PRECURSORI DI MALIGNITA’
STORIA NATURALE DEI TUMORI
• LA CANCEROGENESI E’ UN PROCESSO
MULTIFASICO
• Più eventi sono necessari per la
transizione da tessuto normale a tumore
maligno
Storia Naturale dei Tumori
•
•
Eventi più numerosi nel caso di tumori frequenti nell'età adulta/anziana
(colon, mammella, polmone,vescica) rispetto a quelli frequenti in età
pediatrica (retinoblastoma, leucemie)
Relazione tumori età
_______________________________________________________
cellula normale/
lesioni
lesioni
lesioni
lesioni
microambiente normale
preneoplastiche
benigne
invasive
metastatiche
↑
↑
↑
↑
↑
↑
↑
_______________________________________________________
EVENTI GENETICI ED EPIGENETICI
↑
Storia Naturale dei Tumori
•
•
Eventi più numerosi nel caso di tumori frequenti nell'età adulta/anziana
(colon, mammella, polmone,vescica) rispetto a quelli frequenti in età
pediatrica (retinoblastoma, leucemie)
Relazione tumori età
_______________________________________________________
cellula normale/
lesioni
lesioni
lesioni
lesioni
microambiente normale
preneoplastiche
benigne
invasive
metastatiche
↑
↑
↑
↑
↑
↑
↑
_______________________________________________________
EVENTI GENETICI ED EPIGENETICI
↑
Storia Naturale dei Tumori
I vari tipi di tumori sono diversi fra loro per quanto
riguarda la storia naturale, cioè
• insorgenza monoclonale, oligoclonale o policlonale
• presenza di lesioni preneoplastiche più o meno
definite
• numero e tipo di eventi necessari per l’acquisizione
della malignità
• durata dell’intera storia e delle sue fasi
• evoluzione ed aggressività
• sedi metastatiche
• interazioni con l’ospite
Tumori appartenenti a uno stesso tipo istologico e con
agente cancerogeno simile presentano generalmente
storie naturali simili
Progressione
•
Sequenza di eventi genici e non- che colpiscono una cellula fornendole le
competenze per la malignità e la resistenza a terapie
_______________________________________________________
cellula normale/
lesioni
lesioni
lesioni
lesioni
microambiente normale
preneoplastiche
benigne
invasive
metastatiche
↑
↑
↑
↑
↑
↑
↑
↑
_______________________________________________________
EVENTI GENETICI ED EPIGENETICI
•
•
In una cellula si accumulano attivazione di oncogeni, inattivazione di geni
oncosoppressori, e alterazioni di geni coinvolti nella malignità
Implicazioni cliniche :prevenzione, diagnosi precoce, terapia
PROGRESSIONE
Progressione
• Succedersi di alterazioni che conferiscono
vantaggio di crescita e/o
metastatizzazione.
• Origina una progenie di cellule con
sempre maggiore malignità.
• Anche le terapie esercitano pressione
selettiva,
• Implicazioni importanti per la terapia
Intervenire prima possibile
Combinare terapie appropriate per ridurre
lo sviluppo di farmaco resistenza
Progressione
Modello colon-retto (Modello di Vogelstein e Kinzler)
Epitelio normale
↓
←
Epitelio iperproliferativo
↓
←
Adenoma lievemente atipico
↓
←
Aden. moderatamente atipico
↓
←
Adenoma fortemente atipico
↓
←
Carcinoma
↓
←
Metastasi
Inattivazione APC (cr 5)
Ipometilazione del DNA
Attivazione K-RAS (cr12)
Inattivazione di
DCC/SMAD4 (cr 18)
Inattivazione TP53 (cr 17)
Altre alterazioni ?
Progressione
Numero di eventi (hits)
• Retinoblastoma 2?
• Colon > 7
• Ca polmone 10-20?
The process of neoplasia begins with cell
transformation.
A variety of chemical carcinogens as diverse
as benzene, cigarette smoke, and nitrites
can initiate and/or promote this process.
Radiation, either as low level long-term
environmental gamma rays or as higher dose
therapeutic radiation, can also produce
genetic mutations in cells.
Some persistent infectious agents such
human papillomavirus can lead to cellular
transformation as well.
Genetic damage with DNA alterations leads to point mutations of genes,
translocations of genetic material between chromosomes, and gene
reduplication with amplification.
These alterations transform proto-oncogenes into oncogenes.
The proto-oncogenes within cells may play a role in growth promotion and
regulation in normal cells, perhaps in embryogenesis, but are typically
"turned off" in adults. They are "turned on" by transformation and lead to the
uncontrolled growth that defines neoplasia.
Neoplasia, or uncontrolled cellular proliferation, can result either from
mutations that "turn on" the oncogenes that stimulate growth, or
from mutations that result in loss of tumor suppressor genes and their products
that inhibit cellular growth.
Oncogenesis
Mechanism
Action
Overexpression of growth factor receptors (such as epidermal
growth factor, or EGF)making cells more sensitive to growth stimuli
Growth
promotion
Increased growth factor signal transduction by an oncogene that
lacks the GTPase activity that limits GTP induction of cytoplasmic
kinases that drive cell growth
ras
c-sis
Lack of normal gene regulation through translocation of
a gene where it is controlled by surrounding genes to a
place where it is no longer inhibited
c-abl
BRCA-1
Lack of regulation of cell adhesion with loss of growth control
through cell interaction
APC
Loss of down-regulation of growth promoting signal transduction
NF1
Loss of regulation of cell cycle activation through sequestation of
transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of inhibition
of cell proliferation that allows DNA repair
Limitation of
Apoptosis
C-erb-B2
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
Loss of normal growth inhibition
Loss of
Tumor
Suppressor
Gene
Function
Example
Overexpression of gene, activated by translocation, prevents apoptosis
p53
bcl-2
Oncogene
c-erb-B2
ras
c-sis
c-abl
c-myc
BRCA-1
APC
NF-1
Rb
p53
bcl-2
Associated Neoplasms
Breast and ovarian carcinomas
Many carcinomas and leukemias
Gliomas
Chronic myelogenous leukemia,
acute lymphocytic leukemia
Lymphomas
Breast and ovarian carcinomas
Colonic adenocarcinomas
Neurofibromas and neurofibrosarcomas
Retinoblastomas, osteosarcomas,
small cell lung carcinomas
Many carcinomas
Chronic lymphocytic leukemia, lymphomas
PRECURSORI MORFOLOGICI
MACROSCOPICI
MICROSCOPICI di
MALIGNITA’
…esempi….
e
UTERO
Corpo
Utero con iperplasia endometriale
Endometrio normale- Fase proliferativa
Iperplasia endometriale
The first step
toward neoplasia
is cellular
transformation. The
chronic irritation
from cigarette
smoke has led to
an exchanging of
one type of
epithelium (the
normal respiratory
epithelium at the
right) for another
(the more resilient
squamous
epithelium at the
left). Thus, there is
metaplasia of normal
respiratory laryngeal
epithelium to squamous epithelium in response to chronic irritation of smoking.
The two forms of cellular transformation that are potentially reversible,
but may be steps toward a neoplasm, are:
Metaplasia: the exchange of normal epithelium for another type of epithelium.
Metaplasia is reversible when the stimulus for it is taken away.
Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible
if the factors driving it are eliminated.
UTERO
Cervice
Epitelio squamoso
cervicale
Cervice uterina normale
The cervical os is small and round,
typical for a nulliparous woman.
The os will have a fish-mouth shape
after one or more pregnancies.
This is the next step toward neoplasia. Here, there is normal cervical squamous
epithelium at the left, but dysplastic squamous epithelium at the right.
Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium.
Dysplasia is still reversible
Some epithelia are accessible enough, such as the cervix, that cancer screening can be
done by sampling some of the cells and sending them to the laboratory. Here is a cervical
Pap smear in which dysplastic cells are present that have much larger and darker nuclei
than the normal squamous cells with small nuclei and large amounts of cytoplasm
When the entire epithelium is dysplastic and no normal epithelial cells are present, then
the process has gone beyond dysplasia and is now neoplasia. If the basement membrane
is still intact, as shown here, then the process is called "carcinoma in situ" because the
carcinoma is still confined to the epithelium. Neoplastic epithelium is termed carcinoma.
MAMMELLA
Iperplasia duttale
Origina nei dotti terminali intra ed extra lobulari ed è
dovuta alla proliferazione delle cellule epiteliali o delle
cellule epiteliali e mioepiteliali
Iperplasia duttale tipica (IDH)
Iperplasia duttale atipica (AIDH)- Rischio x Carcinoma: 4-5
Carcinoma intraduttale
(IDCA)
AIDH
Si manifesta spesso in associazione con la malattia fibrocistica, con le
lesioni sclerosanti o con il papilloma
Papilloma della mammella
•
•
Papilloma solitario  non rappresenta un fattore di rischio
Papillomi multipli  aumentato rischio di sviluppo di
carcinoma e possibile associazione con il carcinoma duttale
in situ (DCIS)
Papillomatosi florida (adenoma) del capezzolo
Mostra un’associazione elevata con il carcinoma
Stomaco
Intestinal
metaplasiaassociated
atypia in a
case of chronic
atrophic
gastritis with
intestinal
metaplasia.
The foveolar
epithelium is
replaced
by intestinal
type epithelium
with
hyperchromatic,
Intestinal metaplasia in chronic
autoimmunegastritis.
The foveolar epithelium is replaced
by intestinal epithelium composedof
mucin (goblet) cells and
absorbtive columnar cells
elongated and pseudostratified
nuclei, atypical cytologic features that appear
to be confined to the lower halves of the pits.
Note that there is no glandular crowding and
that the foveolae, although reactive, are parallel
to each other and separated by moderately
abundant lamina propria
The immunohistochemical stain for proliferation marker Ki-67 shows normal staining
pattern: infrequent labeling of the nuclei in the lower half of the pits
Adenocarcinoma gastrico
(freccia) e
mucosa adiacente
non neoplastica
Adenocarcinoma gastrico
ulcerato e mucosa
adiacente con atipie (freccia)
a
a-Hemigastrectomy specimen, surgery performed for antral
adenocarcinoma. The histologic section of gastric mucosa
adjacent to the gastric cancer shows non-neoplastic gastric
mucosa (right) adjacent to intestinal metaplasia (left). The
intestinalized mucosa is composed of irregular, branched
foveolae with epithelial buds at the deep aspect, lined by a
mucin-depleted epithelium with hyperchromatic nuclei and
scattered goblet cells
b
b-The metaplastic gastric epithelium (left)
is contrasted with the non-intestinalized
gastric epithelium (right). The nuclei of
intestinal metaplasia are elongated,
hyperchromatic and pseudostratified.
These features appear to involve the surface epithelium focally, finding that is suggestive of low-grade
dyspalsia. The nuclei of the normal gastric mucosa (right) although hyperchromatic and elongated, have
less crowding and overlapping thant those of the metaplastic epithelium
High-grade dysplastic epithelium
characterized by low-cuboidal cells with
markedly increased N:C ratio, depleted
cytoplasmic mucin and enlarged, round
nuclei, with loss of nuclear polarity,
pseudostratification, and prominent
irregular nucleoli
Immunohistochemical stain for proliferation
marker Ki-67 shows increased nuclear labeling
with a predominant upper pit and surface
epithelium distribution
Colonscopia
Intestino normale
Polipo- Displasia Adenomatosa
Intestino
A small adenomatous polyp (tubular adenoma) is seen here. This lesion is called a "tubular
adenoma" because of the rounded nature of the neoplastic glands that form it. It has smooth
surfaces and is discreet. Such lesions are common in adults. Small ones are virtually always
benign. Those larger than 2 cm carry a much greater risk for development of a carcinoma,
having collected mutations in APC, DCC, K-ras, and p53 genes over the years.
colonoscopic appearance of rectal polyps that proved to be tubular adenomas
This small adenomatous polyp (tubular adenoma) on a small stalk is seen microscopically
to have more crowded, disorganized glands than the normal underlying colonic mucosa.
Goblet cells are less numerous and the cells lining the glands of the polyp have
hyperchromatic nuclei. However, it is still well-differentiated and circumscribed, without
invasion of the stalk, and is benign
This adenomatous polyp has a hemorrhagic surface (which is why they may first be
detected with stool occult blood screening) and a long narrow stalk.
The size of this polyp--above 2 cm--makes the possibility of malignancy more likely,
but this polyp proved to be benign.
Here are multiple adenomatous polyps of the cecum. A small portion of terminal ileum
appears at the right.
This is familial polyposis in which the mucosal surface of the colon is essentially a carpet
of small adenomatous polyps. Of course, even though they are small now, there is a 100%
risk over time for development of adenocarcinoma, so a total colectomy is done, generally
before age 20
A microscopic comparison of normal colonic mucosa on the left and that of an
adenomatous polyp (tubular adenoma) on the right is seen here. The neoplastic glands
are more irregular with darker (hyperchromatic) and more crowded nuclei.
This neoplasm is benign and well-differentiated, as it still closely resembles the normal
colonic structure.
Crypt abscesses are a histologic finding more typical with ulcerative colitis. Unfortunately,
not all cases of inflammatory bowel disease can be classified completely in all patients
Over time, there is a risk for adenocarcinoma with ulcerative colitis. Here, more normal
glands are seen at the left, but the glands at the right demonstrate dysplasia, the first
indication that there is a move towards neoplasia
Fegato
Liver is divided histologically into lobules. The center of the lobule is the central vein. At
the periphery of the lobule are portal triads. Functionally, the liver can be divided into three
zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated
blood from hepatic arteries enters. Zone 3 is located around central veins, where
oxygenation is poor. Zone 2 is located in between
..displasia
su
cirrosi…
Microscopically with cirrhosis, the regenerative nodules of hepatocytes are
surrounded by fibrous connective tissue that bridges between portal tracts.
Within this collagenous tissue are scattered lymphocytes as well as a
proliferation of bile ducts
The malignant cells of this hepatocellular carcinoma (seen mostly on the right) are
well differentiated and interdigitate with normal, larger hepatocytes
(seen mostly at the left).
..Prostata..
Prostatic intraepithelial neoplasia (PIN), which is dysplasia of the epithelium lining
prostate glands, is a probable precursor of prostatic carcinoma. The appearance of PIN
may precede carcinoma by 10 or more years. It can be divided into low grade and
high grade PIN.
Low grade PIN may
be found even
in men in middle age
Compare the normal prostatic gland at the left with the group of acini at the right with
prostatic intraepithelial neoplasia (PIN), a precancerous cellular proliferation found in a
single acinus or small group of acini.
This is prostatic intraepithelial neoplasia (PIN), a precancerous cellular
proliferation found in a single acinus or small group of acini. PIN can be low or
high grade (as seen here). The finding of PIN suggests that prostatic
adenocarcinoma may also be present (about half the time with high grade PIN).
At high magnification, this poorly differentiated prostatic adenocarcinoma
demonstrates cells with nucleoli and mitotic figures
…Cute…
Caso n. 1: Donna di 17 anni con neoformazioni pigmentate multiple della cute
del dorso; quella indicata dalle frecce, di 0,5 per 0,3 cm.
NEVO DISPLASTICO
TUMORI MALIGNI DEI TESSUTI MOLLI…fattori etiopatogenetici,
precursori…
Incidenza: in complesso simile nel mondo; 15% in soggetti <15 anni;
40% in soggetti > 55 anni; più frequenti negli uomini;
diversa incidenza per età a seconda dell’istotipo
Patogenesi: per lo più sconosciuta; rara l’insorgenza da tumori
benigni(eccezione: MPNST su neurofibroma)
Fattori ambientali: traumi: possono rivelare un tumore sottostante;
sarcomi sono stati descritti dopo anni di latenza su:cicatrici da
caustici o da calore, in sede di pregresse fratture,vicino ad impianti
plastici o metallici
carcinogeni ambientali:modelli animali(angiosarcomi indotti da
dimetilidrazina; altri sarcomi da metilcolantrene);
asbesto(crocidolite, crisotile)
mesoteliomi;erbicidi contenenti
acido fenossiacetico, clorofenoli, diossina; cloruro di vinile
angiosarcoma epatico; radiazioni
angiosarcoma mammella (+
linfedema cronico)
Sarcoma post irradiazione. Sviluppo nel campo irradiato, almeno
tre anni dopo, su tessuto precedentemente normale(MFH)
Virus oncogeni: HHV8
in immunodepressi
sarcoma di Kaposi; EBV
leiomiosarcomi
Fattori immunologici: la perdita della immunosorveglianza regionale può
contribuire allo sviluppo di angiosarcomi su linfedema cronico
Fattori genetici: Neurofibromatosi tipo 1: trait autosomico dominante;
gene NF1cr.17; Neurofibromatosi tipo 2: gene NF2, cr 22; sindrome
di Gardner: autosomica dominante (fibromatosi mesenterica): gene
APC, cr. 5(incapacità a degradare la -catenina); sindrome di Li
Fraumeni: cr. 17, gene p53, rabdomiosarcoma familiare;
Retinoblastoma familiare, bilaterale: cr 13, gene Rb1, osteosarcomi;
malattia di Osler-Weber-Rendu: autosomica dominante
…atipia?...
Adipocytic tumors:
a possible model of tumor progression
12q13-15
Lipoma
Lipoma
with
minimal Atypia
HMGI-C
rearrangement
Dei Tos, 2004
Atypical
Lipoma/WD LPS
duplication
HMGI-C
cdk4
mdm2
overexpression
Dedifferentiated
LPS
ring chromosomes/giant markers
HMGI-C
CDK4
MDM2
overexpression/Amplification