Avaliao prognstica das

neoplasias!

Prof. Ana Flix!

Faculdade de Cincias Mdicas!
30 de Novembro de 2015!

PROGNSTICO!

Prognstico!
Diagnstico !
Tipo histolgico!
Diferenciao !

Estadiamento!
Marcadores de prognstico!

Consequncias do crescimento
tumoral !
Leso e condio pre-malignas!

Prognstico!
Diagnstico !
Tipo histolgico!
Diferenciao !

Estadiamento!
Marcadores de prognstico!

Consequncias do crescimento
tumoral !
Leso e condio pre-malignas!

TIPO HISTOLGICO!

Carc pavimento celular

Leiomiosarcoma

Melanoma maligno

Carcinoma ductal

Linfoma no Hodgkin

GIST

Carc. neuroendcrino

Linfoma Hodgkin

Seminoma

Tipo
histolgico
segundo a
classificao da
OMS!

Tipo histolgico!
Categorias de prognstico!
(dependentes do tipo histolgico e estdio )!
Bom (80% aos 5 anos)!

Intermdio!

Mau (<20% aos 5 anos)!

Seminoma!

Carcinoma da mama!

Carcinoma do pulmo!

Teratoma !

Carcinoma do coln!

Carcinoma do pncreas!

Coriocarcinoma!

Carcinoma do recto!

Carcinoma do estmago!

Melanoma maligno!

Carcinoma da laringe!

Carcinoma do esfago!

Carcinoma basocelular!

Carcinoma do tero!

Carcinoma hepatocelular!

Osteosarcoma!

Mesotelioma maligno!

Carcinoma do endomtrio tipos histolgico e o prognstico!

Tipo

Todos os estdios

Endometriide

92%

Viloglandular

94%

Adenoscamoso

65%

Seroso

10-30%

Clulas claras

39 - 42%

Indiferenciado e
Desdiferenciado

58%

COMO SE IDENTIFICA O
TIPO HISTOLGICO?!

Tipo histolgico!
Observao microscpica (cito e
histologia) em coloraes de rotina e em casos
seleccionados dever ser complementada com: !

imunohistoqumica !
Tumores pouco diferenciados!
Metstases reveladoras!
Deteco de molculas com valor prognstico e
teraputico!

diagnstico molecular !
Linfomas/leucemias; e Sarcomas; etc!
Prognstico!
Doena mnima!

Caso clnico!
Homem, 63 anos com
queixas de rouquido
h 1 ano recorre ao
mdico por dispneia e
perda de peso de 10kg
nos ltimos meses.
Refere hbitos
tabgicos e alcolicos
desde sempre.!
No exame objectivo !
mau estado geral !
emagrecimento
acentuado!
perda de massas
musculares!
tumor com 4 cm na
laringe !

Imunohistoqumica

Microscopia electrnica

Carcinoma pavimento celular, tipo sarcomatide!

DIAGNSTICO!

MARCADORES IMUNOFENOTPICOS!

Cito-queratinas

Cito-queratinas

Cromogranina
Sinaptofisina

Carc pavimento celular

Carcinoma ductal

Carc. neuroendcrino

Vimentina
Desmina
Actina

CD45
CD20
CD3

CD15
CD30

Leiomiosarcoma

Linfoma no Hodgkin

Linfoma Hodgkin

pS100
HMB45

CD117
CD34

CD117
PLAP

Melanoma maligno

GIST

Seminoma

CD20

MARCADORES EM
MICROSCOPIA
ELECTRNICA!

Desmossomas
Fil. intermdios

Lumes
Desmossomas
Fil. intermdios

Carc pavimento celular

Carcinoma ductal

Fil. finos
Fil. intermdios

Leiomiosarcoma

Linfoma no Hodgkin

Melanossomas
Melanoma maligno

GIST

Grnulos
neuroendcrinos

Carc. neuroendcrino

Linfoma Hodgkin

Seminoma

MARCADORES
MOLECULARES!

Carc pavimento celular

Leiomiosarcoma

Melanoma maligno

Status gene
erBB2
Carcinoma ductal

Carc. neuroendcrino

Marcadores
cromossmicos
clonalidade

Linfoma no Hodgkin

Linfoma Hodgkin

cKit

iso12

GIST

Seminoma

DO INFORMAO DE
ALVOS E DE RESPOSTA
TERAPUTICA!

Status gene
erBB2

Carc pavimento celular

Carcinoma ductal

Leiomiosarcoma

BRAF, cKIT
Melanoma maligno

Linfoma no Hodgkin

Carc. neuroendcrino

Linfoma Hodgkin

cKit, PDGF,
Succinil
GIST

Seminoma

Future cancer diagnosis

- omics
Revolu<onary technologies became feasible
(cost and <me)
Whole genome - genome
En<re epigene<cs altera<ons - epigenome
Quan<fy all RNA transcriptome
Measuring proteins proteosome
All metabolites metabolome
.

23

Journal of Pathology
J Pathol 2010; 220: 307315
Published online 17 November 2009 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/path.2636

Invited Review

Does massively parallel DNA resequencing signify the end

of histopathology as we know it?
Samuel AJR Aparicio1,2,3 * and David G Huntsman2,3
1 Molecular Oncology, BC Cancer Agency, 675 W10th Avenue, Vancouver V5Z 1L3, Canada
2 Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver V5Z 1L3, Canada
3 Department of Pathology, University of British Columbia, G227-2211 Wesbrook Mall, Vancouver,

*Correspondence to:
Samuel AJR Aparicio, Molecular
Oncology, BC Cancer Agency,
675 W10th Avenue, Vancouver
V5Z 1L3, Canada.
E-mail: saparicio@bccrc.ca
No conflicts of interest were
declared.
Received: 1 September 2009
Revised: 23 September 2009
Accepted: 26 September 2009

BC V6T 2B5 Canada

Abstract
Next-generation DNA sequencing devices have revolutionized cancer genomics by bringing
whole genome resequencing of patients tumours within practical and economic reach.
We present an overview of the techniques involved and review early results from the
resequencing of cancer genomes. The possible impacts of whole-genome and trancriptome
resequencing in clinical cancer research and the practice of pathology are discussed.
Copyright 2009 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
Keywords: DNA sequencing; mutational heterogeneity; cancer genome; transcriptome;
tissue sampling; mutational landscape; tumour evolution

24

Introduction
At the dawn of the microarray and systems biology

with a rigorous evidence base normally takes at least

as long as the course of disease in individuals. Most

25

weights in the wide range of 0.18 kB [37] to 21 kB [38]. These DNA

fragments have distinctly lower molecular weights than genomic
DNA. The cfDNA fragments apparently circulate as nucleoprotein
complexes; however, in healthy individuals, the main part of cfDNA is
found adsorbed to the surface of blood cells [39].
The mechanisms of the occurrence of cfDNA in blood under normal
and pathological conditions are not yet fully understood. Several
processes have been discussed as being responsible for the quantitative and qualitative changes of cfDNA in cancer patients (Fig. 1). In

Biopsia lquida!

suggests a strong interaction between the tumor cells and their a

non-tumor cells that results in the increased release of DNA fro
tumor cells and the detection of non-tumor cfDNA [53]. Moreo
generally low ratio of tumor cfDNA to the increased total cfDN
plasma of cancer patients might be supported by the higher degr
rate of tumor DNA compared with that of DNA derived from non
cells [54].
Altogether, similar specic alterations of DNA such as muta
strand stability found both in the tumor and in the cfDNA pr

Table 1
Some milestones in the clinical research of circulating cell-free DNA in the blood.
Year

Event

Ref

1948
1965
19661973
1972/1975
1977
1989
19941999
1997
1998
20002010
2010

Discovery of cell-free DNA in blood

Circulating DNA as a possible factor in oncogenesis
Detection of high levels in patients with systemic lupus erythematosus, rheumatoid arthritis, leukemia, and other diseases
Methodical aspects of determining in normal plasma samples
Detection of increased values in cancer patients depending on tumor stage and treatment
Evidence of similar characteristics between circulating DNA and tumor DNA in cancer patients
Evidence of further tumor-related genetic alterations in circulating DNA
Presence of fetal DNA in plasma of pregnant women
Description of plasma DNA chimerism after transplantation
Circulating DNA in diagnosis and prognosis of numerous diseases (tumors, trauma, heart infarction, stroke etc.)
Oncogenic transformation of cultured cells by circulating DNA in plasma

[1]
[2]
[3
[6,7
[8]
[9]
[10
[17
[18
[19
[26

Dis<nct cancers that oOen harbour gains-of-func<on muta<ons in the

serine/treonine kinase BRAF

BRAF(OMAS)
27

BRAFomas
BRAF
inhibitors

Malignant melanoma

BRAF (V600E)
mutation

Colon carcinoma

Langerhans cell
histiocytosis

Papillary thyroid carcinoma

Hairy cell leukemia

It is impossible to distinguish an isolated benign tumor cell from

an isolated malignant tumor cell. This distinction can be made
only through examination of tissue architecture.
Benign tumor !
An abnormal proliferation of
cells driven by at least one
mutation in an oncogene or
tumor suppressor gene.
These cells are not invasive
which distinguishes them
from malignant cells. !

Malignant tumor !
An abnormal proliferation of cells
driven by mutations in oncogenes
or tumor suppressor genes that
has already invaded their
surrounding stroma.!

NEOPLASM - DEFINITION
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW.
Cancer genome landscapes.
Science. 2013 Mar 29;339(6127):1546-58.

29

DIFERENCIAO!

Graduao da diferenciao das

neoplasias malignas !
Grau de semelhana com o tecido
normal!
Caractersticas das clulas!
Pleomorfismo !
Dimenses dos ncleos!

Actividade mittica!

Diferenciao !

G1

normal

G2

Semelhana com o
normal morfofuncional!

G3

Anaplasia!

Mitoses !

grau de diferenciao!
definido pelo grau de semelhana
do tumor com o tecido que lhe d
origem!
pode ser subdividido em:!
bem, mdio ou pouco diferenciado!
Graus 1, 2 e 3 (eventualmente 4)!
baixo grau e alto grau!
ou, em casos especficos, tem um
sistema prprio!

H critrios especficos para cada neoplasia

exemplos!
adenocarcinoma do clon e recto!
Baixo e Alto grau!

adenocarcinoma do endomtrio!
Grau 1, 2 e 3!

adenocarcinoma da prstata!
Gleason!

Adenocarcinoma do endomtrio!

Grau 1
<5% de reas
slidas

Grau 2
> a 5% e <50%
de reas slidas

Avaliao da morfologia de ncleos por fazer up gradings

Grau 3
> de 50% de
reas slidas

Adenocarcinoma da prstata!
score combinado de Gleason!

Adenocarcinoma da prstata!
score combinado de Gleason!
3

Adenocarcinoma da prstata!
score combinado de Gleason!
3

3+4=7

Adenocarcinoma da prstata!

3+4=7 4+3=7
o predomnio de
reas de grau
histolgico 4 pode
retirar a indicao
operatria

Prognstico!
Diagnstico !
Tipo histolgico!
Diferenciao !

Estadiamento!
Marcadores de prognstico!

ESTADIAMENTO!

Estadiamento !
Avaliao clnica de pacientes com neoplasia
incide sobre !
a
!Extenso local e disseminao tumoral
!
!
Histria e exame fsico!
Estudo analtico (bioqumico, hormonal,)!
Estudo imagiolgico!
ESTUDO ANTOMO-PATOLGICO!

T Tumor
N Gnglios linfticos
M Metstases a distncia

Crescimento invasivo do Adenocarcinoma

do clon

Estadiamento
De acordo com os elementos
T - Tumor
N - Gnglios linfticos
M Metstases a distncia

ADENOCARCINOMA DO
ENDOMTRIO!

Prognstico!
Diagnstico !
Tipo histolgico!
Diferenciao !

Estadiamento!

Marcadores de prognstico!

Marcadores de prognstico!
Vrios tipos de elementos clnico e
morfolgicos que so teis para
estimar grupos de doentes com uma
evoluo clnica e que so utilizados
na seleco da teraputica!

Carcinoma endometriide do endomtrio!

OUTROS PARAMETROS
MORFOLGICOS DE
PROGNSTICO!

Factores de prognstico !
com utilidade !
comprovada
!

marcadores com utilidade

provvel!

Tipo celular!
Grau histolgico!
Invaso vascular
linftica!
Estdio da FIGO!
p53!
Ploidia tumoral!

Receptores de
estrognios!
Bcl2!
Ki67!
ErbB2!
Densidade
microvascular!

Dados morfolgicos (que no entram no

estadiamento na maioria dos tumores)

ex. Invaso linfo-vascular!

Factor de prognstico independente da presena de

metstases em gnglios linfticos!

Marcadores tumorais
(ver tabela Robbins)

Protenas indicadoras da presena

de tumores com possibilidade de
serem usadas no diagnstico e na
orientao teraputica!
SEROLGICOS!
IMUNOHISTOQUMICOS!

Marcadores tumorais!
Antignios onco-fetais

alfa-fetoprotena!
antignio carcinoembrionrio!

Isoenzimas

fosfatase cida prosttica!

NSE!

Marcadores tumorais!
Hormonas
!
Tiroglobulina!
Calcitonina!
HCG!
Catecolaminas!
!

Mucinas

Ca 125
Ca 19-9
Ca 15-3

Marcadores tumorais!
Protenas especficas
Figado
Imunoglobulinas!
Antignio
especfico da
prstata (PSA)!

PSA

Marcadores tumorais!
Marcadores moleculares
Amplificao de genes!

Marcadores tumorais!
ndice de proliferao!
Receptores hormonais!
Expresso de alvos
teraputicos!
Doena residual mnima!

ERBB2 - CISH

exemplo!

CARCINOMA DA MAMA!

Biomarcadores prognstico e de orientao

teraputica com utilidade comprovada
!

Tipo histolgico!
Receptores de
estrognios e
Grau histolgico!
progesterona!
Invaso vascular
ERBB2!
linftica!
Utilidade em grupo
Estdio!
restricto!
ganglionar axilar!
Ki-67!
a distncia!
SEM utilidade comprovada em uso clnico h mais de 5
anos mas onde so depositadas grandes esperanas!
Testes moleculares tipo Oncotype DX test ; MammaPrint test

CARCINOMA DA MAMA!

com utilidade comprovada

Tipo histolgico!
Receptores de
estrognios e
Grau histolgico!
progesterona!
Invaso vascular
ERBB2!
linftica!
Utilidade em grupo
Estdio!
restricto!
ganglionar axilar!

Ki-67!
a distncia!

Outros
Oncotype DX test !
Em casos seleccionados!
Custo aproximado 3000$!

Manifestao de novo de uma neoplasia maligna aps

tratamento e aps um perodo de tempo durante o qual a
neoplasia no era detectvel!

RECIDIVA!

Neoplasia maligna em disseminao ou agravamento local!

PROGRESSO!

Tipos de recidiva!
Local / Regional !

A distncia!

No mesmo local!
Em gnglios
linfticos locoregionais!

Noutra localizao /
rgo!

Como se avalia o risco de recidiva?!

diferente em todos os doentes!
Depende de factores de prognstico!
No possvel garantir a cura!

Sobrevivncia!
Avalia-se habitualmente:!
Taxa de sobrevivncia aos 5 anos!
Taxa de sobrevivncia relativa!
Na comparao com a populao sem doena!

Caractersticas clnicas das neoplasias!

efeitos dos tumores sobre o hospedeiro!
Efeitos locais !
Efeitos a distncia !
Sndromes paraneoplsicas !
Caquexia !
Metstases!

causas de morte em doentes com neoplasia!

Efeitos das neoplasias benignas!

Pela sua localizao!

N de tumores!
Produo hormonal !
Alteraes gastro-intestinais !
Tamanho !
Torso e enfarte !

Efeitos das neoplasias benignas!

Pela sua localizao!

Adenomas pituitrio
comprimem a pituitria normal
e o quiasma ptico!
Craniofaringiomas comprimem
e invadem o hipotlamo!
Mixoma auricular bloqueia a
circulao intra-cardaca !
Meningiomas comprimem o
crebro!
Quistos colides bloqueiam o
fluxo do liquor!
Adenomas pleomrficos
comprimem o nervo facial!

MENINGIOMA!

Efeitos das neoplasias benignas!

N de tumores!
Lipomas na "adiposis
dolorosa!
Tumores neurais no
Sndrome de Von
Recklinghausen's;!
Hamartomas na
esclerose tuberosa,
etc.)!

Efeitos das neoplasias benignas!

Produo hormonal!
Adenomas da
pituitria, adrenais,
insulinomas,
vipomas, reninomas,
outros)!

Alteraes gastro-intestinais !

Hemorragia!
Obstruo!
Intussuspeco!
Perda de potssio !

Efeitos das neoplasias benignas!

Tamanho!
cistadenomas
mucinosos do ovrio
com 20 kg, etc.!

Torso e enfarte !
tumores do ovrio!

Efeitos das neoplasias malignas!

Invaso das estruturas normais
!

e/ou!

Leso cerebral e herniao !

Edema pulmonar!
Fracturas sseas!
Trombocitopenia, granulocitopenia, anemia !
Hemorragia (trombocitopenia e invaso vascular)!
Obstruo do ansas gastro-intestinais!
Derrame peural!
lceras e fstulas!
Caquexia!
..!

Sndrome paraneoplsica!
Podem ser a 1 manifestao de uma
neoplasia!
Podem provocar problemas clnicos
graves e letais!
Podem simular doena disseminada
(metstases) e perturbar o raciocnio
para a teraputica!

Sndrome paraneoplsica!
Sinais e sintomas no relacionados
directamente com a progresso local
ou a distncia da neoplasia!
Sinais e sintomas no relacionados
com secreo tumoral!

ocorre em cerca de 10% dos

doentes portadores de neoplasia
maligna!

Efeitos das neoplasias malignas!

Sndromes paraneoplsicas !
Febre !
Sndrome de CUSHING !
Virilizao!
Feminizao!
Hiponatrmia !
Hipoglicmia !

Efeitos dos tumores malignos!

Sndrome carcinide (flushing, asma e
diarreia)!
Policitmia !
Trombocitose!
Anemia hemoltica auto-imune!
Sndrome de hiperviscosidade!
Neuropatia perifrica!
Miastenia gravis!

Causas de morte por neoplasia!

PNEUMONIA uma das causas mais frequentes de morte
em pacientes com cancro.!
NEUTROPENIA (invaso da MO por clula sneoplsicas)!
IMMUNOSUPPRESSO NO ESPECFICA!
OBSTRUO DAS VIAS EREAS (derrame pleural,
acamado) !
ATELECTASIAS por dificuldade em tossir, acumulao de
secrees com colapso alveolar e infeco !
ASPIRAO de alimentos e de VMITO !
NARCTICOS suprimem o estmulo respiratrio !

SPSIS ( habitualmente bacilos gram(-) com choque (no

facilmente identificvel uma origem da infeco pulmo,
bexiga, tumor necrosado)!

Causas de morte por neoplasia!

HEMORRAGIA (crebro, intestino, outro local) comum
em pacientes com trombocitopnia (invaso da MO)!
TROMBOEMBOLISMO PULMONAR (acamados e
alguns pacientes ambulatrios)!
FALNCIA RENAL (infiltrao tumoral, obstruo
ureteral) !
SNDROMES PARANEOPLSICAS!
DOENA IATROGNICA espervel em doentes que
foram submetidos a cirurgia, radioterapia e quimioterapia
mesmo se forem curados Ann. Int. Med. 111: 411, 1989!
SUICDIO E a EUTANSIA !
Menos comuns so: falncia de rgos como o fgado,
tamponamento cardaco, etc.!

Sndrome da lse tumoral!

A morte celular em massa pode levar
morte dos doentes (tipos)!
Hipercalimia!
Paragem cardaca!

Hiperfosfatmia!
Hiperuricmia !
Insuficincia renal crnica!

Hipocalcmia!

1 em cada 140 000 casos (?)!

REGRESSO
ESPONTNEA!

Regresso espontnea de tumores!

Hemangioma em crianas
!
2,6% dos recm nascidos!
Incio s 2 a 4 semanas !
Regresso ocorre pelos 10
anos (80-90%)!

Mecanismo
desconhecido!

Regresso tumoral!

Carcinomas de clulas renais!

Neuroblastoma!
Melanoma maligno!
Coriocarcinoma!
Hepatocarcinoma!
Carcinoma da bexiga!

Neuroblastoma !
Sistema nervoso
simptico!
Neuroblastoma!
Ganglioneuroblastoma!
Ganglioneuroma!

!
Mecanismos!
Diferenciao!
Hipometilao do ADN!
Diminuio da actividade da
telomerase!

Melanoma maligno!
Primrio pode regredir!
Estudo de 5000 melanomas malignos!
2,2 casos em 1000 com regresso total do
primrio!

Mecanismo!
Imunolgico (CD4+)!
World

J.

Surg.

19,

352-358,

1995

Spontaneous
Regression
of Human
Association
with Infiltrating
CD4 +
Gary
M.
Halliday,
Frances
J. T e f a n y ,
Department
Australia

Ph.D,
M.B.,

o f Dermatology,

Melanoma/Nonmelanoma
T
Cells

Anita
Patei,
M.B.,
B.S.,
Michelle
J. H u n t ,
B.S.,
M.Med.,
Ross
St.C.
Barnetson,
M.D.
University

o f Sydney, Royal

Prince

Alfred

Abstract.
Spontaneous
regression
occurs
in
some
human
malignant
melanomas
and
basal
cell
carcinomas
(BCCs).
We
have
compared
the
cellular
infiltrate
in
regressing
and
nonregressing
tumors
in
order
to
analyze
the
mechanism
by which
regression
occurs.
Regressing
primary
melanomas
and
BCCs
were infiltrated
with
a larger number
of C D 4 * ,
but
no!
C D 8 +,
T
lymphoc~es
than
were
seen
in
nonregressing
tumors.
The
number
of
interleukin
2
receptor-positive
(eariy
activation
marker)
but
not
transferrin
receptor-positive
(intermediate
activation
m a r k e r ~T cells
was increased,
indicating
that the infiltrating
T cells were activated.
Large
numbers
of
Langerhans
cells,
macrophages,
and
other
class
II
major
histocompatibility
complex
(MHC)-expressing
cells were present but were
no!
increased
in
the
regressing
tumors.
There
were
no
detectable
B
lymphoeytes,
and
the
regressing
tumor
cells
displayed
levels
of H L A - D R
expression
similar
to
those
of
the
nonregressing
tumors.
Comparison
of
sqnamous
cell
carcinoma
(SCCs)
with
keratoacanthomas
(KAs),
which
are
likely
to
be
a
spontaneously
regressing
form
of
SCC,
also
showed
increased
infiltration
of activated
CD&-,
but
not
C D 8 +, T c e l l s w i t h i n
the
KA.
A
murine
ultraviolet
((W)-induced
squamous
tumor
that
spontaneously regresses when
transplanted
into
immunocompetent
syngeneic
mice
was
also
infiltrated
with
increased
numbers
of
activated
CD&-,
but
not
C D 8 +.
T
cells
prior
to
and
during
rejection.
These
results
indicate
that
spontaneous
regression
of human
skin
tumors
is
l i k e l y to b e i m m u n o l o g ically
mediated,
and
that
CD4 +
T
lymphocytes
seem
to
mediate
this
regression.

There
is C o n s i d e r a b l e e x p e r i m e n t a l e v i d e n c e t h a t s k i n t u m o r s c a n
i n d u c e effective i m m u n e r e s p o n s e s in m i c e . E p i t h e l i a l skin t u m o r s
[1]
and
melanomas
[2]
are
able
to
immunize
syngeneic
mice
against subsequent
Challenge w i t h t h e
s a m e t u m o r line. A d d i t i o n ally,
some
ultraviolet
(UV)
light-induced
skin
tumors
in
mice,
which
grow
progressively
in
immunosuppressed
hosts,
regress
when
transplanted
into
syngeneic
immunocompetent
mice.
This
r e s u l t i m p l i e s t h a t t h e i m m u n e s y s t e m is r e s p o n s i b l e f o r t h i s t u m o r
regression
[1,
3].
As
transplantation
experiments
cannot
be
perf o r m e d in h u m a n s ,
evidence that
the
immune
system plays a role
in
controlling
the
growth
of
human
tumors
is
less
direct.
The
antigen
M A G E - 1 , w h i c h is c a p a b l e o f c a u s i n g r e j e c t i o n o f h u m a n
melanomas,
has
been
cloned
[4].
This
antigen,
associated
with
HLA-A1,
is
recognized
by
cytotoxic
T
lymphocytes,
which
are
c a p a b l e o f d e s t r o y i n g M A G E - l - p o s i t i v e t u m o r c e l l s [5]. S t u d i e s o f
Correspondence

to:

G.

Halliday,

Ph.D.

Hospital,

M.B.,

B.S.,

Missenden

Skin

WORLD
Journal

of

SURGERY
9
1 9 9 5 by the Soci~t~
Internationale de Chirurgie

Cancer:

M.Med.,

Road,

Camperdown,

New

South

Wales

2050,

cellular
infiltrates
and
other
markers
of
immunologic
activation,
as
well
as
isolation
of
cytotoxic
lymphocytes
from
patients,
suggests t h a t
the
immune
s y s t e m at l e a s t limits g r o w t h o f h u m a n
melanomas
and
nonmelanoma
skin c a n c e r s
[6, 7].
Analogous
to
the
UV-induced
regressor
tumors
in
mice,
a
number
of
human
skin
tumors
regress
spontaneously.
Most
studies
on
the
role
of
the
immune
system
in
controlling
human
skin
cancers
have
used
progressively
growing
tumor
material,
where
tumor
growth
is o u t p a c i n g
tumor
destruction.
In
contrast,
tumor
cell
death
exceeds
tumor
growth
in
regressing
human
tumors,
providing
valuable
material
for
analysis
of
the
biologic
process
that
can lead
to t u m o r
destruction.
L i t t l e is k n o w n
about
spontaneously
regressing
human
skin
tumors.
We
have
been
studying
spontaneous
regression
of
human
primary
malignant
melanoma
[8], b a s a l c e l l c a r c i n o m a s
(BCCs)
[9], a n d
keratoacant h o m a s ( K A s ) [10] o v e r t h e p a s t 5 y e a r s , a n d h e r e w e c o n t r a s t a n d
review these
findings.
It has b e e n
recognized for a n u m b e r
of years that some human
melanomas
regress
spontaneously.
Spontaneously
regressing
human melanomas
are infiltrated with large n u m b e r s
of lymphocytic
c e l l s [11],
and
cytotoxic T
cell c l o n e s h a v e b e e n
established
from
a
regressing
melanoma
[12],
suggesting
that
regression
may
be
immunologically mediated.
The
prognostic
significance
of
melanoma
regression,
however,
remains
obscure
as
metastasis
still
o c c u r s in t h e s e p a t i e n t s
[13, 14]. M e l a n o m a r e g r e s s i o n c o u l d o f t e n
escape
detection
and
hence
may
be
more
common
than
is
reported.
I t is a l s o l i k e l y t h a t w i t h i n
a regressing lesion individual
tumor
cells
progress
and
change
their
tumor
antigens
so
they
cannot
be
recognized
by
the
ongoing
immune
response.
These
cells m a y t h e r e f o r e
survive r e g r e s s i o n a n d f o r m m e t a s t a s e s . B C C s
also
spontaneously
regress,
although
this
subject
has
undergone
even
less
study
than
melanoma
regression.
BCCs
are
more
numerous
in
immunosuppressed
patients
[15],
and
regressing
BCCs
are
infiltrated
with
large
numbers
of
inflammatory
cells
[16],
suggesting
that
the
immune
response
may
play
a
role
in
regression
o f BCCs.
Keratoacanthoma
is
another
example
of
a
regressing
human
skin t u m o r .
K A s can b e c o m p a r e d with s q u a m o u s
cell c a r c i n o m a s
(SCCs),
which
generally
run
a
progressive
course
that
leads

15 of 16 cancer patients analyzed.

These anecdotal examples hint at the promise of personalized (N-of-one) medicine to target therapies to the
specific genomic alterations of each cancer patient. A
typical cancer genomics workflow is depicted in Figure 1.
This process has been reviewed elsewhere extensively
[11-13] and is arguably converging on some level of
standardization and automation. The major bottleneck
in the process currently lies in the final steps of interpretation and report generation. The challenge is to determine
the significance of tumor-specific genomic changes in

Clnical data

effects of single nucleotide variants (SNVs) and to a lesser

degree insertions and deletions (indels). The overall accuracy of these methods is generally low [14] and very little
has been done for other event types such as chimeric transcripts and copy number variants (CNVs).
Because computational predictions are inadequate, this
challenge of biological and clinical interpretation of genomic events is primarily a challenge in knowledge management. There is a finite collection of knowledge about
these events in the biomedical literature, and every cancer
genome analyst desires access to the entirety of that

Tissue

Increase value
AP report

Clinical decision
Figure 1 The interpretation bottleneck of personalized medicine. A typical cancer genomics workflow, from sequence to report, is
illustrated. The upstream, relatively automated steps (shown by their light color here) involve (1) the production of millions of short sequence
reads from a tumor sample; (2) alignment to the reference genome and application of event detection algorithms; (3) filtering, manual review
and validation to identify high-quality events; and (4) annotation of events and application of functional prediction algorithms. These steps culminate
in (5) the production of dozens to thousands of potential tumor-driving events that must be interpreted by a skilled analyst and synthesized in a
report. Each event must be researched in the context of current literature (PubMed), drug-gene interaction databases (DGIdb), relevant clinical trials
(ClinTrials) and known clinical actionability from sources such as My Cancer Genome (MCG). In our opinion, this attempt to infer clinical actionability
represents the most severe bottleneck of the process. The analyst must find their way through the dark by extensive manual curation before handing
off (6) a report for clinical evaluation and application by medical professionals.

Good et al. Genome Biology 2014, 15:438

Organizing knowledge to enable personalization of medicine in cancer

89

Precursores clnicos !

LESO E CONDIO PREMALIGNA!

provavelmente!
todas as neoplasias desenvolvem-se a
partir!
condio e leso pr-maligna!
neoplasias benignas!
outras!

leso pr-maligna
condio pr-maligna!

condio pr-maligna!
condio pr-maligna uma doena
que condiciona risco aumentado de
desenvolvimento de uma neoplasia
maligna!
uma condio pr-maligna um
antecedente ou um precursor temporal
de neoplasia maligna!

condio pr-maligna!
no-hereditria!
hiperplasia do endomtrio!
colite ulcerosa!
metaplasia pavimentosa do brnquio!
metaplasia de Barrett!
cirrose heptica!
gastrite atrfica!

condio pr-maligna!
hereditria!
PAF - polipose adenomatosa familiar
(APC)!
HNPCC - sndrome de Lynch!
MEN - neoplasia endcrina mltipla!

condio pr-maligna!

RISCO aumentado de
desenvolvimento de neoplasia
maligna!

leso pr-maligna!
leso pr-maligna uma leso ou
alterao histolgica que antecede o
desenvolvimento de uma neoplasia
maligna = DISPLASIA!
a leso pr-maligna o antecedente
local ou o precursor lesional de
malignidade!

condio = precursor temporal

leso = precursor lesional

colite ulcerosa!
Doena inflamatria crnica
intestinal
!
Processo inflamatrio recurrente, de etiopatogenia
desconhecida, limitado ao clon e recto com
manifestaes extra-intestinais!

 Homem, 44
anos!
Episdios de
diarreia com
muco e
sangue!
Desconforto
abdominal!

Inflamao activa

Inflamao quiescente

colite ulcerosa
risco de carcinoma!
durao da doena!
< 10 anos (<1%) !
> 20 anos (5-10%) !
> 30 anos (5-20%) !
> 10 anos (risco 1-2% / ano) !

extenso da doena!
RR (1,7 doentes com proctite)!
RR (14,8 doentes com pancolite)
!
!!

leso pr-maligna!
displasia
!

displasia!
termo impreciso mas PRTICO!
alteraes celulares muito irregulares que
ultrapassam a hiperplasia mas ainda no
so suficientes para serem chamadas de
neoplasia!
nos epitlios, h um grau de displasia que
se mistura com o carcinoma in situ!

CONDIO PR-MALIGNA
!
(METAPLASIA DE BARRETT)
!

LESO PR-MALIGNA
!
(DISPLASIA EM METAPLASIA DE BARRETT)
!

NEOPLASIA INVASIVA
!
(ADENOCARCINOMA)
!

NEOPLASIAS BENIGNAS!

OUTRAS LESES!

outras!
restos embrionrios!
rim!
maxilar!

leses inflamatrias crnicas!

lceras crnicas da pele!
osteomielite e fistulizao!