PROGRESIA TUMORALA:

INVAZIA LOCALA SI
METASTAZAREA

ef lucr. Dr. Mihai MARINCA

Sumar

Boala metastatic semnificatii biologice, clinice si prognostice

Invazia local aderare, distrugere, locomotie

Metastazarea fazele cascadei metastatice

Angiogeneza tumoral semnificaie clinic i terapeutic

Profilaxia cancerelor profilaxia primar, secundar i teriar

Screeningul cancerelor condiii, metode, rezultate

Metastazarea definiie

Cancerele nu sunt boli statice, ci dinamice.

Metastazarea este procesul de rspndire (diseminare) a celulelor maligne

din tumora primar n alte compartimente (organe, esuturi, umori) ale
organismului sau transferul bolii maligne de la un organ (sau de la o parte a
acestuia) la un alt organ sau esut cu care acesta nu este n contact
anatomic.

Metastazarea i invazia local reprezint trsturile biologice eseniale ale

fenotipului malign
cauze majore de morbiditate la pacienii cu cancer
responsabile pentru majoritatea (70-90%) eecurilor terapeutice i deceselor prin cancer

Metastazarea reprezint procesul fundamental care difereniaz tumorile benigne

de cele maligne i principala problem terapeutic n oncologie, deoarece
transform un cancer de organ ntr-o boal a ntregului organism (sistemic)
cu alte cuvinte, determin o boal comun majoritii cancerelor boala metastatic

Metastazarea este un proces biologic ineficient deoarece foarte puine celule

ajung s colonizeze le distan (decathlon champions)
Fenotipul malign

Cretere necontrolat

Reducerea Independena fa
sensibilitii la de semnalele
apoptoz inhibitorii

Cancer

Dezvoltarea i
meninerea unei Invazia i
vascularizaii tumorale
(angiogenez)
metastazarea

Potenial nelimitat de cretere

Adapted from Hanahan, et al. Cell 2000

Etapele cascadei metastatice
Varianta lung

Proliferarea celular tumoral necontrolat

Detaarea celulelor din tumora primar
Invazia i degradarea matricei extracelulare
Ataarea celulelor tumorale la membrana bazal (ancorarea)
Distrugerea proteolitic a membranei bazale
Migrarea celulelor maligne prin brea membranei bazale n strom
Stimularea formrii de vase de snge noi (angiogeneza)
Ptrunderea celulelor tumorale n vasele de snge i/sau limfatice (intravazarea)
Supravieuirea i transportul celulelor n circulaie (citemia malign)
Oprirea lor n vasele (capilare) ale unor organe aflate la distan (arest n cicula ie)
Scparea celulelor tumorale din vasele de snge sau limfatice (extravazarea)
Creterea i dezvoltarea celulelor sub forma unor tumori secundare (metastaze)
Interaciunea cu mecanismele imune ale gazdei i rezistena la tratament
Generalizarea metastazelor (metastazarea metastazelor)
Etapele cascadei metastatice
Varianta scurt

ESENIALE:

1. Invazia i motilitatea

2. Intravazarea i supravieuirea n circulaie

3. Blocarea (arestul) n circulaie i extravazarea

4. Creterea n organe la distan

Etapa 0: Modificri genetice

Primul pas n tumorigenez const din acumularea modificrilor genetice

precum:
Mutaii la nivelul proto-oncogenelor cu iniierea proliferrii necontrolate
Pierderea genelor supresoare cu achizitionarea capacitilor de rezisten la
apoptozei i instalarea instabilitiii genice

Instabilitatea genic = mutaii spontane ale ADN celular prin:

Modificri genice
Modificri epigenetice - modificarea expresei genice prin:
metilare
(acetilare sau fosforilare)
Cancer tends to involve multiple mutations
Invazia local

Invazia este un proces activ n 3 pai:

Detaarea celulelor tumorale (loosening up) i aderarea de componentele

membranei bazale (MB)
Distrugerea (liza) MB cu degradare matricei extracelulare (MEC)
Migrarea (locomoia) celulelor tumorale
Etapa I Detasarea celulelor maligne si aderarea la MB

Detaarea celulelor canceroase din tumora primar:

expresiei moleculelor de adeziune (ex. E-caderine)
pierderea jonciunilor intercelulare
Caderinele sunt receptori de adeziune intercelulari, constitueni ale jonciunilor
intercelulare

Ataarea de componentele MB: integrine

Integrinele servesc ca receptori pentru numeroase componente ale MEC incluznd:
Fibronectina

Laminina
Collagenul
Vitronectina
Semnalizarea prin integrine i receptorii factorilor de cretere permite celulelor tumorale
s detecteze polaritatea i ataarea de MEC
Procesul de invazie local n trei etepe

Pas I- Aderare de MB:

- molecule de adeziune: interaciuni:
integrine (CAM) laminina
laminine receptors fibronectina,
proteoglicani
caderine E, P i N vitronectin, colagen IV,
Pas II Distrucia (liza) membranei bazale
- metaloproteinaze ( MMP, matrixine) syntesis: MMP
- seric proteinase
- stromelizina
- aspartases- Catepsina D

Pas III - Migrarea

- Factori de motilitate -AMF
 Pasul I Aderarea de membrana bazal

Aderarea
After losing attachment with neighbors, malignant cells interact with the ECM in order to
degrade, remodel, attach, and invade through this matrix.

Molecule de adeziune: integrins

laminin receptors
caderine E ( epithelial), P (placentar), and N ( neural)
CD 44
immunoglobulins
Invasion starts with alterations in cell adhesion.
In many cases this entails the loss of E-cadherin, which is the prototype member of the
cadherin family (cell-cell adhesion molecules)

Integrine signaling works together with growth factor receptors by allowing cells to
sense ECM attachment and polarity.
Bariere externe- matricea extracelular ce limiteaz
progresia tumoral
Organism= compartiment celular + matricea
extracelulara
Matricea extracelular (MEC) = membrana bazala (MB) +
stroma interstiial i de organ

Membrana bazal: colagen structure: colagen I,II,III and

IV,V
structur non colagenic-
fibronectin
- laminin
-
proteoglicani
SPEP II- Distrugerea membranei bazale

Matrixines metalloproteinases (MMP): lytic enzymatic activity of malignant cells

Colagenase I, II, III, IV, V
Stromelisine
Gelatinase A, B
Seric proteinase - plasminogen activator
Cistein proteases
Aspartase endoglicosidase

Cleavage products of matrix components derived from collagen and proteoglicans

also have growth-promoting, angiogenetic and chemotactic activities.
TREAPTA III- Migrarea (locomoia)

Factorii autocrini de cretere (factor de automotilitate - AMF):

Chemothaxine
Autotaxine

Pseudopod- oraganit celular senzor

Cytoskeleton modification
 Invazia tisular i METASTAZAREA

Caracteristic esenial a tumorilor maligne.

Proces precoce (!), complex, multistadial (cascada metastazrii) reglat de:

gene care promoveaz iniierea (ex., MET), progresia (ex., MMP1) i
virulena invaziei i metastazrii (ex., RANK);
gene supresoare ale metastazrii (ex., diferite GST).

Aplicaii clinice:
semntura metastazrii (identificarea unui set de gene de metastazare)
rol prognostic + decizii terapeutice;
ex., MammaPrint test i Oncotype Dx pentru cancerul de sn
terapii intite;

ex., ARQ 197 inhib gena MET de iniiere a metastazrii

18
 Micromediul tumoral acioneaz ca un factor
de presiune selectiv asupra celulelor tumorale

Celule stem canceroase

Fibroblaste asociate Celule canceroase

tumorii (clone cu diferite mutaii
oncogene +GST)

Celule endoteliale
Celule imune
Pericite inflamatorii

Tumora = organ complex celule

specializate heterogene
(strom + parenchim)
ntre care se stabilesc Celule canceroase
interaciuni moleculare complexe invazive
19
Infiltrate celulare n micromediul tumoral

Tumorile prezint o
varietate de celule ale
sistemului imun care
contribuie la formarea
stromei esutului malign.
Tumorile posed celule
infiltrante aparinnd att
sistemului imun nativ ct i
celui de adaptare precum
MDSC, macrofage, DC,
mastocite, eosinofile,
neutrofile, celule NK i
limfocite. Aceste celule
formeaz o reea reglatorie
complex care stimuleaz
proliferarea tumoral si
creeaz un mediu permisiv
pentru eludarea
INTERACIUNILE DINTRE CELULELE TUMORALE I
STROM

21
Cancer mamar
ANGIOGENEZA
Angiogeneza este esentiala pentru nutriia, creterea i
supravieuirea celulei tumorale

Tumorile mai mari de 2mm in diametru necesita un suport independent de

snge pentru a supravieui i crete

1. Folkman. In: Kufe, Pollock, Weichselbaum, eds. Cancer Medicine (Holland). 6th ed. Hamilton, Ontario: BC Decker; 2000
2. Bergers, Benjamin. Nat Rev Cancer 2003; 3. Folkman. NEJM 1971; 4. Folkman. J Natl Cancer Inst 1990
 Angiogenesis: essential for Tumor Growth
and Malignant Progression

PremalignantMalignant Tumor Vascular Micro- Metastatic

tumor tumor growth invasion metastases growth
Angiogenic
switch

Stages at which angiogenesis plays a role in

tumor progression
Fazele angiogenezei tumorale

Celulele hipoxice sau euturile lezate produc i eleibereaz factori de cretere

angiogenetici (proteine) care difuzeaz n esuturile de vecintate.
Factorii de cretere angiogenetici (ex VEGF) se leag de receptorii endoteliali
localizai pe celulele endoteliale sau de vasele de snge preexistente n vecintate.
Factorii proangiogenetici se leag de receptorii lor, celulele endoteliale devin activate.
Semnalele sunt transmise de la suprafaa celulei endoteliale la nucleu. Mainria celulei
endoteliale ncepe s sintetizeze noi molecule, inclusiv enzime.
Enzimele dizolv mici orificii n membrana bazal a tuturor vaselor de snge de
vecintate.
Celulele endoteliale ncep s se divid (prolifereaz) i migreaz prin fantele create
n mengrana bazal a vaselor existente spre esutul tumoral ( tumora).
Moleculele specializate numite molecule de adeziune (CAM) sau integrinele (avb3,
avb5) servesc ca i crampoane pe care se dezvolt mugurii vasculari care sunt mpini
nainte.
Enzime de liz (metaloproteinaze sau MMP) sunt produse local i dizolv esuturile din
faa mugurilor vasculari pe care acetia se acomodeaz. Pe msur ce vasele se
extind, esutul este remodelat n jurul vaselor.
Celulele endoteliale sub form de muguri vasculari sunt remodelate pentru a forma
un tub vascular de snge.
Tubii vasculari individuali se conecteaz la ansele vasculare prin care ncepe s circule
sngele.
n final, vasele de snge nou-formate sunt stabilizate de celulele musculare specializate
( celule musculare netede, pericitele) care ofer un suport structural. Curgerea sanguin prin
vase ncepe!
Fazele angiogenezei tumorale
Angiogeneza tumoral

1. Faza prevascular (diametru 2-3mm), tumoare alb

- faza dormant asimptomatic
# 1 milion de celule tumorale
- proliferare compensat de rata de moarte celular
2. Faza de switch ctre un fenotip proangiogenic, tumoare roie
- factorul de hipoxie tisular (HIF) i prezena de celule moarte (AT1)
- modificarea echilibrului proangiogenic
- permite tumorii s creasc i s prolifereze susinut
- permite diseminarea metastatic
Hypoxia

Under hypoxic conditions, the hypoxia inducible factor (HIF) transcriptional regulatory
proteins HIF-1 and HIF-2 are no longer hydroxylated by a family of oxygen-
regulated proline hydroxylases (PHD1-3), which disables the binding of the von
Hippel-Lindau (VHL) tumor suppressor protein.
By adapting to the selective pressure of hypoxia, tumor cells acquire the ability to
withstand harsher microenvironments by switching to glycolysis
resisting cell death
inducing angiogenesis
invading through the ECM
Both expression of HIF-1 levels and tumor hypoxia predict for worse overall survival
and a higher risk for metastasis
Mediatori moleculari ai angiogenezei tumorale

PROANGIOGENIC ANTIANGIOGENIC
______________________________________________________________
VEGF-A, VEGF-B, VEGF-C Trombospodin (TSP1)
PDGF Angiogstatin
FGF (FDF2, FGF1) Arrestin (fragment de colagen IV)
Angiopoietin (ANG1, ANG2) Canstatin (fragment de colagen IV)
IL 8 Tissue inhibitors of
TNF- metalloproteinases (TIMP)
IFN-, IFN-
Acid retinoic
Fibronectin
Endostatin
 Angiogenesis un pas esential in progresia
tumorala
Angiogeneza + Limfangiogeneza = Love
Era terapiei antiangiogenice

The era of antiangiogenic drug

development began with the publication
in 1971 of a landmark hypothesis article
in the New England Journal of Medicine
by Judah Folkman

Physiologic appearance of the angiogenic switch

Images reproduced with permission from Judah Folkman.

The angiogenic switch leads to neovascularization, as shown in a rat

tumor model1

Reference: 1. Folkman J. N Engl J Med. 1971;285:1182-1186.

6
VEGF: element central al angiogenezei tumorale

Hypoxia PDGF
IGF-1
EGF

IL-8
Binding and activation
VEGF release of VEGFR
bFGF

COX-2
Nitric oxide
Oncogenes

Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)

Survival Proliferation Migration

Permeability
ANGIOGENESIS
Inhibiia VEGF: activitate terapeutic

Antibodies inhibiting Anti-VEGF antibodies Soluble VEGF

VEGF receptors (e.g. Avastin) receptors

VEGF
VEGFR-2

Small molecule VEGFR

inhibitors (TKIs)

Ribozymes
Agenii anti-angiogenici

EARLY EFFECTS CONTINUED EFFECTS

1 Regression 2 Normalisation 3 Inhibition

Improves
Decreases Suppresses new
delivery of
tumour size vessel growth
chemotherapy

Willett, et al. Nat Med 2004; Gerber, Ferrara. Cancer Res 20

Cile de diseminare

Celulele tumorale diseminea prin una din urmtoare le ci:

Diseminare limfatic (carcinoame)
Circulaie hematogen (sarcoame)hematogenous spread
Diseminare direct pe calea seroaselor (peritoneal, pleural) caviti i suprafee
Perineural
Circulaia sangvin

Circulaia sanguin i limfatic reprezint un mediu foarte ostil pentru celulele

tumorale, 80% dintre acestea fiind distruse la acest nivel.
Celulele tumorale se protejeaz prin legarea de factori de coagulare inclusiv
trombina, fibrinogenul, factorul de cretere tisular i fibrina formnd emboli.
O mare parte adopt agregarea de alte elemente figurate sangvine (agregare
heterotipic), altele agreg ntre ele (agregare homeotipic), iar restul circul libere.
Distrugerea celulelor tumorale n timpul citemiei
caracteristici ale celulelor tumorale: deformabilitatea, agregabilitatea de suprafa i
moleculelor de adeziune
factori din mediul gazd: turbulenele sanguine, celulele NK, macrofagele i trombocitele.
trecerea prin patul capilar: noi solicitri prin forele de adeziune i oxidul nitric (NO)
produs de celulele endoteliale (efecte multiple ce pot influena soarta metastazrii:
vasodilataie, agregare plachetar i efecte citotoxice asupra macrofagelor).
Hipoxia crete potenialul de metastazare prin creterea rezistenei la apoptoz,
prin pierderea funciei genei supresoare p53, creterea expresiei moleculelor
antiapoptotice a familiei Bcl-2 i scderea expresiei moleculelor proapoptotice,
creterea factorului de hipoxie tisular (HIF).
Blocarea (sechestrarea) n patul capilar

Odat aflai n circulaie, embolii tumorali se ataeaz ferm de stratul intern al

intimei vaselor i sunt sechestrai n teritoriile capilare ale diverselor organe. Dup
sechestrarea celulelor tumorale n snge sau limf au loc urmtoarele evenimente:
Aderena la endoteliu;

Retracia celulelor endoteliale;

Distrugerea MB vasculare;

Locomoia celulelor tumorale n parenchimul organului gazd.

Extravazarea

Cancer cells can mimic leukocytes and bind to endothelial E- and P-selectins.

Molecular mediators of extravasation include the cytoskeletal anchoring

protein Ezerin:
links the cell membrane to the actin cytoskeleton
engages the cell with its microenvironment
Dormana

A major limiting step in metastasis is acquiring the ability to sustain growth

within a distant site after extravasation.

Many cancers such as breast and prostate will not give rise to metastasis until
10 or even 20 years after eradication of the primary tumor.

This latency is referred to as metastatic dormancy and is thought to arise from

microscopic disease that, with time, acquires the ability to sustain growth.
Caracteristici metastaice in diverse organe
in functie de tipul de cancer
The Seed and Soil Hypothesis

1889 - Stephen Paget propune teoria

seed and soil :
Capacitatea diferitelor cancere de a
forma metastaze n anumite organe
se datoreaz dependenei
seminei (seed, cancerul) de
teren (soil, organul la distan)

The Distribution of Secondary

1915 - James Ewing propune
Growths inteoria
Cancer of the Breast
The Lancet, 1889
hemodinamic bazat pe fatorii
mecanici i circulatori.

Stephen Paget
1855 1926
 Un model integrat al metastazarii

Somatic evolution of cancer during growth at the primary site results in the
selection of tumorigenic functions (light blue) that are fulfilled by
tumorigenic genes.
Metastasis-specific functions are considered those that act on tumor cells
after intravasation and enable them to home to, penetrate, or colonize
distant organs (orange). Genes that provide such functionality are
Interactions between cancer and
the bone microenvironment lead to
a vicious cycle. Cancer cells can
migrate to the bone
microenvironment under the
influence of CXCL12, which also
leads to cell activation and
migration via CXCR4.
The tumor cell secretes factors that
promote osteoclast differentiation
such as osteopontin (OPN) and
interleukin-11 (IL-11).
Proteases such as matrix
metalloproteinase 1 (MMP1) and
MMP7 are also secreted.
Parathyroid hormone-related
protein (PTHrP) can lead to
production of membrane bound
RANKL on osteoblasts. This leads to
RANK-mediated osteoclast
activation.
Other cytokines may also inhibit
production of osteoprotegerin
(OPG), which antagonizes
Rolul sistemului imun n metastazare

15-20% of cancer deaths are related to infections and inflammation.

A rapid response is mounted by a front line composed of innate immune cells
such as neutrophils, macrophages, mast cells, dendritic cells, eosinophils,
and natural killer (NK) cells.
The purpose is to restore homeostasis through several phases: inflammation,
tissue formation, and tissue remodeling.
Tumor-associated macrophages (TAMs) can comprise a large proportion of
tumor bulk.
Clinical evidence also is pointing toward innate immune cells in cancer
progression.
Factorii care indic potenialul metastatic al unei tumori

Gradul de invazie a ganglionilor limfatici (N).

Mrimea tumorii.
Markeri histologici:
(1) Gradul de difereniere tumoral ( G): G2,3 versus G1
(2) Profunzimea invazei n compartimentele tisulare
(3) Prezena invaze limfatice (L1,L2) si vasculare (V1,V2)- embolii vasculari
Metastazarea- concluzii

Boala metastatic determin decesul majoritii pacienilor cu cancer.

Fenomenul de metastazare transform cancerul dintr-o boal de organ ntr-
una sistemic.
Mutaiile genetice, micromediul tumoral i interaciunile cu celulele gazdei
dirijeaz diseminarea metastatic a celulelor tumorale.
Procesul de metastazare este un proces complex, selective i ineficient care
poate fi mprit n patru etape: invazia, intravazarea, supravieuirea n
circulaie i extravazarea. Colonizarea celulelor tumorale necesit capacitatea
de a prolifera n esuturi strine i angiogeneza.
Creterea metastazelor reprezint etapa final a numeroase evenimente letale
n urma crora supravieuiesc un numr redus de celule.
Formarea unei nie premetastatice este esenial pentru creterea celulelor
maligne extravazate.
Specificitatea metastazelor de organ este determinat att de fluxul sangvin
ct i de factorii specifici de organ.
Tumorile primare prezint celule stem care recapituleaz formarea tumorilor
dintr-o singur celul, celule care prezint expresia modificrilor genetice cu
creterea potenialului metastatic.
Terapiile sistemice antiimetastatic vor trebui s anihileze numeroase ci
biologice care controleaz proliferaraea, invazia i angiogeneza.
Prevenia cancerelor
Prevenia primar

Primary prevention aims to reduce the incidence of cancer by:

controlling (avoiding) exposure to risk factors
increasing an individuals resistance to risk factors (by immunisation or
chemoprevention).
Medical education
Legislation
Fiscal measures
Temporal and spatial restrictions
Advertising interdictions
Preventie secundar

Prevenia secundar presupune identificarea i tratamentul unor leziuni

precanceroase sau cancere n stadii precoce, fr expresie clinic, a cror
eradicare poate suprima evoluia spre neoplazie invaziv i metastazant

Prevenia secundar detecteaz boala dup debutul patogenezei sale i include

- screening-ul sau depistarea precoce (cutarea unor leziuni premaligne),
i pe de alt parte
- diagnosticul precoce (diagnosticul bolii n faza asimptomatic sau cu
simptome minime, inclus parial i n prevenia teriar).
Prevenie teriar

Tertiary prevention usually defined as:

prevention of loco-regional relapse and/or metastatic disease after

(hopefully curative) primary treatment by surgery or radiotherapy

maintenance of quality of life of patient by successful prevention of

suffering ( from pain, disease, and treatment-related side-effects and
complications).
SCREENING
Conditii pentru screening-ul unui cancer

1968 Wilson and Jungner ghid de screening:

Cancerul respectiv sa fie o problema important de sanatate publica.

Istorie natural cunoscut.

S prezinte o perioad de laten (asimptomatic) lung

S existe un tratament eficient

S fie accesibil unui test pentru public si profesionisti.

S existe un test de laborator sensibil si specific pentru examinare

Testul trebuie s fie acceptabil publicului larg

S existe ghiduri de tratament pentru tumorile inclusiv cele borderline

Costurile bolii diagnosticate precoce s fie echilibrate pentru ngrijirile

medicale.
Persoanele depistate prin screening s triasc mai mult dect cele
diagnosticate n faza simptomatic.
Caracteristicile unui test de screening ideal

Sensibilitatea- reprezint procentul de indivizi cu un examen pozitiv (numii

adevrai pozitivi) dintr-o populaie de adevrai bolnavi sau procentul de
pacieni cu testul negativ din cei etichetai ca fali negativi.
Specificitate- semnific probabilitatea ca un test s fie negativ ntr-o populaie
fr boal. ntr-o populaie, indivizii al cror test este negativ reprezint
adevraii negativi, n timp ce acei ce prezint testele pozitive reprezint
falii pozitivi.
Cost redus
Lipsit de riscuri
Simplu
Uor de administrat
S poat fi implementat n mas
S conduc la instituirea unui tratament eficace
S conduc mortalitatea specific
Costuri psihologice i financiare, s nu determine rezultate fals pozitive
Validitatea uni test
SCREENINGUL CANCERULUI DE COL UTERIN
Cancer de col uterin- factori de risc

Risk factors for the development of cervical cancer

Infection with human papillomavirus (HPV)
Age, race, and socioeconomic status
Degree of immunosuppression (e.g., HIV positivity, transplant patients)
Sexual activity*
Tobacco smoking

Sexual behavior is probably largely a surrogate for the risk of exposure to HPV.
*
Routine Screening and Early Detection for Cervical Cancer
and its Prevention
Colposcopy
Pap Smear

A pap smear can reveal the presence of the human papillomavirus:

On the left, normal cells.
On the right, cells infected with the virus.
Ghid de screening cancer de col uterin
Screening cancer de col uterin - metodologie

Rolul depistrii precoce este bine stabilit n cancerul de col uterin, mortalitatea prin
acest tip de cancer scznd cu circa 70% n ultimii 30 de ani n rile cu programe
de screening eficiente.
Screening-ul cancerului de col uterin const din examinarea de rutin a frotiului
citologic cervico-vaginal Babe-Papanicolau (Pap-test).
Persoanele cu anumii factori de risc (infecie cu HIV, imunosupresie, expunerea in
utero la dietilstilbestrol, tratament prealabil pentru o displazie neoplazie
intraepitelial cervical [CIN] de grad 2/3, sau pentru cancer cervical) trebuie
screenate la intervale mai reduse. Vrsta maxim pentru screening-ul cancerului de
col uterin nu este clar definit.
Aspectele citologice (normal, displazie/CIN, malign) sunt clasificate actual dup
sistemul Bethesda. Dac rezultatele unui test Papanicolau sunt pozitive, se va
recomanda colposcopia, eventual cu utilizare de acid acetic glacial. Leziunile
epiteliului cervical (displaziile) cu grad redus de risc vor fi urmrite periodic, pn la
remisiune/progresie, iar cele cu risc crescut trebuie tratate prin proceduri loco-
regionale ablative/excizionale.
Cea mai important problem n depistarea precoce a cancerelor de col uterin
rmne aceea legat de atragerea unui numr ct mai mare de femei n aciunea
de screening, mai cu seam din categoria celor cu factori de risc crescut
SCREENINGUL CANCERULUI MAMAR
Breast Cancer

Indications for genetic testing in breast cancer*

A first-degree relative with breast cancer before age 40
Two or more relatives with breast or ovarian cancer at any age
Three or more relatives with breast, ovarian, or colon cancer at any age

* The indications for genetic testing in breast cancer and in other cancers are in rapid
evolution as the true risks become better defined and as prevention (e.g., tamoxifen)
and early detection (e.g., mammography, MRI) strategies mature.
Cancerul mamar
Mijloace de screening

Mammography

Breast self
examination
(BSE)

MRI

Clinical breast
examination
(CBE)
Ultrasound
Metode de screening

Mammography
Relative breast cancer-specific mortality decreased by 15%
Absolute mortality benefit for annual screening starting at age 40 = 4 per 10,000
at 10.7 years, vs. 5 per 1,000 for women screened annually starting at age 50
Absolute benefit approximately 1% overall, but depends on inherent breast
cancer risk, which rises with age

CBE
BC mortality similar for women aged 50-59 undergoing screening CBEs with or
without mammograms.

BSE
No difference in breast cancer mortality seen after 10 years; 40% of women
enrolled, however, were younger than 40 years.
http://www.cancer.gov/cancertopics/pdq/screening/breast/healthprofessional#Section_175
Cancer mamar- studii de screening
Screening of women at high risk for familial breast cancer by mammography,
ultrasonography, and MRI: sensitivity and specificity of each modality
 Screening

Screening mammography prospective, randomized trials

Rolul IRM in screening
Ritmul de screening

Normal risk

Age 20-39: CBE every 1-3 years

Age 40: annual CBE and mammography

Increased risk

Prior thoracic irradiation, age 25: CBE every 6-12 months

annual mammography
starting 8-10 years after RT or at age 25

Family/genetic predisposition, age 25: CBE every 6-12 months

annual mammography
annual breast MRI
starting 5-10 years prior to youngest case in the family
! genetic counseling offered
! risk reduction strategies discussed
NCCN Guidelines on Breast Cancer Screening v1.2016
Breast Cancer: Recommended Screening Algorithm
SCREENING-UL CANCERELOR COLO-RECTALE
Cancerul colo-rectal

Metode de screening n cancerul colo-rectal:

Testul de depistare a hemoragiilor oculte n materiile fecale (FOBT)
(Recto-sigmoidoscopia) Colonoscopia
Colonografia tomografic computerizat ( colonoscopia virtual)

Irigoscopia cu dublu contrast

Testarea ADN n celulele descuamate n materiile fecale
Irigoscopia cu bariu n dublu contrast- Clisma baritat

Nu identific 50% din adenoame

Nu identific 5-10% din CRC

Clisma barita cu dublu contrast
FOBT-Hemocult

Detecteaz numai 25-27% din CRC

90%-rezultate fals + pentru CA

Teste repetate - complian redus

Nu identific pacienii cu polipi adenomatoi

Varianta rehidratat are sensibilitate mai

mare dar specificitate mai mic - teste inutile
Colonoscopia

Cea mai bun metod de screening

Vizualizeaz in 90% din cazuri ntreaga
mucoasa a colonului
Biopsie/Polipectomie/marcarea leziunii
Standardul n dg polipilor
Baz - stratificarea riscului n vederea
screening-ului
Complicatii severe rare
Cost mare
n anul 2012 - Screening cu
sigmoidoscopia flexibil reduce decesele
prin CCR!
Un studiu mare (154.000 pacieni urmrii pe
o perioad de 11,9 ani) a demonstrat o
reducere cu 21% a incidenei CCR i cu 26%
a deceselor
N Engl J Med 2012; 366; 2345-2357
Dar

Rectosigmoidoscopia flexibil

Nu descoper 40-50 % din adenoame

Nu descoper 30% din CRC

Nu necesit sedare

Mai ieftin

Colonoscopia normal

La 5 ani de la o colonoscopie normal <1% au dezvoltat adenoame <

1cm, nici unul CCR

10 ani - interval sigur

Classic & Virtual
Colonoscopy
Capsule Endoscopy
Performanele colonocopiei optice virtuale
Ritmul de testare pentru sreening
Recomandari de screening
Routine Screening and Early Detection for Colorectal
Cancer and its Prevention
SCREENING-UL CANCERULUI DE PROSTAT
Digital Rectal Exam, PSA and Endorectal Prostate
Ultrasonography
Metode de screening n cancerul de prostat

Diagnosticul precoce (screening-ul) n cancerul de prostat, la brbatul

asimptomatic, se va realiza prin:
- evaluarea periodic a PSA,
- examinarea rectal digital (ERD) i/sau examinarea ecografic endorectal;
screening-ul n CP nu a probat o ameliorare a supravieuirii;
valorile serice ale PSA trebuie msurate la pacienii care se prezint cu simptome
urinare;
dac valorile serice totale ale PSA sunt de 0-2g/l, probabilitatea de a avea cancer
de prostat este de 1%; dac PSA > 10g/l, probabilitatea de cancer de prostat
este de 50%;
diagnosticul patologic se va efectua din specimenele de esut prostatic obinut prin
biopsie pe ac, echoghidat;
anatomo-patologul trebuie s raporteze grading-ul tumoral utiliznd fie scala OMS,
fie clasificarea Gleason.
Prostate Cancer
Screening and Early Detection
SCREENING-UL CANCERELOR PIELII
Skin Cancers. Predisposition and Risk Factors
NONMELANOMA MELANOMA
Ultraviolet light (sun) exposure Ultraviolet light exposure
(cumulative)
(intermittent)
Genetic
Xeroderma pigmentosum
Nevoid basal cell syndrome Genetic
Melanocortin receptor
Phenotypic variants
Skin complexion
Sunburn/tanning response
Atypical or dysplastic nevi
Degree of freckling Dysplastic nevus syndrome
Premalignant dermatoses
Actinic (solar) keratoses
Leukoplakia
Phenotypic
Chemical, thermal, scar keratoses Less cutaneous
Chronic inflammation pigmentation
Immunosuppression
Prior history of skin cancer
Regula ABCDE

A- Asimetrie
B- Border - margini
C- Culoare
D- Diametru
E- Elevation - supradenivelare
Malignant Melanoma
Summary of All Cancer Screening
Test Sensitivity Specificity % Positive in practice
I. BREAST CANCER
Film screen mammography 77-96% 94% 10-12%
Digital mammography 64% 86% 12%
Clinical breast examination 17-58% 94% 7%
Breast self-examination 42-72% N/A N/A
Clinical evaluation

II. CERVICAL CANCER

Papanicolaou screen test 30-87% 86-100% 8-13%
HPV DNA testing 83-100% 46-89% 5-40%
Acetic acid and direct visualization 80% 81% N/A

III. PROSTATE CANCER

Prostate specific antigen 63- 83% 81-98% 4-27%
(PSA level>4ng/mL)
Digital rectal examination (DRE) 59% -64% N/A N/A

IV. COLON CANCER

Fecal occult blood test 11-86% 91-99% 2,4-9%
Colonoscopy / Sigmoidoscopy 95% 88-94% >5%
Double contrast barium enema 65-85% 45% N/A
Digital rectal examination (~7cm)
Virtual colonoscopy 44-91% 48-96% N/A