Cytogenetic Analysis in

Hematological Malignancies

Hwei-Fang Tien, National Taiwan University Hospital

Cytogenetics in Hematological Malignancies

• Most patients with hematological malignancies have clonal chromosomal abnormalities.

• Some recurrent chromosomal abnormalities are tumor- and even subtype-specific, so are good for diagnosis and classification.

• The pattern of chromosomal aberrations may predict treatment response and clinical outcome and is good for risk stratification.

• Genes located at the breakpoints of the recurrent abnormalities play an important role in the process of tumorigenesis and can be the target of treatment.

Purpose of Cytogenetic Study in Hematological malignancies

1. Diagnosis and classification

2. Risk stratification

3. Selection of proper treatment

4. Follow-up of the response

Recurrent chromosomal abnormalities in Hematological malignancies

CML t(9;22)

AML t(8;21), t(15;17), inv(16), t(9;11), inv(3), t(6;9), t(1;22), -5/5q-, -7/7q-

ALL t(4;11), t(1;19), t(v;11q23), t(12;21)

MDS -5/del(5q), del(20q); -7/del(7q), +8

Lymphoma DLBCL t(3q27)

Burkitt t(8;14) and variant

Follicular t(14;18)

Mantle cell t(11;14)

Marginal zone t(11;18), t(1;14), t(14;18)

Case Demonstration

Diagnosis

BM smears in a patient with bleeding tendency

NTUH, Gene Chromosome Cancer, 1995,12:161

23Y/O, male , PB plt, 3000/μL; Hb, 9.2 gm/dL; WBC, normal

Plt count increased to 533x103/μL after steroid treatment, but dropped again 1 mo later.

BM smears

BM smears

Cytogenetic Abnormalities

NTUH, Gene Chromosome Cancer, 1995,12:161

The pt received splectomy. Final dignosis: hepatosplenic Tγ/δ lymphoma

A new cytogentc- clinicopathological entity of NHL

NK-cell large granular lymphocytosis

NTUH, Br J Haematol, 1998, 103:1124

Cytogenetic Abnormalities

Diagnosis: NK-cell large granular lymphocyte leukemia

PB smears

Differential diagnosis of hypoplastic MDS with AA

BM smears

Name: 林 X 榮 , 46, XY, -7 [20]

Chromosomal abnormality

Diagnosis: hypoplastic MDSNTUH, Leukemia, 2008, 22:544

Case Demonstration

For Lymphoma Staging

BM study for staging in a patients with DLBCL

Pathol exam. of the BM biopsy specimen: no lymphoma involvement

BM smears

BM smears

Same clonal chromosomal abnormalities in bone marrow as in lymph node

Lymph node Bone marrow

DLBCL stage IV with BM involvement is confirmed

Risk Stratification

AML: Impact of Cytogenetics based on 2008 WHO Classification

Medical Research Council , United Kingdom Blood. 2010;116(3):354 , Blood Rev, 2011; 25:39

t(9;22)-7/7q--5/5q-Inv(3), t(3;3)

t(9;11)t(3;5)t(6;9)MDS-relatedother t(11q23)

t(15;17)

t(8;21)Inv(16)

5876 patients

Normal

MDS: New Cytogenetic Scoring System (n=2,754)

Abnormality Overall survival

AML transformation

Prognostic Subgroup

No. ofPts

% Single Double Cplx Median(months)

Median (months)

Very good 81 2.9 del(11q), -Y ― ―

60.8 NR

Good (reference)

1,809 65.7 Normal, del(5q)del(12p), del(20q)

Including del(5q)

―

48.6 NR

Intermediate 529 19.2 del(7q), +8, i(17q)+19, any otherIndependent clones

Any other ―

26.0 78.0

Poor 148 5.4 Inv(3)/t(3q)/del(3q),-7

Including-7/del(7q)

3 15.8 21.0

Very poor 187 6.8 ― ― > 3 5.9 8.2

Abbreviations: AML, acute myeloid leukemia; NR, not reached.

Schanz et al, J Clin Oncol, 2012

MM: Impact of genomic aberrations on OS

Avet-Loiseau et al, Blood. 2007;109:3489

Implication of cytogenetics on survival in MM

overall survival (month)

2001000

Cum

ulat

ive

Sur

viva

l

1.0

.8

.6

.4

.2

0.0

Hyperdipolidy (n=19)

Non-hyperdiploid (n=25)

p=0.025

overall survival (month)2001000

Cum

ulati

ve S

urvi

val

1.0

.8

.6

.4

.2

0.0

Normal karyotype (n=106)

Abnormal karyotype (n=44)

P=0.029

NTUH, Ann Oncol 16:1530, 2005

overall survival (month)

2001000

Cum

ulat

ive

Sur

viva

l

1.0

.8

.6

.4

.2

0.0

FISH_∆13 only, N=23

Without abnormality, N=57

p=0.013

CG_∆13N=8

Survival Analysis:

Combined cytogenetics & FISH

NTUH, Ann Oncol 16:1530, 2005

Prognostic relevance of chromosome aberrations in CLL

Zenz & Dohner, Best Pract Res Clin Haematol. 2007 20:439

17p-

11q-

+12

13q- sole

normal

Implications of 17p-/11q- on OS in CLL

Cytogenetics

FISH

NTUH, Ann Hema, 2013, in press

Follow Up the Clinical Course

Chronic Myeloid Leukemia, Chronic Phase

CML in blast crisis

Indication of Cytogenetic Study

• Unknown cause of cytopenia• Fever of unknown origin• WHO classification of AML and ALL• MDS diagnosis and classification (IPSS, IPSS-R)• Lymphoma diagnosis, classification and

staging work up• Risk stratification of CLL and MM• Follow-up of treatment response

台灣藍鵲（ Formosan Blue Magpie )