement membrane
• Invasion and destruction of surrounding
tissue
• Penetrate organ walls or fungate through
the surface
• Local invasion, like metastasis is a marker
for malignancy
• See Robbins Table 7-2 for benign vs
malignant features
Exceptions to the Rule
• Benign tumors that
may kill the patient
• Malignant tumors
without metastasis
• Meningioma
• Leiomyoma
• Glioblastoma
multiforme
• Basal cell carcinoma
Metastasis
• #1 marker of malignancy
• 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.
• ** On board exams they sometimes substitute
invasiveness for metastasis
Glioblastoma Multiforme (Astrocytoma III/IV
Metastatic melanoma
Cancer Statistics
• 90 % of cancer deaths are due to metastases
• 1/3 of breast and colon cancer patients have
lymph node metastases at diagnosis
• Frequency overall: liver, lung, bone
• #1 endocrine site: adrenal glands
Stage of tumors at diagnosis listed by organ/site
Pathways of Spread
• Direct seeding of body cavities:
peritoneal #1; also pleural, pericardial,
subarachnoid, joint
• Lymphatic spread: carcinoma> sarcoma;
follows natural drainage- breast cancer
(Upper-Outer Quadrant) goes 1st to
axillary nodes
• Hematogenous spread: esp. sarcoma;
also carcinoma; usually veins
• Other: eg. Perineural spread
Breast carcinoma with perineural invasion
Venous Drainage
• Portal: liver
• Caval: lungs
• Paravertebral plexus: thyroid and prostate
carcinomas metastasize to the vertebrae
• Renal Cell CA: invades renal vein and grows
into the vena cava
Liver with metastases
Sentinel LN Biopsy
• “The first node in a regional
lymphatic basin that receives lymph
flow from the primary tumor”
• Dyes and radiolabeled tracers mark
the node
• Breast, colon and melanomas
• In breast carcinomas it replaces a total
dissection of the axillary lymph nodes
and reduces morbidity
ANGIOGENESIS
• Tumors stimulate the growth of host blood
vessels
• Any tumor >2 mm in diameter must have a
vascular supply
• New vessels supply oxygen and nutrients and
endothelial cells secrete growth factors
Tumor-associated Angiogenic
Factors
• VEGF (vascular endothelial growth factor) and
bFGF (basic fibroblast growth factor) are
made mostly by tumor cells but also by
macrophages and stromal cells
ANGIOGENIC SWITCH
• Angiogenesis is delayed; a minority of the
cells become angiogenic
• p53 inhibits angiogenesis by inducing
production of thrombospondin-1 and
down-regulating VEGF
• Angiogenesis inhibitors made by tumor
cells: thrombospondin-1; and angiostatin
(from plasminogen), endostatin/tumstatin
(collagen)
• All are possible therapeutic targets!
Invasion and Metastasis
• Robbins Figure 7-42
• Cells break loose, enter and exit vessels and
establish a secondary growth site
• Rare malignant cells are successful at
metastasis; Robbins Figure 7-43
Steps in Metastasis
•Detachment of cells from the primary tumor
•Invasion of the surrounding tissue
•Penetration to blood and lymphatic vessels
•Arrest at target sites
•Egression (extravasation)
•Proliferation
•Establishment of a new blood supply
Metastatic
Cascade
Invasion of the Extracellular Matrix
(ECM)
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Basement membrane
Interstitial connective tissue
Vessel basement membrane
Vessel basement membrane
Interstitial connective tissue
Tumor Cells in Circulation
• They clump with each other, RBCs and
platelets
• Adhesion to endothelium (integrins-lamininproteinases)
Metastasis Oncogenes
• SNAIL and TWIST (breast cancer)
• E-cadherin is down-regulated and vimentin is
up-regulated
Tumor Tropism
• Different endothelial receptors in
different organs
• Different chemokine receptors on the
tumor cells- eg. breast cancers express
CXCR4 and CCR7 receptors and
“matching” chemokines are at high levels
in lung and lymph nodes
• “unfertile soil” like skeletal muscle
without receptors
Metastases and Tropism
Primary Site and Histology
Organ
Clear cell carcinoma (kidney)
Thyroid
Cutaneous melanoma
Small bowel/brain
Ocular melanoma
Liver
Adenocarcinomas
of the GI tract
Follicular carcinoma, thyroid
Ovary (Kruckenberg
tumor)
Bone
Targeted Therapy
• Signal-transduction Inhibitors
• Block enzymes and Growth Factor Receptors
• GLEEVEC (imatinib)- GIST and CML (abnormal
tumor enzymes);
• IRESSA (gefetinib)- non-small-cell lung cancer
(EGFR)
• Zelboraf (vemurafenib)- blocks B-raf/MEK if
V600E BRAF mutation present with apoptosis
Target (2)
• Monoclonal Antibodies
• Herceptin- invasive breast carcinomas (that
show overexpression of HER-2-neu)
Target (3)
• Anti-angiogenesis
• Angiostatin (from plasminogen)
• Endostatin (from collagen)