Dr Wiwit Ade FW, M.

Biomed, SpPA

Introduction of lymphoma
The

lymphomas are malignant

tumors of lymphoid tissue,
characterized by the abnormal
proliferation B or T cells in
lymphoid tissue .
Lymphomas - these are malignant
neoplasms
derived
from
lymphocytes that form "tumors",
usually in lymph nodes but also in
other organs or in soft tissue.
Unlike the leukemias the tumor
cells do not appear in the blood in
detectable numbers.
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B-cell development
CLL
MCL

stem
cell

memory
B-cell
mature
naive
B-cell

germinal
center
B-cell

MZL
CLL

lymphoid
precursor
progenitor-B

LBL, ALL

MM
pre-B
immature
B-cell

DLBCL,
FL, BL, HL

plasma cell

Essential Points about Lymphomas

they are all malignant
derived from B or T cells
usually arise in lymph nodes, but can form in any
organ
differ from leukemias tumor cells not in peripheral blood
disease not usually centered in marrow

Mechanisms of lymphomagenesis
Genetic alterations
Infection
Antigen stimulation
Immunosuppression

PATHOGENESIS OF LYMPHOMAS
All lymphomas are derived from a single mutated cell

and are thus "clonal" or "monoclonal" in origin.

The specific mutations involved differ from one type of
lymphoma to the next but a large number of them
involve chromosomal translocations.

 translocations are characteristic of specific lymphomas

t(14;18) in follicular lymphomas

t(8;14) in Burkitts lymphoma
clone of cells is immortalized
further mutations often occur leading to tumor

progression
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Chromosomal Translocations

Epidemiology of lymphomas
5th most frequently diagnosed cancer overall for both

males and females

males > females
incidence
NHL increasing over time
Hodgkin lymphoma stable

Clinical manifestations
Variable

severity: asymptomatic to extremely ill

time course: evolution over weeks, months, or years

Systemic manifestations

fever, night sweats, weight loss, anorexia, pruritis

Local manifestations

lymphadenopathy, splenomegaly most common

any tissue potentially can be infiltrated

Classification of Lymphomas
important because lymphomas differ dramatically in

their:
pattern of spread
growth rate
response to treatment and prognosis
Two broad categories of lymphoma:
Hodgkins lymphoma (disease) (~40%)
Non-Hodgkins lymphomas (~60%)
Cells of origin:
- The non- Hodgkins lymphomas are derived from
either B or T lymphocytes.
- The cell of origin in Hodgkins lymphoma is now
known to be of B-cell origin also.

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Classification of lymphoma
lymphoma

Hodgkins
lymphoma

Non
hodgkins
lymphoma
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Lymphoma classification
(based on 2001 WHO)
B-cell neoplasms
Precursor B-cell neoplasms (2 types)
Mature B-cell neoplasms (19)
B-cell proliferations of uncertain malignant potential (2)

T-cell & NK-cell neoplasms

Precursor T-cell neoplasms (3)
Mature T-cell and NK-cell neoplasms (14)
T-cell proliferation of uncertain malignant potential (1)

Hodgkin lymphoma
Classical Hodgkin lymphomas (4)
Nodular lymphocyte predominant Hodgkin lymphoma (1)

The WHO Classification of the Lymphoid Neoplasms

I. Precursor B-Cell Neoplasms
Precursor-B lymphoblastic leukemia/lymphoma
II. Peripheral B-Cell Neoplasms
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic and nodal marginal zone lymphomas
Extranodal marginal zone lymphoma
Mantle cell lymphoma
Follicular lymphoma
Marginal zone lymphoma
Hairy cell leukemia
Plasmacytoma/plasma cell myeloma
Diffuse large B-cell lymphoma
Burkitt lymphoma
III. Precursor T-Cell Neoplasms
Precursor-T lymphoblastic leukemia/lymphoma
IV. Peripheral T-Cell and NK-Cell Neoplasms
T-cell prolymphocytic leukemia
Large granular lymphocytic leukemia
Mycosis fungoides/Szary syndrome
Peripheral T-cell lymphoma, unspecified
Anaplastic large cell lymphoma
Angioimmunoblastic T-cell lymphoma
Enteropathy-associated T-cell lymphoma
Panniculitis-like T-cell lymphoma
Hepatosplenic gd T-cell lymphoma
Adult T-cell leukemia/lymphoma
NK/T-cell lymphoma, nasal type
NK-cell leukemia
V. Hodgkin Lymphoma
Classical subtypes
Nodular sclerosis
Mixed cellularity
Lymphocyte-rich
Lymphocyte depletion
Lymphocyte predominance

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A practical way to think of lymphoma

Category

NonHodgkin
lymphoma

Hodgkin
lymphoma

Survival of
untreated
patients

Curability

To treat or
not to treat

Indolent

Years

Generally
not curable

Generally
defer Rx if
asymptomatic

Aggressive

Months

Curable in
some

Treat

Very
aggressive

Weeks

Curable in
some

Treat

All types

Variable
months to
years

Curable in
most

Treat

Diagnosis requires an adequate

biopsy
Diagnosis should be biopsy-proven before treatment is

initiated
Need enough tissue to assess cells and architecture
open bx vs core needle bx vs FNA

Staging of lymphoma
Stage I

Stage II

Stage III

Stage IV

A: absence of B symptoms
B: fever, night sweats, weight loss

Three types of lymphoma

worth knowing about
Follicular lymphoma
Diffuse large B-cell lymphoma
Hodgkin lymphoma

Non-Hodgkin lymphoma
Incidence
Diffuse
large B-cell
lymphoma

Follicular
lymphoma

Other NHL

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
although considered indolent, 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%

Hodgkin lymphoma
Thomas Hodgkin
(1798-1866)

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
(mixed cellularity)

lacunar cell
(nodular sclerosis)

popcorn cell
(lymphocyte predominance)

Reed-Sternberg cell

The Scream, 1893

Edvard Munch

A possible model of pathogenesis

transforming
event(s)
EBV?

loss of apoptosis

cytokines

germinal
centre
B cell

RS cell
inflammatory
response

Hodgkin lymphoma
Histologic subtypes
Classical Hodgkin lymphoma
nodular sclerosis (most common subtype)
mixed cellularity
lymphocyte-rich
lymphocyte depleted

Hodgkin's Histologic subtypes

Are characteristic patterns of

involvement, and characteristic

variants of Reed Sternberg cell
associated with different subtypes
Nodular sclerosing HL
Most common type Hodgkin's

lymphoma in US/Europe
Usually presents in the anterior
mediastinum and neck of young
adult females
Characterized by fibrotic capsule
and bands subdividing tissue and
Lacunar variant Reed Sternberg
cell

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Histologic subtypes 2
Lymphocyte predominant
Usually presents with limited disease in the

neck of young adults

Associated with L and H (lymphocytic and
histiocytic) or "popcorn cell" variant RS cell
Mixed cellularity
More extensive disease
Older patients than NS and LP
More R-S cells, eosinophils, plasma cells
Mononuclear variant R-S cells
Inherently more aggressive disease

Lymphocyte depleted
Often presents in retroperitoneum, older

patients
Accompanied by loss lymphocytes, sclerosis
and pleomorphic RS cell variants
Also more aggressive disease

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Epidemiology
less frequent than non-Hodgkin lymphoma
overall M>F
peak incidence in 3rd decade

Associated (etiological?) factors

EBV infection
smaller family size
higher socio-economic status
caucasian > non-caucasian
possible genetic predisposition
other: HIV? occupation? herbicides?

Clinical manifestations:
lymphadenopathy
contiguous spread
extranodal sites relatively uncommon except in

advanced disease
B symptoms

Hodgkins lymphoma
It most typically involves the cervical and mediastinal

lymph node groups.

An important clinical feature is its tendency to arise within

lymph node areas.

Late in the course of the disease, vascular invasion leads to

widespread hematogenous dissemination.

Hodgkin lymphoma has a bimodal age distribution with

one peak in the 20s and 30s, and a second peak over the age
of 50.
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Symptoms of hodgkins lymphoma:

General symptoms:
Fever
Weight loss
Loss of appetite
Night sweats
Pruritus
lethargy

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Local Symptoms
lymphadenopathy, splenomegaly, or tissue infiltration/invasion.
Lymphadenopathy is the most common finding that is noticable to

the patient, but is not typically painful.

Other complications of lymphomas :

pleural effusions, ascites

compression of adjacent structures by lymphoma - spinal cord,
ureters, biliary ducts, bowel obstruction
bone marrow failure due to lymphoma infiltration- causing
leukopenia, anemia, thrombocytopenia
autoimmune hemolytic anemia
immune thrombocytopenia
CNS involvement causing neurologic symptoms
hypercalcemia
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Hodgkins Lymphoma
defined by the presence of tumor cells called

Reed-Sternberg cells
Staging very important
usually curable

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 The diagnosis of Hodgkins lymphoma is made when "Reed-

Sternberg cells" are seen in a lymph node along with other

characteristic features.
These cells and other less diagnostic mononuclear forms of
the tumor cell population appear to produce a number of
lymphokines, such as IL-5, that attract other non-neoplastic
lymphocytes, histiocytes, fibroblasts and often eosinophils
into the affected node.
This results in the very characteristic pathologic picture of a
lymph node with large amounts of collagenous fibrous
tissue (from the fibroblasts), numerous small lymphocytes,
histiocytes and eosinophils with relatively few tumor cells.
In fact, on occasion a pathologist will have to search through
several slides before finding the diagnostic Reed-Sternberg
cells.
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Diagnosis
Blood
Lymph node excision biopsy , image guided needle

biopsy.
Chest X-ray, CT of thorax, abdominal, pelvis
and bone marrow biopsystaging of HL

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Staging HL
Confined to single lymph node region
II. Involvement of two or more nodal areas on the same
side of the diaphragm
III. Involvement of nodes on both sides of diaphragm.
IV. Spread beyond the lymph nodes e.g. liver or bone
marrow.
I.

All stages are further divided on the basis of the absence

(A) or presence (B) of the following systemic symptoms:
significant fever, night sweats, and/or unexplained weight
loss of greater than 10% of normal body weight.
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Prognosis of HL
Depends on stage :

>95% in I-A of HL 5-year survival

<40% with IV-B of HL 5-year survival

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Non-hodgkins lymphoma
The non-Hodgkins lymphomas have a range of clinical

aggressiveness that depends much more on the specific

histologic sub-type.
The classification of the specific type of non-Hodgkins

lymphoma is very important to the correct management of a

patient.
Non-Hodgkins lymphomas are also much more frequently

found arising in organ sites other than lymph nodes, such as

stomach, lung, salivary glands and even such unlikely sites as
brain.
The extranodal involvement is common,more than HL.

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 Lymphomas may be grouped by how quickly they are

likely to grow:
Indolent (also called low-grade) lymphomas grow
slowly but poorly responsive to treatment. They tend
to cause few symptoms.
Aggressive (also called intermediate-grade and highgrade) lymphomas grow and spread more quickly,
potential for cure. They tend to cause severe
symptoms.
Many indolent lymphomas become aggressive
lymphomas.

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Low grade non Hodgkin's lymphomas

Small cell lymphocytic
Follicular

(it is the most common type of lymphoma)

Mantle cell
Splenic marginal zone lymphoma
MALT lymphoma

Lymphoplasmacytic NHL

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High grade non Hodgkin's lymphomas

Diffuse large B cell
Diffuse mixed cell lymphoma
Burkitt's lymphoma
Anaplastic large cell lymphoma

Diffuse mixed cell lymphoma

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Clinical manifestations : as HL
Diagnosis :
Blood
Lymph node excision biopsy , image guided needle

biopsy.
Chest X-ray, CT of thorax, abdominal, pelvis
and bone marrow biopsystaging of NHL

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Stages of NHL :
Stage I: The lymphoma cells are in one lymph node group

or in only one part of a tissue or organ (such as the lung).

Stage II: The lymphoma cells are in at least two lymph
node groups on the same side of the organ (on the same
side of the diaphragm).
Stage III: The lymphoma is in lymph nodes above and
below the diaphragm.
Stage IV: Lymphoma cells are found in several parts of one
or more organs or tissues (in addition to the lymph nodes).
Or, it is in the liver, blood, or bone marrow
each stage is subdivided into A and B
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High Grade NHLs

include lymphoblastic and Burkitts lymphomas
very high mitotic rate correlates with rapid

growth, response to treatment and relapse.

Starry-sky
pattern

mitotic

Burkitts
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Tissue needed for diagnosis

Open biopsy :

architectural and cytologic features

fresh tissue available for immunophenotyping
and genetic studies
Fine needle aspiration:
often adequate if node is inaccessible surgically or
patient not surgically fit

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Normal Immunophenotypes
CD20

B cells: CD19,CD20,

CD22, Kappa/lambda

T cells: CD3, CD5,

CD4 or CD8

CD3

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prognosis
Increased age, advanced stage, concomitant disease,

raised LDH and T cell lymphoma are poor prognostic

signs
5-years survival for treated patients
> 50% for low grade
30% for high grade

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Thank you

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