Uroepithelial carcinomas Imad Fadl-Elmula Symposium on: Advances in Parasitology “Education and...
-
Upload
stephanie-martin -
Category
Documents
-
view
216 -
download
2
Transcript of Uroepithelial carcinomas Imad Fadl-Elmula Symposium on: Advances in Parasitology “Education and...
Uroepithelial carcinomasUroepithelial carcinomas
Imad Fadl-ElmulaImad Fadl-Elmula
Symposium on: Advances in Parasitology “Education and Research in Parasitology in the service of Mankind “
Genetic profile of post-bilharzial Genetic profile of post-bilharzial bladder SCCbladder SCC
The somatic mutation theory of cancer
Theodor Boveri (1862-1915)
Acquired genetic changes are
the main causes of malignant
transformation of target cells
Histology The development of Carcinomas
MutatiMutationon
HyperplasiaHyperplasia DysplasiaDysplasiaIn situ CancerIn situ Cancer
Invasive CancerInvasive Cancer
Natural history of cancerNatural history of cancer
ProgressionProgression
Genetic
(Oncogenes/ tr suppressor genes)
Mitogenesis
Immune surveillance
Angiogenesis
Epigenetic
(clonal expansion)
Biology of Cancer!Biology of Cancer!
Promotion
Initiation
Ist Hit Normal Cell
Apoptosis
Rep
air
Mild Dysplasia
2nd Hit
Apopto
sis
Apopto
sis
Severe Dysplasia
Cancer
3rd Hit
Genetic alterations
Normal PIA PIN PCA
inflammation
30 year 80 year
Gene defects
Proliferation
GSTP expression
Oxidative stressOxidative stress
? ?
0
100
Well differentiated Moderately differentiated Moderately differentiated Undifferentiated Undifferentiated Poorly differentiated Poorly differentiated
Uroepithelial cancerUroepithelial cancer
54,000 new cases 12,500 deaths Three times more frequently in € than in
7th most common cancer in 4th most common cancer in €
In areas where Schistosoma haematobium is endemic
The most common cancer (25%) in €
Rarely occur before the age of 40 years
12.500 deaths
Sex€€€ :
7th most common cancer in
4th most common cancer in € in Europe and USA
The most common cancer (25%) in €in the
areas where Schistosoma haematobium is endemic
Age (rare before the age of 40 years)
54.000 new cases in USA 1.883 new cases in Sweden
Race €€:€
12th leading cause of cancer death
Uroepithelial carcinomas
Natural historyNatural history
High incidence of recurrence.
Heterogeneity of the clinical
course.
Multifocality.
Histopathology
Histology Transitional cell carcinoma (TCC) Squamous cell carcinoma (SCC) Adenocarcinoma (AC) Undifferentiated carcinoma (UC)
Grading (Koss, 1975) Well-differentiated carcinoma (G1) Moderately differentiated carcinoma (G2) Poorly differentiated carcinoma (G3)
DiagnosisDiagnosis
CystoscopyCystoscopy
Urine cytologyUrine cytology
AccidentallyAccidentally Excretory urographyExcretory urography
Signs and symptomsSigns and symptoms
Treatment
1. Superficial disease (Ta, T1) Transurethral resection of tumor (TUR-T)
TUR-T + Adjuvant intra-vesical immune- or chemotherapy
2. Invasive disease (T2)
Radical surgery + Pre- or post-operative radiation therapy
Palliative treatment in cases with systemic metastasis
THE PRESENT STUDY
AIMS1. Characterize the genetic alterations in tumors of
tumor
Bladder tumor
Renal pelvis
THE PRESENT STUDY
AIMS1. Characterize the genetic alterations in tumors of
Ureteral tumor
Bladder tumor
Renal pelvis
Aims were:
THE PRESENT STUDY
1. Different etiologies
To characterize the genetic alterations in tumors of:
THE PRESENT STUDY
AIMS1. Characterize the genetic alterations in tumors of
Ureteral tumor
Bladder tumor
Renal pelvis
3. Different histologic types
TCCTCC SCC
Clinical characteristics of TCC and SCC
1. Incidence Middle east, Africa USA, Europe 2. Age 45 years 65 years
3. Sex 4:1 3:1
4. Etiology Biological Chemicals
5. Clinical Invasive and solid Superficial, papillary, and multiple
6. Treatment Radical surgery T-TUR and others
7. Progression Fast Slow (15%)
8. Genetic
SCC TCC
Sole change?
2. Chromosomal abnormalities2. Chromosomal abnormalities involved in initiation processinvolved in initiation process
THE PRESENT STUDY
AIMS1. Characterize the genetic alterations in tumors of
Ureteral tumor
Bladder tumor
Renal pelvis
THE PRESENT STUDY
AIMS1. Characterize the genetic alterations in tumors of
Ureteral tumor
Bladder tumor
Renal pelvis
These goals were approached by analyzing samples from
Sweden Sudan
Sampling-
Collagenase II
Mechanical and enzymatic disaggregation
3-10 Days
Short-term culture
T3-2
T2-1
T2-2
Harvest and preparation of the slides
Hypotonic treatment Fixation
G-Banding
1 T1-T1-2
Analysis
47,X,-Y,del(2)(q21q31),t(3;5)(q27q31),del(5)(q11q13),+7,-9,+r[50]
Karyotyping (ISCN)
Cytogenetic analysis
2. Cytogenetic analyses Complex karyotypes in both tumors
Muscle invasive tumors Squamous differentiation
1. Histopathology
Results
Conclusions
The putative genetic changes that steer The putative genetic changes that steer the differentiation of the neoplastic the differentiation of the neoplastic epithelium in the direction of squamous epithelium in the direction of squamous cells thus remain unknowncells thus remain unknown
Secondary SCCs of the bladder are Secondary SCCs of the bladder are karyotypically indistinguishable from karyotypically indistinguishable from advanced TCCs of the same organadvanced TCCs of the same organ
Clinical conclusions
1. Beside endoscopic removal of superficial
tumors, additional measures against the
intraluminal seeding of cancer cells and
their ability to divide should take place.
2. Surgeons should avoid unnecessary
epithelium trauma during the endoscopic
removal of bladder tumor(s).
Chromosome 9
Rearranged in 92% of the informative
cases
As a single anomaly in two cases, del(9)(p11)
and del(9)(q12q22)
Loss of one copy in 15 cases
Structural rearrangement in 8 cases
Chromosomes 1 and 11
Chromosomes 1 and 11 were rearranged in 10 (33%) and 11 (37%) cases each.
The most common consequences of the changes in chromosome 1 were gain of 1q material and loss of 1p.
The most common consequences of the changes in chromosome 11 were losses of material from 11p
Often found in simple karyotypes in low-grade tumors
Never seen as the sole change but often accompanied chromosome 9
1
2
1234
3
4
12
12345
1
2
6
5432
1
2
1
3
2
112
1
2
34567
1
234
1234
2
1
1
12345612345
65432
1
43
21
2
1
12
3
1234
5
6
789
6
5
432112
1
2345678
3
2
1
2345
3
5
4
321123
45
1
1
123
1
2345
2
3
5432
1
211
2
123
56
1
2
34567
41
2
321211
2
123
1
2
3
4
1
2
21
54321
1
2
1
1
1
2
1
23456
2
3
5432
1
1
2
1
1
1
2
3
4
5
6
3
2
112
345
1
23
4
2
1
1
5
4321
1
12
3
4
12
3
4
2
1
321123
4
1
23
12
1
1
2
3
123456
123
12345
1
1
2
1234
1
2
1234
1
2
3
1 123 3
21
1231234
1
1
2
1
1
2
321121
2345
1
1
2
1
23
1
1
2
32112
3
1
11
2
3
1
2
3
1
2
123
1
11
2
1
1
123
12
3
2
1
123
2
1
11
1
2345678
2
2 4 5
610
11 12
13 14 1516 17 18
20 21 22
X
1
1
2
1
1
1
2
1234
3
4
12
12345
1
2
6
5432
1
2
1
3
2
112
1
2
34567
1
234
1234
2
1
1
12345612345
65432
1
43
21
2
1
12
3
1234
5
6
789
6
5
432112
1
2345678
3
2
1
2345
3
5
4
321123
45
1
1
123
1
2345
2
3
5432
1
211
2
123
56
1
2
34567
41
2
321211
2
123
1
2
3
4
1
2
21
54321
1
2
1
1
1
2
1
23456
2
3
5432
1
1
2
1
1
1
2
3
4
5
6
43213
1123
1
2
2
2
1
1
2
123
43
3
2
112
345
1
23
4
2
1
1
5
4321
1
12
3
4
12
3
4
2
1
321123
4
1
23
12
1
1
2
3
123456
123
12345
1
1
2
1234
1
2
1234
1
2
3
1 123 3
21
1231234
1
1
2
1
1
2
321121
2345
1
1
2
1
23
1
1
2
32112
3
1
11
2
3
1
2
3
1
2
123
1
11
2
1
1
123
12
3
2
1
123
2
1
11
1
2345678
2
12
3
4 5
78 9 10
11 12
13 14 1516 17 18
19 20 21 22
X
Y
1
1
2
1
1
The karyotypic profileThe karyotypic profile of bladder TCC of bladder TCC
is cis characterizedharacterized by: by:
1. Nonrandom chromosomal aberrations
2. Few changes in low-grade and early stage tumors and
massively rearranged karyotypes in muscle invasive ones
2. Losses of chromosomal material
3. Little intratumor cytogenetic heterogeneity
4. Monoclonal origin
Study 7Study 7
Chromosomal aberrations in benign and Chromosomal aberrations in benign and
malignant bilharzia-associated bladder malignant bilharzia-associated bladder
lesions analyzed by comparativelesions analyzed by comparative
genomic hybridizationgenomic hybridization
BBilharzia-associated bladderilharzia-associated bladder cancer cancer
Most common cancer among men (25%)
80% of patients present with muscle infiltrating disease
Long-term survival is obtained in 27–39% of the cases
Low mean age at diagnosis (45 years)
Earlier diagnosis is important for treatment outcome
87% of the cases are SCC type
Distribution of urinary schistosomiasis in Africa (WHO/TDR)
600 million run the risk of becoming infected
Endemic in 74 countries
Preventable disease !!!!!
200 million are infected
250.000 annual deaths
1. To determine the genetic imbalances involved in BAC
2. To find out if preneoplastic bilharzia lesions carry chromosomal
aberrations resembling those seen in carcinomas
3. To see whether the unique etiology yields a distinct cytogenetic
profile compared to chemically induced bladder tumors
Objectives Objectives
MaterialsMaterials
20
Post-bilharzial bladder lesions
6 benign 14 malignant
12 € ƒ 8
Sudan
The National Health Laboratory Khartoum, Sudan
Pathology archives of Ibn Sina hospital, Khartoum, Sudan
MethodsMethods
20-30 paraffin sections20-30 Paraffin sections Control DNA
Normal DNA
Isolation and labelling-
Tumor DNAIsolation and labelling FITC-dUTP
Hybridization to normal metaphase
Cot-1 DNA
Loss (green-to-red ratios < 0.80)
Gain (green-to-red ratios >1.2)
CGH analysis
Fluorescence in situ hybridization (FISH)
Xylene
Absolute ethanol Proteinase K
2xSSC
air-drying
Pericentromeric probes
17
X
9
pBAMX7
pHuR98
p17H8
Analysis
MethodsMethods
ResultsResults
Of the 20 lesions only 7 showed abnormality
6 carcinomas (4 SCC and 2 TCC)
1 granuloma
Chromosomal imbalances varying from 1 to 6 changes
The most common changes (seen in three cases each):
Loss of 1p21-31, 8p21-pter, and 9p
Gain of 19p material
ConclusionsConclusions
1. The cytogenetic profiles of chemical- and bilharzia
induced carcinomas are largely similar.
2. Loss of material from 9p seems to be the initiating event
and gain of material from 19p a later progressional event.
3. Preneoplastic bilharzia lesions carry chromosomal
aberrations resembling those seen in carcinomas.