DCIS

FOCUS ON
I CARCINOMI NON INFILTRANTI
DELLA MAMMELLA
TORINO 18 GIUGNO 2008
Dr.ssa Daniela Terribile
Chirurgia Senologica Pol.Univ.”A.Gemelli” Roma
1
FORME NON INVASIVE DELLA MAMMELLA
FREQUENZA DI ETA' PER IL DCIS e LCIS
25
DCIS
20
LCIS
15
N°
CASI
10
5
0
0
10
20
30
40
50
60
70
80
ETA'
2
LCIS
CARCINOMA LOBULARE IN SITU
definito ora come
NEOPLASIA LOBULARE INTRAEPITELIALE
(LIN)
• Riscontro occasionale
• Non necessita di alcun trattamento se diag pre-op
• Se presente sui margini non richiede ri-escissione
• Non richiede terapie complementari
• Può rappresentare criterio di inclusione in trials di
chemioprevenzione
3
FORME NON INVASIVE DELLA
MAMMELLA
LCIS
The management of lobular carcinoma in situ (LCIS)
Is the same as ductal carcinoma in situ (DCIS) ?
NO !
Lakhani SR, Audretsch W, Cleton-Jensen AM, Cutuli B, Ellis I, Eusebi V,
Greco M, Houslton RS, Kuhl CK, Kurtz J, Palacios J, Peterse H, Rochard F,
Rutgers E; (Eusoma
Group) E.J. of Cancer 2001
4
CARCINOMA DUTTALE IN SITU
( DCIS )
EPOCA PRE SCREENING
~5%
di tutti i carcinomi
operabili
ATTUALMENTE
30%
Unità di Senologia
Centri di riferimento
per lo Scr. Mammog.
5
DCIS
DIFFUSIONE SCREENING MAMMOGRAFICI :
NEGLI ULTIMI 10 ANNI
INCREMENTO DEL 328 %
DELL’INCIDENZA DEL DCIS
DEL 16% PER CARCINOMA INFILTRANTE.
ERNSTER ’97 ; BORDELAU L. 2001
6
Widespread use of screening mammography
A progressive increase in the diagnosis of
DCIS
• SEER data show a 557% increase in DCIS over 20 years, from 2.8% of
newly diagnosed breast cancers in 1973 to 12.5% in 1992.
• DCIS comprise 15–25% of all breast cancers detected at population
screening programs
• There is an estimate of more than 42,000 new cases diagnosed in the
United States every year
, GD Leonard Journal of the National Cancer Institute, 2004
7
DCIS
15- 30% of all breast cancer
90% non palpable
85% detected at mammography
Histology:
Comedo Type
Non-Comedo Type
Mixed
40%
30%
30%
Mammography:
Clustered microcalcifications DCIS 45%
Contralateral DCIS :
15% in 20 years
Wang H., 2000
8
DCIS
IERI
LA MAGGIOR PARTE DEI DCIS
PALPABILI , ASSOCIATI
A SECREZIONE EMATICA
9
IERI
DCIS
UNICA MALATTIA
CON
UNICO TRATTAMENTO
MASTECTOMIA
10
DCIS
OGGI
INSIEME ETEROGENEO DI LESIONI
INDISPENSABILE MODULAZIONE
APPROCCIO CHIRURGICO /
TERAPEUTICO
11
“THE DILEMMA
OF THE
DCIS “
SILVERSTEIN M.J.
1997
“THE SEA OF UNCERTAINITY
SURROUNDING DUCTAL
CARCINOMA IN SITU “
H.G.Welch , 2008
2007
12
DCIS
• DIFFICOLTA’
CLASSIFICATIVE
• DIFFICOLTA’ DI
INQUADRAMENTO
BIOPATOLOGICOCLINICO
• DIFFICOLTA’ DI
CORRELAZIONE CLINICO
-TERAPEUTICA
13
DCIS
Problemi aperti
•
Riproducibilità della definizione istologica
• Work-up strumentale ( rx/cito /isto ) pre operatorio
• Scelta del trattamento chirurgico ( mammella e
ascella )
• Definizione e Importanza dei margini negativi
14
DCIS
Problemi aperti
• Ruolo della radioterapia
• Ruolo dell’ormonoterapia adiuvante
chemiopreventiva
• Significato della recidiva locale
15
DCIS
problemi con la letteratura
corrente
• Differenze nella popolazione
studiata
• Differenze nei criteri di definizione
di margini negativi
• Differenze nella definizione di
microinvasione
• Differenze nel trattamento
• Numero limitato di pazienti
16
DCIS
DIFFICOLTÀ’ DI RIPRODUCIBILITÀ’
DELLA DEFINIZIONE
“Discrepancies in the diagnosis of
intraductal proliferative lesions of the
breast and its management
implications: results of a multinational
survey
Ghofrani et Tavassoli
Virchows Arch.2006
17
DCIS
“Diagnosis of in situ lesions and other preinvasive conditions demands skilled
pathologists “
• Pre-op diagnosis
• Margins work-up
• Definitive diagnosis ( microinv.issue/biological
subgroups )
Wang H, 2000
18
Estensione DCIS
……It
is important to realize that because of
the pathologic characteristics of DCIS, it is
frequently difficult to determine the exact
size of the DCIS, and many pathologists
are reluctant to do so.
Some studies report DCIS size in
millimeters, others in the number of slides
with DCIS, and still others by using its
mammographic size, all of these make
comparisons between studies difficult. …….
M.Morrow , 2007
19
ESTENSIONE DCIS
DCIS: 75-80% rilievo
esclusivamente mammografico
difficile determinazione intraoperatoria
dell’adeguatezza dell’exeresi
20
MAMMOGRAFICAL DCIS SIZE FREQUENTLY DO
NOT CORRELATE WITH THE HISTOLOGICAL
DCIS SIZE
21
THE OCCULT DIFFUSES SPREAD OF DCIS CELLS
INTO THE DUCTAL TREE MAKES DIFFICULT ITS
RADICAL EXCISION
22
WORK UP PREOPERATORIO PER LA
DETERMINAZIONE DELL’ESTENSIONE DELLA
LESIONE
Determination of the presence
and extent of pure ductal
carcinoma in situ by
mammography and magnetic
resonance imaging.
Menell JK Breast J.2005 ]
MRI of the breast for the
detection and assessment of the
size of ductal carcinoma in situ. [
Kim Do Y Korean J Radiol. 2007]
23
DCIS
MULTICENTRIC OR MULTIFOCAL ?
• By applying a correlated radiologicpathologic technique in combination with
a subgross sectioning and extensive
sampling, Holland demonstrated that the
tumor foci are more likely to be distributed
within a given region (breast quadrant).
Holland,Sem D.Pat.,1994
24
DCIS E MULTIFOCALITA’
• ASSENZA DI
CONSENSO SU
DEFINIZIONE
MA IN REALTA’:
IMPOSSIBILITA’ DI
TRASFERIMENTO IN
UNA SOLA
DIMENSIONE DELLA
TRIDIMENSIONALITA’
DEL SITEMA DUTTALE
MAMMARIO
25
DCIS
Work up pre-operatorio per la
determinazione di natura della lesione
• Fine needle biopsy : inadeguata per
definizione invasività
• Core biopsy / Bio vuoto-assistita :
buona definizione invasività ( minore
per microinvasività )
26
ESAME ISTOLOGICO
ESTEMPORANEO
SEMPRE
INADEGUATO
ESAME ISTOLOGICO
DEFINITIVO
27
DCIS
Work up pre-operatorio per la
determinazione di natura della lesione
La % di diagnosi preoperatorie di lesioni non
palpabili è correlata alla % di exeresi adeguate
e con margini indenni ad un unico intervento
Foncam 2005/Gisma 2006
28
DCIS
Work up pre-operatorio per la
determinazione di natura della lesione
tuttavia :
…...Despite recent technological advances
(including Stereotactic-guided directional
vacuum-assisted biopsy), mammographically
guided- wire biopsy remains the "goldstandard" for obtaining a histological
diagnosis in patients with non-palpable,
mammographically detected DCIS …..
Sakorafas GH, Surg Oncol. 2003
29
DCIS
TRATTAMENTO
Il GOLD STANDARD è rappresentato
dalla conservazione del seno con
cosmesi ottimale e minimo rischio di
recidiva o di carcinoma invasivo
30
DCIS
Conservative
Surgery
+ RT
Conservative
Surgery
Recurrence rates
15-40%
5-20%
Half of the recurrences are invasive !!!!!
31
DCIS
…. We are unable to predict which DCIS
will progress to invasive cancer, and we
are unable to predict the time interval to
the development of recurrent DCIS or
invasive carcinoma…..
M.Morrow 2007
32
DCIS
CHIRURGIA
CONSERVATIVA
Trattamento più semplice
ma
più alto rischio recidiva
locale infiltrante
CHIRURGIA CONS + RT
• Se recidiva infiltrante
preclusione di iter
conservativa iterativa
• Se recidiva estesa
preclude buon risultato
ricostruzione-protesi
33
DCIS
DCIS
MASTECTOMIA
+ TAM
-Netta riduzione rischio di recidiva Tossicita’
Ma
- Netto peggioramento della
qualità di vita.
Farmacologica
Effetti collaterali
Soprattutto in
premenopausa
34
Biological variables and
prognosis of DCIS.
To guide optimal treatment histological classification is not
sufficient and additional biological factors are being
investigated for their ability to predict outcome for individual
patients with DCIS
At present, insufficient knowledge on prognostic and
predictive factors in DCIS is available
Integration of translational studies into clinical trials aimed at
optimising the treatment of DCIS are required to achieve this
goal.
van de Vijver MJ 2005
.
35
NUOVE CLASSIFICAZIONI
Ductal carcinoma in situ of the breast: a new
phenotype classification system and its relation
to prognosis.
Warnberg F, Breast Cancer Res Treat. 2002
Basal phenotype of ductal carcinoma in situ:
recognition and immunohistologic profile.
Dabbs DJ,: Mod Pathol. 2006
Ductal carcinoma in situ with basal-like
phenotype: a possible precursor to invasive
basal-like breast cancer.
Bryan BB, Mod Pathol. 2006
36
DCIS
“CLASSIFICAZIONI TRADIZIONALI”
• Grado nucleare
• + Necrosi
• Caratteristiche architetturali
37
DCIS
GRADO NUCLEARE
“ …Nuclear grading is probably the most
important pathological factor that affects
clinical outcome and correlates with
distinct genetic pathways …….”
Tang P et Al Curr Opin Obstet Gynecol. 2007
38
CONFRONTO TRA PROPOSTE
DI CLASSIFICAZIONI
DCIS
LAGIOS
NOTTINGHAM
EORTC
micropapillare
cribriforme
DCIS senza
necrosi
ben differenziato
cribriforme con
anaplasia
DCIS con necrosi
moderatamente
differenziato
comedo
cribriforme con
necrosi
comedo
scarsamente
differenziato
Morrow 1997
39
DCIS
“THE VAN NUYS
PROGNOSTIC INDEX (VNPI)”
Punteggi
o
1
2
T
< 15 mm
16 – 40 mm
Margini
>10 mm
1 – 9 mm
< 1 mm
ANATOMIA
PATOLOGICA
Basso grado
senza necrosi
Basso
grado con
necrosi
Alto grado con
o senza
necrosi
3
> 41
mm
Silverstein MJ, Ductal Carcinoma in Situ of the Breast - 1997
40
“THE VAN NUYS PROGNOSTIC
INDEX (VNPI)”
Punteggio
Trattamento
consigliato
3o4
5, 6 o 7
Escission
e
Escissione
+
RT
DCIS
8o9
MASTECTOMIA
Silverstein MJ, Ductal Carcinoma in Situ of the Breast 1997
41
DCIS
Quale trattamento?
Sola escissione
Escissione e RT
Mastectomia
Basso rischio
Medio-alto rischio
Lesioni diffuse
- G1
- Estensione < 1cm
- Margini indenni (1cm)
- Punteggio 3 o 4(VNPI
- G2-G3
- Estensione < 2cm
- Margini <1cm
- Multifocale estesa
- Multicentrica
- (8o9 VNPI)
- (5,6 o7/VNPI)
Philadelphia Consensus Conference on DCIS 1999
Cancer 2000 , Feb. 15; vol 4;88;
42
DCIS
Indicazioni per la SOLA chirurgia conservativa
• Lesioni di dimensioni istopatologiche
e/o mammografiche
< 2-3 cm.
(maggiori dimensioni se rapporto lesione/seno favorevole)
• Margini indenni > 10 mm per ogni lato
• G1-G2
( sec alcuni AA i G3 possono essere inclusi se i margini >
10 mm)
• Buon risultato estetico preventivabile
43
DCIS
TRATTAMENTO
• Margine ottimale = 10 mm
• Ma possibile modulazione:
- se sola escissione = 10 mm obbligatorio
- se escissione + RT = può essere inferiore a10 mm
Philadelphia Consensus Conference on DCIS 1999
Cancer 2000 , Feb. 15; vol 4;88;
44
MARGINS STATUS IN DCIS
Margin width as the sole determinant of
local recurrence after breast
conservation in patients with ductal
carcinoma in situ of the breast.
Macdonald HR, Silverstein MJ, …, Lagios
M Am J Surg. 2006
45
DCIS E MARGINI
• ASSENZA DI CONSENSO SULLA
DEFINIZIONE DI MARGINE “NEGATIVO”
• > 1 MM
• > 2 MM
• > 4 MM
• > 10 MM
46
MARGIN STATUS IN DCIS
Substantial controversy exists regarding the definition of
a negative pathologic margin in DCIS.
Controversy arises out of the heterogeneity of the disease,
difficulties in distinguishing the spectrum of hyperplastic
conditions, anatomic considerations of the location of the
margin, and inadequate prospective data on prognostic
factors in DCIS.
Margins greater than 10 mm are widely accepted as
negative (but may be excessive and may lead to a less
optimal cosmetic outcome).
Margins less than 1 mm are considered inadequate.
There are insufficient data to make definitive statements
regarding margins between 1 and 10 mm.
NCCN® Practice Guidelines in Oncology – v.2.2007
47
DCIS
DIAMETRO LESIONE
ESTENSIONE AREA A
”RIDOSSO”
MULTIFOCALITA’
48
MARGINS STATUS IN DCIS
DCIS
….Re-excision to achieve clear margins was deemed
appropriate if an initial attempt was unsuccessful.
How many attempts at re-excision were acceptable
before admitting that clear margins could not be
achieved was not clear.
A majority of the panelists did concur that, at least in
theory, whatever might be necessary to clear the
margins was acceptable, consistent with the
patient's desire for breast conservation and the final
aesthetic result.
49
MARGINS STATUS IN DCIS
• Re-excision for ductal carcinoma in situ: the
surgeon's least favorite operation.
Ward BA, Cancer J. 2006
• Long-term outcome for mammographically
detected ductal carcinoma in situ managed
with breast conservation treatment:
prognostic significance of reexcision.
Vapiwala N Solin LJ. Cancer J. 2006
50
DCIS
Residual disease after re-excision for tumour-positive surgical
margins in both ductal carcinoma in situ and invasive carcinoma
of the breast: The effect of time.
Schouten van der Velden AP, Van de Vrande SL, Boetes C, Bult P, Wobbes T.
Department of Surgical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
J Surg Oncol. 2007 Dec 1;96(7):569-74.
51
The influence of margin width on local
control
Probability of freedom from recurrences with margins less than 1 mm wide
Probability of freedom from recurrences with margins 1
to 10 mm wide
Silverstein,
Silverstein, N Engl J Med - 1999
52
The influence of margin width on local
control
Probability of freedom from recurrences with margins at least 10 mm
wide
Silverstein,
Silverstein, N Engl J Med - 1999
53
The influence of margin width on local control
EORTC trial 10853
Time to local recurrence according to margin status and
treatment
100
EL+RT; free marg
80
EL; free marg
60
40
EL+RT; involved marg
20
EL; involved marg
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
years after diagnosis
Bijker N, J Clin Oncol - 2001
54
DCIS
Clinical presentation and surgical quality in
treatment of ductal carcinoma in situ of the breast
…..However, the cornerstone in
prevention of recurrent disease is the
quality of the primary surgical
procedure.
Residual tumour within the treated
breast probably will give rise to a
tumour recurrence……
Schouten A.P,et Al Acta Oncologica 2006
55
Extension of excision
Dilemma of the surgery
Tumorectomy Wide biopsy
Quadrantecty
Margins
Cosmetic result
56
Chirurgia Oncoplastica
Integrazione tra tecniche di
chirurgia oncologica e chirurgia
plastica
Consente di ottenere:
• Exeresi più radicali
• ˜ rischio di recidive locali
• Migliori risultati estetici
57
il dcis multifocale può essere
trattato conservativamente ?
DCIS
“MULTIFOCALE”
NON E’ UGUALE A
DCIS “ESTESO “
58
Margin width may be more important
than RT in avoing the risk of local
recurrence after breast
-conservation
breast-conservation
surgery
59
Do all patients treated with
breast-conservation surgery
require postexcisional
radiation therapy ?
60
Why not give RT to every
conservatively treated patient with DCIS?
• RT is expensive and time consuming
• RT is accompained by significant side effects in a
small percentage of patients (cardiac and pulmonary)
• Radiation
fibrosis
of
the
breast
makes
mammographic follow-up more difficult
• RT precludes its use if an invasive recurrence
develops at a later date
• RT with its skin and vascular changes make skinsparing mastectomy if needed in the future more
difficult to perform
Silverstein, V Annual Multidisciplinary Symposium on Breast Disease
Disease
- 2000
61
DCIS and RT
Radiotherapy following breast-conserving
surgery for screen-detected ductal
carcinoma in situ: indications and utilisation
in the UK. Interim findings from the Sloane
Project.
Dodwell D,, Leeds, UK
Br J Cancer. 2007 Sep 17;97(6):725-9.
62
DCIS and RT
Local recurrences after different treatment strategies for
ductal carcinoma in situ of the breast: a population-based
study in the East Netherlands.
In a defined population outside
a trial setting, RT after BCS for DCIS
lowered recurrence rates. Besides the use
of RT, a microscopically complete excision
of DCIS is essential.
This is especially true for patients with
symptomatically detected DCIS and with
tumors that contain comedo necrosis, as
these groups are at particular high risk
CONCLUSIONS:
Schouten van der Velden Br J Cancer. 2007
63
DCIS and RT
64
DCIS and RT
65
DCIS
DCIS e MASTECTOMIA
QUANDO?
< 25% DEI DCIS
66
MARGINS STATUS IN DCIS
Well-performed mastectomy and
reconstruction were considered
preferable to multiple attempts at reexcision that destroy the contour and
size of the breast.
67
DCIS e MASTECTOMIA
QUANDO ?
• MULTICENTRICITA’ ESTESA
• CONTROINDICAZIONI RT ( SE G> 1 )
• RISULTATO ESTETICO SFAVOREVOLE
DELLA CHIRURGIA CONSERVATIVA
• ( ESTENSIONE DCIS/ DIMENSIONI
MAMMELLA)
• IMPOSSIBILITA’ DI OTTENERE
MARGINI INDENNI
• VNPI: da 10 a 12
Schwartz GF 2002
68
Mastectomia per DCIS
Vantaggi
• Prevenzione di recidive locali
• Trattamento di foci occulti multicentrici
• Trattamento di foci occulti invasivi
Svantaggi
• Impatto psicologico
• Morbidità
• Maggiori costi “ospedalieri”
69
DCIS e MASTECTOMIA
COME ?
MASTECTOMIA SEMPLICE
+/RICOSTRUZIONE
“SKIN SPARING MASTECTOMY”
70
DCIS e MASTECTOMIA
COME ?
LA RICOSTRUZIONE DEVE ESSERE
OFFERTA AD OGNI DONNA
CANDIDATA ALLA MASTECTOMIA
71
TRATTAMENTO
DCIS
DCIS
SE DCIS PURO:
Coinvolgimento ascellare < 1%
Linfoadenectomia ascellare
NON INDICATA
Biopsia del linfonodo sentinella?
72
Metastasi in linfonodi ascellari
in selezione di studi con DCIS and DCISM
Silverstein, J Am Coll Surg, 2001
73
Metastasi in linfonodi sentinella in pazienti
con DCIS
Silverstein, J Am Coll Surg,
2001
74
Distribuzione dei carcinomi in situ per
esecuzione del LS e grado della lesione
LS eseguito
Basso
LS non eseguito
Basso
0%
20%
Medio
Alto
Medio
40%
Alto
60%
80%
?
?
100%
75
Biopsia linfonodo sentinella in pazienti
con DCIS
Indicazioni
• Tumori estesi
• Micro-invasione su core
biopsy
• Previsione di mastectomia
Silverstein, 2000, Cox 2004.2006,Cody 2006, Giuliano 2007
76
DCIS and SN biopsy
Sentinel node biopsy is not a standard procedure in
ductal carcinoma in situ of the breast: the experience of
the European institute of oncology on 854 patients in 10
years.
Intra M, Ann Surg. 2008 Feb;
Outcomes for women with ductal carcinoma-in-situ and a
positive sentinel node: a multi-institutional audit.
Moore KH, Sweeney KJ, Wilson ME, Goldberg JI, Buchanan CL, Tan LK,
Liberman L, Turner RR, Lagios MD, Cody Iii HS, Giuliano AE, Silverstein
MJ, Van Zee KJ. Ann Surg Oncol. 2007
77
DCIS
TRATTAMENTO
Recidiva dopo sola chirurgia conservativa
RI-ESCISSIONE + RT*
Recidiva dopo chirurgia conservativa + RT
RI-ESCISSIONE O MASTECTOMIA*
*in relazione al rapporto lesione/mammella
78
79
DCIS
TRATTAMENTO
RADIOLOGO
RX PREPRE-OPERATORIO
PATOLOGO
CHIRURGO
+
PAZIENTE
ACCURATO STUDIO
DEL PEZZO
CARATTERIZZAZIONE
BIOPATOLOGICA
RX PEZZO
OPERATORIO
RX POSTPOST-OPERATORIO
RADIOTERAPISTA
SCELTA DEL TRATTAMENTO PIÙ IDONEO
80
DCIS
La complessità degli aspetti biologici e
terapeutici del DCIS possono
provocare nelle pazienti un trauma
psicologico MAGGIORE che per
carcinomi invasivi
Risk perceptions and psychosocial outcomes
of women with ductal carcinoma in situ:
longitudinal results from a cohort study.
Partridge A, Winer E et Al J Natl Cancer Inst. 2008
81
DCIS
OVERTREATMENT RISK
CAVEAT
RISK/BENEFIT FOR A HIGH RATE CURABLE
DISEASE :
• Side effects of the treatment
• Unsatisfactory cosmetics
• Implant or flap complications
• Breast fibrosis
• II malignances of Rt and tamoxifen
82
DCIS
Understanding the carcinogenesis of ductal
carcinoma in situ at the molecular level may
lead to an optimal individualized therapy with
minimal over or undertreatment.
Tang P et Al Curr Opin Obstet Gynecol. 2007
83
DCIS
Il trattamento del DCIS è costantemente
sotto valutazione e revisione e può essere
repentinamente modificato da nuove
osservazioni.
I provvedimenti terapeutici devono essere
presi dal medico responsabile
partecipazione della paziente
con
la
84