Lymphoma

Dr Mohammed Alqahtani
CSLT(CG), CLSp(CG), RT,MBA, Ph.D
Genomic Medicine Unit Founder & Director
Center of Excellence in Genomic Medicine Research Founder & Director
 Overview
Konsep, klasifikasi, biologi
Epidemiologi
Presentasi klinis
Diagnosis
Pementasan
Tiga jenis penting dari limfoma
 How Cancer Develops
Sel-sel normal diprogram untuk berkembang
biak, mati ketika mereka sudah tua
Sinyal untuk berkembang biak dan mati
dikontrol oleh gen tertentu
Mutations can occur in these genes
If enough mutations occur in genes controlling
growth or cell death a cell begins to multiply
uncontrollably
The cell has then become cancerous or
malignant
 Features common to cancer
cells
Growth in the absence of go signals
Growth despite stop signals
Locally invasive growth and metastases
to distant sites
 Bone Marrow
Present in the soft inner part of some bones
such as the skull, shoulder, blade, ribs, pelvis,
and backbones. (Occupies central cavity of
bone)

The bone marrow is made up of blood-forming

stem cells, lymphoid tissue, fat cells, and
supporting tissues that aid the growth of blood
forming cells.
 Bone Marrow
Spongy tissue where development of all
types of blood cells takes place
All bones have active marrow at birth
Adulthood - vertebrae, hip, shoulders,
ribs, breast and skull contain marrow
Bone Marrow Aspiration/Biopsy
 Hematopoietic
Malignancies

Lymphoma is a general term for

hematopoietic solid malignancies of
the lymphoid series.

Leukemia is a general term for liquid

malignancies of either the lymphoid
or the myeloid series.
 Conceptualizing
lymphoma
neoplasms of lymphoid origin, typically
causing lymphadenopathy
leukemia vs lymphoma
lymphomas as clonal expansions of
cells at certain developmental stages
 Apakah Limfoma Itu
Limfoma adalah kanker yang dimulai
oleh "transformasi maligna" dari limfosit
dalam sistem limfatik
Banyak limfoma diketahui karena mutasi
genetik tertentu
limfoma folikular karena berlebih dari
BCL-2 (gen yang blok sel mati
terprogram)
 Apakah Sistem Limfatik ??
@_@
Terdiri dari organ-organ, seperti amandel,
limpa, hati, sumsum tulang dan jaringan
pembuluh limfatik yang menghubungkan
kelenjar, yang disebut kelenjar getah bening
kelenjar getah bening di seluruh tubuh
Kelenjar getah bening partikel asing
menyaring cairan limfatik
Mengandung B dan limfosit T
 Lymphatic System
Kelenjar getah bening bertindak sebagai filter
untuk menghilangkan bakteri, virus, dan
partikel asing
Kebanyakan orang akan memiliki "kelenjar
bengkak" pada saat yang sama sebagai
respon terhadap infeksi
AKU CINTA ISTRIIKUU ^_^
 Blood Cell and
Lymphocyte Development
STEM CELLS

Multipotential Multipotential
myeloid cells lymphocytic cells

Differentiate & mature into 6 Differentiate & mature into 3

Types of blood cells Types of lymphocytes

red cells basophils T lymphocytes

neutrophils monocytes B lymphocytes
eosinophils platelets Natural Killer Cells
 Lymphocytes
Most lymphocytes are in lymph nodes,
spleen, bone marrow and lymphatic vessels
20% of white blood cells in blood are
lymphocytes
T cells, B cells, natural killer cells
B cells produce antibodies that help fight
infectious agents
T cells help B cells produce antibodies and
they fight viruses
 T-Cells and B-Cells

Immature lymphocytes that travel to the

thymus differentiate into T-Cells
T is for thymus
Immature lymphocytes that travel to the
spleen or lymph nodes differentiate into B
cells
"B" stands for the bursa of Fabricius, which is
an organ unique to birds, where B cells
mature.
 ALL CLL Lymphomas MM
nave

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML Myeloproliferative disorders

Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
 B-cell development
memory
B-cell
stem CLL mature
germinal
center
cell
naive B-cell
B-cell
lymphoid
progenitor

progenitor-B
MM
ALL
pre-B DLBCL,
immature FL, HL
B-cell plasma cell
 Classification

Biologically rational Clinically useful

classification classification
Diseases that have distinct Diseases that have distinct
morphology clinical features
immunophenotype natural history
genetic features prognosis
clinical features treatment
 Klasifikasi
Biasanya diklasifikasikan oleh bagaimana
sel-sel terlihat di bawah mikroskop dan
seberapa cepat mereka tumbuh dan
menyebar
limfoma agresif (limfoma bermutu tinggi)
Malas Limfoma (limfoma tingkat rendah)
Lymphoma classification
(2001 WHO)
B-cell neoplasms
Pendahulu
Dewasa Non-
Hodgkin
T-cell & NK-cell neoplasms Lymphomas

pendahulu
dewasa
Hodgkin lymphoma
Tiga limfoma umum

limfoma folikel
Difus limfoma sel B besar
Hodgkin lymphoma
 Relative frequencies of
different lymphomas

Non-Hodgkin Lymphomas

Diffuse large B-cell

Hodgkin NHL Follicular
lymphoma
Other NHL

~85% of NHL are B-lineage

 Follicular lymphoma
most common type of indolent
lymphoma
usually widespread at presentation
often asymptomatic
not curable (some exceptions)
associated with BCL-2 gene
rearrangement [t(14;18)]
cell of origin: germinal center B-cell
 defer treatment if asymptomatic
(watch-and-wait)
several chemotherapy options if
symptomatic
median survival: years
despite indolent label, morbidity and
mortality can be considerable
transformation to aggressive lymphoma
can occur
 Diffuse large B-cell
lymphoma
most common type of aggressive
lymphoma
usually symptomatic
extranodal involvement is common
cell of origin: germinal center B-cell
treatment should be offered
curable in ~ 40%
B-Cell Lymphoma (80%)
B-Cells help make antibodies, which are
proteins that attach to and help destroy antigens
Lymphomas are caused when a mutation arises
during the B-cell life cycle
Various different lymphomas can occur during
several different stages of the cycle
Follicular lymphoma, which is a type of B-cell
lymphoma is caused by a gene translocation which
results in an over expressed gene called BCL-2,
which blocks apoptosis.
T-Cell Lymphoma (15%)
The T-cells are born from stem cells,
similar to that of B-cells, but mature in the
thymus.
They help the immune system work in a
coordinated fashion.
These types of lymphomas are categorized
by how the cell is affected
Anaplastic Large cell Lymphoma, t-cell lymphoma
caused by a gene translocation in chromosome 5
Mekanisme lymphomagenesis

perubahan genetik
Infeksi
stimulasi antigen
imunosupresi
 Epidemiologi limfoma

jantan > betina

Insidensi
NHL naik
Hodgkin lymphoma stabil
di NHL: 3 yang paling sering didiagnosis
kanker pada laki-laki dan 4 pada wanita
di HL: 5 yang paling sering didiagnosis
kanker pada laki-laki dan 10 perempuan
 Incidence/100,000/annum

0
20
40
60
80
100

0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49

Age (years)
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
Age distribution of new NHL
 Faktor risiko NHL
imunosupresi dan immunodeficiency
penyakit jaringan ikat
riwayat keluarga limfoma
agen infeksius
radiasi pengion
 manifestasi klinis
Variable
keparahan: asimtomatik untuk sangat sakit
Tentu saja waktu: evolusi selama beberapa
minggu, bulan, atau tahun
manifestasi sistemik
fever, night sweats, weight loss, anorexia, pruritis
Local manifestations
limfadenopati, splenomegali paling umum
jaringan apapun berpotensi bisa disusupi
 Other complications of
lymphoma
bone marrow failure (infiltration)
CNS infiltration
immune hemolysis or thrombocytopenia
compression of structures (eg spinal
cord, ureters)
pleural/pericardial effusions, ascites
Non-Hodgkins Lymphoma
Staging
Tahap adalah istilah yang digunakan untuk
menggambarkan luasnya tumor yang telah
menyebar melalui tubuh (I dan II dilokalisasi
sedangkan III dan IV yang maju.
Setiap tahap kemudian dibagi ke dalam kategori A, B,
dan E
A: Tidak ada gejala sistemik
B: sistemik Gejala seperti demam, keringat malam
dan penurunan berat badan
E: Penyebaran penyakit dari kelenjar getah bening ke
organ lain
Tahap dari Limfoma
Stage I Stage II Stage III Stage IV

A: absence of B symptoms
B: fever, night sweats, weight loss
Staging
 Gejala
Pembengkakan menyakitkan kelenjar getah
bening yang terletak di leher, ketiak dan
selangkangan.
Demam tak terduga
Keringat dingin
Selalu kelelahan
Turun berat badan drastis
Kulit gatal-gatal
Cancer Sourcebook
 Penyebab dan Faktor
Risiko
Penyebab pasti masih tidak diketahui
risiko lebih tinggi untuk individu yang :
Terkena bahan kimia seperti pestisida atau
pelarut
Terinfeksi dg Epstein-Barr Virus
Riwayat keluarga NHL (meskipun ada pola
herediter telah ditetapkan)
Terinfeksi HIV

Lymphoma.org
 Diagnosis? Studi Staging

Tulang aspirasi sumsum dan biopsi

scan radionuklida :
GI x-rays
analisis cairan tulang belakang
CT scans
Magnetic Resonance Imaging (MRI)
Biopsi
Diagnosis membutuhkan Biopsi
yang memadai

Diagnosis harus dibuktikan dengan

biopsi sebelum pengobatan dimulai
Perlu jaringan cukup untuk menilai sel
dan arsitektur
open bx vs core needle bx vs FNA
 Pengobatan
Non-Hodgkins Lymphoma biasanya diobati
oleh tim dokter termasuk dermatologists, ahli
onkologi medis dan onkologi radiasi.

Dalam beberapa kasus seperti untuk indolen

limfoma, Dokter mungkin menunggu untuk
memulai pengobatan sampai pasien mulai
menunjukkan gejala, yang dikenal sebagai
"menunggu waspada"
 Pilihan Pengobatan
Kemoterapi
Radiasi
Transplantasi sumsum tulang belakang
Operasi
Bortezomib (Velcade)
Immunotherapi
Menggunakan sistem kekebalan tubuh sendiri
dikombinasikan dengan bahan yang dibuat di
laboratorium.
 Kelangsungan Hidup
Kelangsungan hidup Tarif luas bervariasi
menurut jenis sel dan pementasan.

1thn Kemampuan bertahan hidup : 77%

5 th Kemampuan bertahan hidup : 56%

10 th Kemampuan bertahan hidup : 42%

Cancer.org
Hodgkin lymphoma

Thomas Hodgkin
(1798-1866)
Classical Hodgkin Lymphoma
 Hodgkin lymphoma
cell of origin: germinal centre B-cell
Reed-Sternberg cells (or RS variants)
in the affected tissues
most cells in affected lymph node are
polyclonal reactive lymphoid cells, not
neoplastic cells
Reed-Sternberg cell
 RS cell and variants

classic RS cell lacunar cell popcorn cell

(mixed cellularity) (nodular sclerosis) (lymphocyte
predominance)
 A possible model of
pathogenesis
loss of apoptosis
transforming
event(s)
EBV?

cytokines
germinal
centre RS cell
inflammatory
B cell
response
 Hodgkin Limfoma
subtipe histologis
Hodgkin limfoma Klasik
nodular sclerosis (subtipe yang paling umum)
campuran cellularity
limfosit-banyak
limfosit berkurang / habis
 Epidemiologi
kurang sering daripada non-Hodgkin
lymphoma
Secara keseluruhan M>F
Insiden puncak pada 3 dekade
 incidence/100,000/annum

0
1
2
3
4
5
6

0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54

Age (years)
55-59
60-64
65-69
70-74
75-79
80-84
85+
Distribusi usia kasus
limfoma Hodgkin baru
 Terkait faktor
(etiologi?)
EBV infeksi
ukuran keluarga kecil
status sosial ekonomi yang lebih tinggi
caucasian > non-caucasian
kemungkinan predisposisi genetikother
: HIV? pendudukan? herbisida?
 manifestasi klinis
Limfadenopati
Bersebelahan
situs ekstranodal relatif jarang kecuali
pada penyakit lanjut
B gejala
 Treatment and
Prognosis
Tahap Penangan Kemungki Overall 5
an nan year
kegagalan survival
I,II ABVD x 4 70-80% 80-90%
& radiation

III,IV ABVD x 6 60-70% 70-80%

 Komplikasi jangka
panjang dari
pengobatan
Kemandulan
MOPP > ABVD; pria > wanita
sperma perbankan harus didiskusikan
Menopouse dini
keganasan sekunder
skin, AML, lung, MDS, NHL, thyroid,
breast...
penyakit jantung
 A practical way to think of
lymphoma
Kategori Kelangsun Curability To treat or
gan pasien not to treat
tak dirawat

Non- Pelan tahunan Tidak dapat Umumnya

Hodgkin disembukan mengacu Rx jika
lymphoma asimtomatik

Agresif Bulanan Beberapa dirawat

dapat
disembuhkan

Sangat Mingguan Beberapa dirawat

agresif dapat
disembuhkan

Hodgkin Semua tipe Bulan ke Rata-rata dirawat

lymphoma Tahun dpt
disembuhka
n
 Lab Studi Diagnostik

Biopsi kelenjar getah bening

aspirasi sumsum tulang dan biopsi
Imunohistokimia
Arus cytometry
Studi genetik molekuler
FISH
Sitogenetika
 Lab sitogenetika
t(14,18) common (about 30%)
Bcl-2
Pola pertumbuhan folikel
t(8,14) ! common in Burkitts ! c-myc
Beberapa anomali umum
Korelasi antara perubahan sitogenetika
dan hasil adalah variabel
 FISH analisis parafin
tertanam bagian jaringan

Dalam slide berikutnya dua contoh dari

limfoma hibrid dengan probe split-
terpisah ditampilkan.
 Large cell
lymphoma

Case 1
Truncated
nuclei

Truncated
nucleus

Myc split-
apart
probe:

Probe 1+2
FISH analysis of paraffin embedded tissue
Interpretation of results
Case 1 Case 2

Signals (even in truncated cells) are Some nuclei contain split signals,
fused, excluding a translocation . indicating a translocation.
FISH analysis of paraffin embedded tissue
Interpretation of results
Case 1 Case 2

Signals (even in truncated cells) are Some nuclei contain split signals,
fused, excluding a translocation . indicating a translocation.
 FISH analysis of paraffin
embedded tissue sections
There are now plentiful examples of how the FISH procedure
is needed in routine lymphoma diagnosis.

MALT lymphomas with the t(11;18)(q32;q21) translocation: For many

laboratories FISH analysis is more convenient than a PCR procedure for
detecting such cases.

Burkitt-like lymphomas: Cases suggestive of Burkitts lymphoma but with

atypical features should be analysed by the FISH technique for evidence
of MYC translocation.

What future applications of the FISH technique are likely to

emerge in the future?
One area lies in the detection of chromosomal amplifications
and deletions of clinical significance. (CGH)
For example specific patterns of chromosomal gains or losses have been
noted in diffuse large B cell lymphoma.

Bea et al (2005) Blood 106:3183-3190 Tagawa et al Blood. (2005);106:1770-1777

For example specific patterns of chromosomal gains or losses have been
noted in diffuse large B cell lymphoma.

Bea et al (2005) Blood 106:3183-3190 Tagawa et al Blood. (2005);106:1770-1777

For example specific patterns of chromosomal gains or losses have been
noted in diffuse large B cell lymphoma.

Bea et al (2005) Blood 106:3183-3190 Tagawa et al Blood. (2005);106:1770-1777

For example specific patterns of chromosomal gains or losses have been
noted in diffuse large B cell lymphoma.

Bea et al (2005) Blood 106:3183-3190 Tagawa et al Blood. (2005);106:1770-1777

 Molecular Cytogenetic
Lab
Recurrent molecular abnormalities in
lymphoma
t(14;18) / Bcl2 - JH in follicular lymphoma
t(11;14) / Bcl1 - JH in Mantle Zone lymphoma
t(3;14) / Bcl6 - JH in Diffuse Large Cell
lymphoma
t(8;14) / cMyc - JH in Burkitt lymphoma
t(2,5) / ALK-NPM in Anaplastic Large Cell
Lymphoma
 Histology Lab
RS cell and variants

classic RS cell lacunar cell popcorn cell

(mixed cellularity) (nodular sclerosis) (lymphocyte
predominance)