Chapter

5.

NeoplasiaXu

HT病例ＸＸＸ，女，21歲主訴：近半年左下肢膝關節附近疼痛，活動后加重，一個月前發現左股骨下端局部隆起，逐漸長大，疼痛難忍，來診。查體：左股骨下端局部腫物，壓痛（＋）處置：1.

左股骨下端X線正側位像胸部X線正側位像左股骨下端腫物穿刺活檢檢查結果1.左股骨下端X線正位像：左股骨下端占位病變，骨皮質破壞,骨膜反應。

2.胸部X線正側位像：未見明顯異常臨床診斷：惡性骨腫瘤？活檢病理診斷：骨肉瘤治療原則手術切除化

療放

療支持療法什么是腫瘤？具有哪些特性？腫瘤有哪些種類、各自特點？腫瘤生物學行為如何？對機體有何影響？腫瘤的結局如何？腫瘤是如何發生發展的？如何防治？思考題Chapter

5.

NeoplasiaTumors

is

common

diseases.Bad

news:

Malignant

tumor

(cancer)

is

thesecond

leading

cause

of

death

in

some

countries(The

first

leading

cause

is

cardiovasculardiseases.)According

to

American

Cancer

Society

estimatesin

2003,

about

23%

of

all

deaths

in

the

UnitedStates

(1500

cancer

deaths

per

day).Good

news:The

rapid

progress

has

been

made

inunderstanding

the

molecular

basis

andbiological

behavior

of

cancer

and

cancertherapy.

Many

cancers

can

be

cure

or

arresFor

example:

breast

cancer,

cervical

canBut

many

problems

still

need

to

be

solvedSection

1.

Definition

and

morphologyTwo

question:What

is

tumor?

DefinitionWhat

are

tumors

look

like?Morphology※DefinitionNeoplasia

literally

means

the

process

of“new

growth”

and

a

new

growth

is

calleda

neoplasm.tumor

was

originallyappliedtotheswelling

caused

byinflammation.Oncology

is

the

studyof

tumors

orneoplasms.Cancer

is

the

common

term

for

allmalignant

tumors.NeoplasiaIn

1953,

The

eminent

British

oncologist

Willis

hadgiven

neoplasia

a

famous

definition:

“A

neoplasm

is

aabnormal

mass

of

tissue,

the

growth

of

which

exceeds

ais

uncoordinated

with

that

of

the

normal

tissues

andpersists

in

the

same

excessive

manner

after

cessationthe

stimuli

which

evoked

the

change.”A

more

scientific

difinition:

“Neoplasia

is

genet

disease,

in

which

the

growth

of

tumors

is

loss

of

responsiveness

to

normal

growth

control,

and

shows

an

excessive

hyperplasia

with

abnormal

differentiationTumor

(neoplasm):under

the

stimulation

of

tumorgenic

agenta

single

cell

of

local

tissue

loss

thecontrolling

to

its

growth

at

the

gene

leveexcessive

proliferation

to

form

neoplasDistinguish

between

neoplasticandnon-neoplastic

hyperplasiaNeoplasticMonoclonalityAbnormal

morphologyandfunctionNon-neoplasticPolyclonalityNormal

morphologyandfunctionAbnormal

differentiationPersistent,

autonomousMatured

differentiatLimitedHarmful

Beneficial※Morphology

and

structureMacropathology:

The

gross

appearance

of

tumors

isvaried,

reflecting

the

nature

of

the

tumor

to

some

extenNumber

and

Size:

variousShape:

sessile,

papillary,

nodular,

lobular,cystic,

fungating,

ulcerated,

and

infiltratingColor:

dependent

on

histogenesis

andsecondary

changes

(hemorrhage,

necrosis)Consistency:

Parenchyma-stroma

ratio,Secondary

changesCapsule:

benign

with

intact

capsuleSecondary

changes:

hemorrhage,

necrosisNumber

and

size:variousFibroadenomaPolypous

adenomapapillarypolypousShape:

relate

to

histogenesis,site

and

biologic

behaviorPapillomaPolypous

adenomaBenignNodular

or

lobularcysticLipomaFibroadenomaMucinous

cystadenomaBenignFungatingUlceratedInfiltrativeMalignantColor:The

color

of

a

benign

tumor

resembles

that

of

the

normal

tiswhich

it

derived.The

color

of

the

cut

surface

of

a

malignant

tumor

may

be

graand

often

varied

due

to

secondary

changes

(hemorrhage,degeneration

and

necrosis).CapsuleThe

benign

tumor

is

usually

circumscribed

by

a

clearlydefined

border

and

often

encapsulated

by

thin

fibrous

caThe

malignant

tumor

is

invasive

and

poorly

circumscribeFibromaCarcinoma

of

stomachConsistencyResembles

the

normal

tissueit

derived

fromTumors

are

usually

firmer

thansurrounding

tissuesProportion

of

parenchymaand

stromaSecondary

changesAdipose

tissueLipoma:

softCartilageChondroma:

hardScirrhouscarcinomaConsistencyParenchyma-stroma

ratiostroma>ParenchymahardMedullary

carcinomaConsistencyParenchyma>StromasoftSecondary

changesNecrosisHemorrhageHistological

structureAll

tumors

have

basic

two

components:ParenchymaMajor

component

of

tumor:

neoplastic

cellDetermine

the

biologic

nature

and

specificityStromaComposed

of

CT

and

BV

→support

the

tumorGrowth

speed

depend

on

the

stroma

blood

supplyLC

infiltration

→immune

reactiontotumorParenchymaStromaStromal

BVFibrosarcomaNO

stromal

BVTake

home

question:√What

is

neoplasia?

(The

definition)√How

to

describe

the

gross

appearance

oa

tumor?

(Number,

size,

shape,

color,

consistenccapsule,secondary

changes)What

is

neoplastic

atypia?The

atypia

of

tissue

architectureThe

atypia

of

neoplasic

cellsSection

2. Neoplastic

atypia※What

is

atypia?Atypia:

Neoplastic

tissue

has

various

extent

ofdifferences

with

its

originated

normal

tissue,

bcell

morphologically

and

tissue

architecturallyDifferentiation:

The

degree

towhich

a

neoplasiccells

resembles

its

originated

normal

mature

celboth

morphologically

and

functionally.Anaplasia:

Lack

of

differentiation

ofmalignant

neoplastic

cell,

with

obviouslyatypia.Anaplastic

tumor:

composed

ofundifferentiated

cell.Pleomorphism:

obviousvariation

in

size,

shapeobviously

atypia?Atypiaof

tissue

architectureRefers

to

difference

between

neoplastictissue

and

its

originated

normal

tissueThe

arrangement

of

neoplastic

tissueThe

polarization

of

neoplastic

tissuethe

relationship

with

stromaIntestinal

adenomaAdenocarcinomaSquamous

cell

carcinomaAtypia

of

neoplastic

cellsPleomorphism

of

neoplastic

cellsVariation

in

size

and

shapeGenerally

larger

than

normal

cells→tumor

giant

cellsPleomorphism

of

nucleus1.

Increased

nucleus:The

nuclear-

to

-

cytoplasmic

ratio

mayapproach

1:1

instead

of

the

normal

1:4

-

6.2.

Variation

in

size,

color

and

shape

ofnucleus:①

Size:

Huge,

two

ormore

nuclei,

bizarre

nucllarge

nucleoli

are

usually

present.②

Color:

The

nuclei

contain

an

abundance

ofDNA

andare

extremely

darkstaining③

Shape

:i)

The

shape

is

usually

extremely

variablthe

chromatin

is

coarsely

clumpedii)

Increased

mitotic

figures

:Atypical,

bizarre

mitotic

figuresproducingtripolar,

quadripolar,

or

multipolar

spindles.Normal

structureAdenocarcinoma◆

Changes

ofcytoplasmCytoplasm:Basophilic

→nucleoprotein

increasedAbnormal

products

or

secretion:Mucus,

glycogen,

lipidhelpful

to

determine

histogenesis

of

tumMucoid

carcinomaSquamous

cell

carcinomaMelanoma

of

theskinUltrastructural

changes

(electron

microOrganelles

:

signs

of

histogenesisNeuroendocrine

granules→neuroendocrine

tumorTonofilament

and

desmosomes→squamous

cell

carcinomaMyofilament

and

dense

body

→SMCTake

home

questions:√

What

is

atypia?

(The

definition)√

What

is

atypia

include?Theatypiaoftissue

architectureThe

atypia

of

neoplasic

cells–––Cell

nucleusCytoplasmUltrastructureSection

3.

Growth

and

spread

of

tumoGrowth

pattern

of

tumorBiology

of

tumor

growthSpread

of

neoplasms

(Invasionand

metastasis)Mechanisms

of

invasion

andmetastasisGrading

and

staging

of

tumor1.

The

growth

of

tumorGrowth

pattern

of

tumorExpansiveExophytic1.growth2.growthInfiltrating3.growthGrowth

pattern

of

tumorExpansivegrowth:The

mode

of

mostbenign

tumornodularintact

capsuleLeiomyomaSites:

surface

of

body,

body

cavities or

tract

organs.Shape:

papillary,

polypoid,

caulifloGrowth

pattern

of

both

benign

(has

apedicle)

and

malignant

tumor

(also

grow

binfiltrating)2.

Exophytic

growth:ExophyticgrowthThe

mode

of

most

malignanttumorabsenceof

capsule,

infiltrate

and

destroysurrounding

tissue3.

Infiltrating

growthII.

Biology

of

tumor

growthMonoclonality:

Tumor

is

formed

by

a transformedcell

proliferationThe

natural

history

of

most

malignant

tumors can

be

divided

into

four

phases:Malignant

transformation

in

the

target

cellClonal

growth

ofthe

transformed

cellsLocal

invasionDistant

metastasisThe

multiple

factors

that

influencetumor

growth

are

considered

underthree

headings:kinetics

of

tumor

cell

growthTumor

angiogenesisTumor

progression

and

heterogeneityKinetics

of

tumor

cell

growthDoubling

time

of

tumor

cellsGrowth

fractionTumor

cell

production

and

lossDoubling

time

of

tumor

cells:In

reality,

cell

cycle

time

for

many

tumoequal

to

or

longer

than

that

ofcorresponding

normal

cellsgrowth

oftumor

is

not

associated

with

ashortening

of

cell

doubling

timeGrowth

fraction:

the

proportion

of

cellswithin

the

tumor

population

that

are

in

theproliferative

pool

(

S

+

G2

phase

).①

Early

stage

→vast

majority

oftransformed

cell

are

in

the

proliferativepool

→high

growth

fraction②

As

tumors

continue

to

grow

→cellleavethe

replicative

pool

→by

differentiatingand

by

reversion

to

Go

→in

rapidly

growing

tumors

→

approximately

20%Tumor

cell

production

and

loss:Growth

of

tumors

are

determined

by

theexcess

of

cell

production

over

cell

loss.The

rate

of

tumor

growth

depends

on:Growth

fractionDegree

of

imbalance

between

cellproduction

and

cell

lossHigh

grow

fraction:Clinical

course

is

rapid

(lymphoma)susceptibility

to

chemotherapyLow

grow

fraction

(cell

production

exceedcell

loss

by

only

about

10%):Grow

at

a

much

slower

pace

(car.

of

colon)no

susceptibility

to

chemotherapyTumor

angiogenesisAngiogenesis

is

a

necessary

biologiccorrelate

of

malignancy:

tumors

cannotenlarge

beyond

1

to

2

mm

in

diameter

orthickness

unless

they

are

vascularized.Angiogenesis

is

requisite

not

only

forcontinued

tumor

growth,

but

also

formetastasis.Neovascularization

has

dual

effect①

Perfusionsuppliesnutrients

and

oxygen②

Newly

formed

endothelial

cellsecreting

polypeptides

such

asinsulin-like

GF,

PDGFstimulate

the

growth

of

tumor

cellHow

do

growing

tumors

developa

blood

supply?①

Tumor

associated

angiogenesis

factorsproduced

bytumor

cellsinfiltrated

inflammatory

cVEGF,

FGF,

PDGF②

Tumor

induce

antiangiogenesis

moleculeWP53

→induce

thrombospondin

1→

inhibit

formation

of

BVP53

gene

mutation

→thrombospondin

1↓→BV↑Plasminogen,

collagen,

transthyretin→proteolytic

cleavage→angiostatin,

endostatin,

vasculostatin,→potent

angiogenesis

inhibitors◆

Tumor

progression

and

heterogeneityTumor

progressionMalignant

tumor

become

moreaggressive

in

the

processofgrowthaccelerated

growthlocal

invasiondistant

metastasis2.

Tumor

heterogeneityIn

the

process

of

growth,

monoclonal

tumor

cellgenerate

subclones

with

different

characterisInvasiveness,

rate

of

growthhormonal

responsivenesssusceptibility

to

antineoplastic

drugs3.

Mechanism:Mutant

additional

genes

damage2.

Spread

of

neoplasmsLocal

invasion(direct

spread)MetastasisLymphatic

metastasisHematogeneous

metastasisTranscoelomic

metastasis (Metastasis

in

body

cavities) (seeding)Spread

of

neoplasmsDirect

spreadMalignant

tumor

C

→infiltrate

tissue,lymphatic,

BV,

nervous

tissueMetastasisMalignant

cells

from

primary

site

invadeinto

lymphatics,

BVs

and

body

cavities

and

reacdistant

site

continues

growth

to

formthe

same

type

tumor

with

primary

tumor①The

most

common

pathway

for

theinitial

dissemination

of

carcinoma②

Sarcoma

may

also

use

this

route③

The

most

common

site:LungArm

pit,

groin,

cervical

glands(1)

Lymphatic

metastasis:LeftGastrointestinal

tract

supraclavicularLNRetrogrademetastasisAfferent

lymphaticsSubcapsular

sinusTumor

emboliPrimary

tumorLymphatic

noduleEfferent

lymphaticsLymphaticmetastasisLymphaticmetastasis(2)

Hematogeneous

metastasis①

The

favored

pathway

ofsarcoma.②

Metastatic

pathway:Caval

blood

lungPortal

blood

liverPulmonary

v(cap)

brain,

bone,

kidneyVertebral

vein

paravertebral

plexusbrain

(

Prostate,

thyroid)③

Common

sites:

lung

(most),

liver,

bon④

Features

of

hematogeneous

metastatic

tummultiple,

rounded

nodules

with

clear

border,scattered

in

distribution,

closetosurfaceoforgChoriocarcinomaCarcinomaumbilicusHematogeneousmetastatic

tumor

locatedsurface

of

the

organ

forms

umbilication

becof

central

hemorrhage

and

necrosis(3)

Transcoelomic

metastasis(Metastasis

in

body

cavities

or

Seeding)①

Definition:

Malignant

tumor

cell

of

anorgan

in

body

cavity

penetrate

into

the

surfaceof

the

organ

and

break

off

to

seed

in

the

surface

of

the

organs

of

body

cavity

and

formmetastatic

tumor.TranscoelomicmetastasisColloid

carcinoma

ofstomachseed

inthe

sur

eof

inte

tine②

krukenberg

tumor:Gastric

carcinoma

destroy

gastric

walland

tumor

cell

seed

in

the

ovaries

to

formmetastatic

tumor③

Sitesperitoneal

cavity

(most

common)pleural,

pericardial,subarachnoid,

joint

space④

Surgical

instruments:

rarean

artificial

mode

ofdisseminationThe

mechanisms

of

invasion

andmetastasisThe

mechanism

of

local

invasionVascular

dissemination

and

homingof

tumor

cellsMolecular

genetics

of

metastasis◆

The

mechanism

of

local

invasioDetachment

of

the

tumor

cells

from

each

other

:Down-regulation

of

E-cadherin

(CAM)

expressionAttachment

to

matrix

components:Integrin

(epithelium)

binding

to

laminin

(BM)Degradation

of

extracellular

matrix:Tumor

cellsecrete

proteolytic

enzymesinduce

host

cell

to

elaborate

proteases(4)

Migration

of

tumor

cells:

Mediated

byTumor

cell

derived

motility

factorsCleavage

products

of

matrix

components◆

Vascular

dissemination

and

homing

oftumor

cellsSingle

tumor

cell

is

destroyedby

nature

killer

cell

(NKC)Formation

of

platelet-tumor

aggregateEnhance

the

survival

and

implantabilityTumor

emboli

involve

adhesionto

endothelium

cells

(EC)Egress

through

the

basement

membrane

(BM)prostate

to

bonelung

to

adrenal,

brainbreast

to

lung,

liver,

boneTumor

cell

express

the

adhesion

moleculeswhose

ligands

are

expressed

on

the

EC

of

the

target

organs.Some

target

organs

may

liberatechemoattractants

to

recruit

tumor

cellto

the

site.Some

organs

may

be

an

unfavorable

soilfor

the

growth

of

tumor

seeding:

suchas

spleen,

heart,

skeletal

muscleOrgantropism◆

Molecular

genetics

of

metastasisNo

single

metastasis

gene

has

been

found.The

gene

that

encode

E-cadherin,

inhibitorsof

metalloproteinases,

nm23,

etc.

isconsidered

metastasis

suppressor

genes.III.

Grading

and

staging

of

tumorGrading

of

tumor:According

to

degree

of

differentiatioand

the

number

of

mitoses:Grade

Ⅰ:

well-differentiatedGrade

Ⅱ:

moderately-differentiateGrade

Ⅲ:

poorly-differentiatedGrade

Ⅳ:

undifferentiatedWell-differentiatedModerately-differentiaPoorly-differentiatedUndifferentiatedStaging

of

tumor:Based

onsize

of

the

primary

lesion,its

extent

of

spread

to

LNdistant

metastasis:UICC

(international

union

against

cancer)TNM

classification

of

malignant

tumoursT:

primary

tumor,

T1~T4

→increasing

sizeN:

Regional

LN

involved,

N0→no

involved;

N1-N3M:

distant

metastasis,

M0→no;

M1-M2Take

home

question:How

tumor

growth?

(growth

pattern)How

neoplasms

Spread?

(Invasion

and

metastasis)The

concepts

of

metastasis,

carcinomaumbilicus

and

transcoelomic

metastasis,tumor

progression

and

heterogeneity?Try

to

explain

The

process

of

tumor

cellslocal

invasionSection

4.

Effects

of

tumor

on

hosBenign

tumor:

less

effectsLocal

oppression

and

obstruction:Relate

to

site

and

secondary

changeImportantorgans:

intestinal,

brain→herniaTumor

of

endocrine

glands:

systemic

symptoms–

Acidophilic

adenoma

of

hypophysis

cerebri:gigantism

or

acromegaly–

Adenoma

of

pancreatic

islets:

fatal

hypoglycMalignant

tumorLocal

compression

+

obstruction

+

painConstitutionalsymptoms: Fever,

infection,

night

sweatCachexia:Refer

to

the

state

of

progressive

loss

oweight,

anemia,

weakness

and

systemicfailure.4.

Paraneoplastic

syndrome

(

PNS

)Neoplastic

product

(ectopic

hormones)Abnormal

immune

reaction

(cross

immune,autoimmune,

immune

complex

)Other

unclear

causesLead

to

lesions

of

endocrine,

nervous,digestive

system

and

so

on(1)

Ectopic

endocrine

syndrome:Some

non-endocrine

tumors

elaboratehormones

or

hormone-like

substance

causeendocrine

disorder.①

Hypercalcemia:

parathormone

-like

substanceelaborated

by

carcinoma

of

lung,

kidney②

Hypoglycemia:

elaboration

of

insulin-likesubstance

by

fibrosarcoma,

mesotheliomaHypertrophic

osteoarthropathy:Formationof

bone,

arthritis

of

theadjacent

joint

and

clubbingof

the

digits.Vascular

and

hematologic

syndrome:Migratory

thrombophlebitis,endocarditisSection

6.

Differences

betweenBenign

and

malignant

tumor

※Degree

ofdifferentiationMitotic

figurestructure

is

typicalrare

and

normalobvious

atypiaincreasedno

pathologic

mitoticRate

of

growthGrowth

patternslowexpansiveexophyticwell

demarcatedpathologic

mitoticrapidinfiltrativeexophytic

poorly

demarcatedBenignwellmalignantpoorly※

Difference

between

benign

and

malignant

tu(PartI)rarecommon(

hemorrhage,

necrosis)SecondarychangesLocal

invasiveMetastasisRecurrenceEffectsnoninvasiveabsent

rarecompressionlocally

invasivecommoncommon/view3/M01/1C/20/wKh2BF1z