LYMPHOMA

Recommended textbook:
Hoffbrand A.V, 2011, Essential Heamatology, 6th edn., Wiley-Blackwell, Birmingham
Yabluchansky M, Bogun M, et al., Lymphoma, Lecture in Internal Medicine, Karazin National University Medical
School, Ukraine
 Hematopoietic Malignancy
Leukemia, myeloma, and lymphoma - are blood cancers
Derived from blood-forming cells in the bone marrow
Can enter blood streams and travel to distant sites
May progressively become malignant
cancerous cells that have the ability to invade locally or
metastasise and destroy healthy tissues

Leukemia - begins in bone marrow, produces abnormal

white blood cellS
Myeloma - develops in bone marrow, produces abnormal
plasma cells
Lymphoma - produces abnormal lymphocytes in bone
marrow, thymus, spleen, etc.
 Bone Marrow
Soft and spongy tissue that occupies the central cavity of
bone
All bones have active marrow at birth
Adulthood - skull, shoulder, blade, ribs, pelvis, and
backbones contain marrow
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
Where development of all types of blood cells takes place
 How Cancer Develops
Normal cells are programmed to multiply
They are also programmed to die when they are old or
when they are damaged beyond repair
Signals to multiply or die are controlled by specific
genes
Mutations can occur in these genes
If enough mutations occur in genes controlling growth or
cell death, cells begin to multiply uncontrollably
These cells then become cancerous or “malignant”
 Mutations
The sequence of a DNA molecule may be altered through mutation in
many different ways - major types of sequence alteration include:

Base substitution
– one base is replaced by another base.
Insertion
– one or more bases are inserted into the DNA sequence.
Deletion
– one or more bases are deleted from the DNA sequence.
Inversion
– a segment of DNA is inverted, but remains at the same overall location.
Duplication
– a segment of DNA is duplicated; the second copy usually remains at the
same location as the original.
Translocation
– a segment of DNA is transferred from its original location to another position
either on the same DNA molecule or on a different DNA molecule.
Features common to cancer cells

Growth in the absence of “go” signals

Growth despite “stop” signals
Locally invasive growth
Metastasis to distant sites
Lymphoma
 What are Lymphomas?
Lymphomas - cancer that begin by “malignant
transformation” of lymphocytes in the lymphatic system
Lymphomas are a group of disorders involving neoplastic
proliferation of lymphocytes or the failure of these cells to
undergo apoptosis
Many lymphomas are known to be due to specific
genetic mutations
Associated with an overexpression of BCL-2 - gene that
blocks programmed cell death
Malignant cells can metastasise to other areas of the
body - away from their zone of origin
Although often slow-growing, all lymphomas are
considered malignant because they can very easily
become widely spread throughout the body
 Proposed Mechanisms

Genetic alterations
Infection
Antigen stimulation
Immunosuppression
 ALL CLL Lymphomas MM
naïve

B-lymphocytes
Plasma
Lymphoid cells
progenitor T-lymphocytes

AML Myeloproliferative Disorders

Hematopoietic Myeloid Neutrophils
stem cells progenitor
Eosinophils

Basophils

Monocytes

Platelets

Red cells
Lymphoma
– basically, the cancer of the lymphatic system
– associated with accumulation of cancerous lymphocytes in
lymph nodes and other lympoid tissues
– end result is development of solid tumor

Lymphadenopathy
– enlargement of lymph nodes
– characteristic clinical feature

May spill over into blood

– infiltrate organs outside the lymphoid tissue through metastasis
 Major types
Lymphomas are divided into two major types:
– Non-Hodgkin’s lymphoma (NHL)
– Hodgkin’s Lymphoma

Reed-Sternberg cell
– characteristic histological difference between those two types
of lymphomas
– basis for diagnosis of Hodgkin lymphoma.
Reed-Sternberg Cell
 Epidemiology of lymphomas

Males > females

Incidence
– NHL increasing
– Hodgkin lymphoma stable
In NHL: 3rd most frequently diagnosed
cancer in males and 4th in females
In HL: 5th most frequently diagnosed
cancer in males and 10th in females
 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

Usually classified by how the cells look under a

microscope and how quickly they grow and spread
– Aggressive lymphomas (high-grade lymphomas)

– Indolent Lymphomas (low-grade lymphomas)

 Lymphoma classification
(2001 WHO)
B-cell neoplasms
– precursor
– mature Non-
Hodgkin
T-cell & NK-cell neoplasms Lymphomas
– precursor
– mature

Hodgkin lymphoma
Three common lymphomas

Follicular lymphoma (NHL)

Diffuse large B-cell lymphoma (NHL)
Hodgkin lymphoma
 Relative frequencies of different
lymphomas

Non-Hodgkin Lymphomas

Hodgkin NHL
lymphoma

~85% of NHL are B-lineage

 Complications of lymphoma

Bone marrow failure - infiltration

CNS infiltration
Immune hemolysis or thrombocytopenia
Compression of structures - e.g. spinal cord,
ureters
Pleural and pericardial effusions and ascites
A practical way to think of lymphoma
Category Survival of Curability To treat or
untreated not to treat
patients

Non- Indolent Years Generally Generally defer

Hodgkin not curable Rx if
lymphoma asymptomatic

Aggressive Months Curable in Treat

some

Very Weeks Curable in Treat

aggressive some

Hodgkin All types Variable – Curable in Treat

lymphoma months to most
years
Hodgkin Lymphoma
 Hodgkin Lymphoma
Hodgkin lymphoma encompasses a distinctive group of
neoplasms that are characterized by the presence of a tumor
giant cell - the Reed Sternberg (RS) cell
Arise in a single lymph node or chain of lymph nodes and typically
spread in a stepwise fashion to other parts of the body

Neoplasm
any new and abnormal growth
specifically, a new growth of tissue in which the growth is uncontrolled and
progressive
malignant neoplasms are distinguished from benign, in that the malignant show a
greater degree of anaplasia and have the property of invasion and metastasis
also called tumour

Anaplasia
a loss of differentiation of cells and their orientation to one another and to their exial
framework and blood vessels, a characteristic of tumour tissue
also called dedifferentiation and undiffrentiation
 Epidemiology
HL is less frequent than non-Hodgkin lymphoma
Overall - more males affected than females
HL accounts for about 5% of cancers in persons <15
yr of age and for about 15% in persons ≥15 yr of age
Most common in the European race
Mostly, those in higher socio-economic status are
affected
 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+
Age distribution of HL cases
 Associated risk factors
Epstein-Bar virus (EBV) infection
Higher socio-economic status
Caucasian > non-caucasian
Possible genetic predisposition
Other - HIV? Occupation? Herbicides?

Epstein-Barr virus (EBV)

– supported by serologic studies and the frequent presence of
EBV genome in biopsy material
Immunodeficiency
– either congenital or acquired, increases the risk
Family Hx
– genetic predisposition or a common exposure to the same
etiologic agent could account for an apparent increased risk in
twins and first-degree relatives
 Symptoms
Systemic symptoms considered important in staging
– unexplained fever
– weight loss
– drenching night sweats
– pruritus
– lethargy
– anorexia
– pain that worsens after ingestion of alcohol

Because of the impaired cellular immunity, concomitant

tuberculous or fungal infections may complicate
Hodgkin disease and predispose to numerous other
complications
 Clinical manifestations
Lymphadenopathy
Contiguous spread
Extranodal sites relatively uncommon except in
advanced disease

Painless, firm, cervical, supraclavicular lymphadenopathy is the

most common presenting sign
May present with general systemic lymphadenopathy in advanced
disease state
An anterior mediastinal lymph node enlargment is often present
Depending on the extent and location of disease, patients might
present with signs and symptoms of airway obstruction, pleural or
pericardial effusion, hepatocellular dysfunction, or bone marrow
infiltration resulting in anemia, neutropenia, or thrombocytopenia
Nephrotic syndrome is a rare but recognized presenting
manifestation of Hodgkin disease
Classical Hodgkin Lymphoma
 WHO HL Histologic subtypes
HL is classified into two distinct entities - based on
morphology and immunochemistry

Nodular lymphocyte-predominant HL (5% of cases)

RS cell absent
Classical Hodgkin lymphoma (95% of cases):
RS cells present but do vary in number and shape
– nodular sclerosis - variant of RS cells
– mixed cellularity - abundant RS cells
– lymphocyte-rich - scanty RS cells
– lymphocyte depleted - varying amount of RS cells
 Histologic subtypes

Most cases previously classified as lymphocyte depleted are now

considered to represent high-grade non-Hodgkin lymphoma.
Histology - Reed Sternberg cell
 RS cell and variants

classic RS cell
(mixed cellularity)
lacunar cell
(nodular sclerosis)
popcorn cell
(lymphocyte-rich)
Non-Hodgkin Lymphoma
 Non-Hodgkin Lymphoma
NHL results from malignant clonal proliferation of
lymphocytes of T-, B-, or indeterminate cell origin.
In equatorial Africa, 50% of childhood cancers are
lymphomas
Very high incidence of Burkitt’s lymphoma and possibly
related to the immunosuppressive effects of malaria.
Unlike that of Hodgkin lymphoma, the incidence of NHL
increases steadily throughout life.
In some situations there is overlap with acute lymphoblastic
or B-cell leukemia.
Patients with lymphoblastic NHL and >25% lymphoblasts in
the bone marrow are treated as if they had acute
lymphoblastic leukemia
Whereas, patients with B-cell ALL are treated similarly to
patients with Burkitt’s lymphoma even if no extramedullary
disease is present.
 Risk factors for NHL

Immunosuppression or immunodeficiency
Connective tissue disease
Family history of lymphoma
Infectious agents
Ionizing radiation
 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
 Pathogenesis
EBV infection has a major role in the pathogenesis of
Burkitt lymphoma - EBV genome is present in tumor cells
in 95% of "endemic" cases in equatorial Africa compared
with 15% in "sporadic" cases in US.
How EBV contributes to the pathogenesis of Burkitt
lymphoma remains unclear.
Congenital or acquired immunodeficiency also predisposes
to the development of NHL.
Epidemiologic studies have also implicated pesticide
exposure as a possible risk factor
Note:
– Mosquito nets are being treated with pesticides in that global effort to eradicate
malaria
– Is that safe?
– Or may it be a possible risk facfor or precurser to development of cancers and other
medical conditions?
 Classification
Classification and main development profiles of NHL
Diagnosis of Lymphomas
 Diagnosis
Prompt tissue diagnosis and staging is important
because of the rapid growth rate of lymphomas
For diagnosis, several tests are required in order to
determine:
type of lymphoma
how advanced it is
what types of treatments will be most effective
what treatments you’ll best tolerate
There are several types of lymphoma - thus knowing the
type is essential to make right decisions about treatment
 Tools for diagnosis
A variety of tools are used to gather complex
information about lymphoma for accurate
diagnosis, including:
Physical exam
Blood tests
Bone marrow biopsy
Lymph node biopsy
Imaging tests
 Physical Exam
Questions should be asked about:

Symptoms
How long they’ve been happening
Personal and family history of cancer
Previous exposure to chemicals
Whether you smoke or used to smoke
Any medical conditions

Look for signs of lymphoma, such as:

Enlarged liver or spleen
Pale skin
Swollen lymph nodes
 Blood Tests
Blood tests are essential for accurate since they can
show presence of lymphoma cells or abnormal levels of
normal cells:
Blood smear
Complete blood count (CBC)
Erythrocyte sedimentation rate (ESR)
Lactate dehydrogenase (LDH)
Other blood tests
Testing for certain viruses
Blood smear
Determines whether the cells are Hodgkin or non-Hodgkin

Complete blood count (CBC)

A meeasure of red blood cells, white blood cells, and platelets.

Erythrocyte sedimentation rate (ESR)

The rate at which red blood cells settle to the bottom of a tube - a way to
measure the amount of inflammation in the body.

Lactate dehydrogenase (LDH)

Detects protein released by damaged cells.

Other blood tests

Measure chemicals that show how organs such as the liver and kidneys are
functioning
Determine whether lymphoma has spread to those parts of the body.

Testing for certain viruses

Test for HIV and hepatitis B - risk factors for lymphoma, and can affect
treatment
 Tissue Biopsies
Bone marrow biopsy
Fine needle aspirate biopsy of bone marrow is done

Lymph node biopsy

Preferably to have an entire intact lymph node over fine needle
aspirate (FNA) or core biopsy
Formal excisional biopsy should be done and not FNA - ensure
adequate tissue is obtained
This allows the pathologist to accurately determine the pattern
of involvement and further, to carry out immunologic and
molecular testing where possible
Techniques for staging of lymphomas
Laboratory
Full blood count
ESR
Bone marrow aspirate
Liver function test
LDH
C-reactive protein

Radiology
Chest x-ray
CT scan - thorax, abdomen, chest, pelvis
MRI, etc.
Bone scan
 Ann Arbor Staging System
Stage is the term used to describe the extent of tumor
that has spread through the body
I and II are localized
III and IV are advanced
Each stage is then divided into categories A and B
A
No systemic symptoms
B
Systemic Symptoms such as fever, night
sweats and weight loss
Spreading of disease from lymph node to
another organ
 Staging

A: absence of B symptoms
B: fever, night sweats, weight loss
STAGE I
– Involvement of a single lymph node region or of a single extralymphatic organ
or site
STAGE II
– Involvement of two or more lymphoid regions on the same side of the
diaphragm; or localized involvement of an extralymphatic organ or site and of
one or more lymph node regions on the same side of the diaphragm
STAGE III
– Involvement of lymph node regions on both sides of the diaphragm, which
may be accompanied by localized involvement of an extralymphatic organ or
site or by splenic involvement
STAGE IV
– Diffuse or disseminated involvement of one or more extralymphatic organs or
tissues, with or without associated lymph node enlargement

Stages are further categorized as:

A or B - based on the absence or presence, respectively, of systemic
symptoms of fever and/or weight loss

Bulky disease
– based on mediastinal mass larger than one third thoracic diameter; lymph
node masses ≥10 cm in diameter and/or four or more nodal regions involved
Treatment of Lymphomas
 Treatment Prognosis
Chemotherapy is preferred over radiotherapy - negative
effects later in life
Chemotherapy, based on the same regimens used in
early stage disease, is considered the primary treatment
for patients with advanced disease
Newer and more aggressive regimens have been
developed
Surgical excision of localized intra-abdominal tumors often
precedes the diagnosis of NHL and should always be
attempted, if feasible
In this and other situations, multiagent chemotherapy is
the primary treatment
In contrast to HD, second malignancies and infertility have
not been major problems in long-term survivors of NHL
 New treatment approaches

High-dose chemotherapy
Allogenic stem-cell transplantation
Radiolabelled monoclonal antibody treatment
Vaccination
Summary on Lymphomas
What is the Lymphatic System?
Made up of organs, such as the tonsils, spleen, liver,
bone marrow and a network of lymphatic vessels that
connect glands, called lymph nodes
Lymph nodes filter - bacteria, viruses, and other
foriegn particles out of the lymphatic fluid
Contain B and T lymphocytes:
B lymphocytes, also called B cells - originate and mature
in bone marrow, migrate to secondary lymphoid organs
where they differetiate into different antibodies
T lymphocytes, also called T cells - originate in the bone
marrow and mature in the thymus, where they multiply
and differentiate into - helper, regulatory, cytotoxic, and
memory T cells
 Lymphomas as disease
This group of diseases is divided into Hodgkin’s disease
and non-Hodgkin’s lymphomas
In both, there is replacement of normal lymphoid structure
by collections of abnormal cells:
– Hodgkin’s disease being characterized by the
presence of Reed-Sternberg (RS) cells
– Non-Hodgkin’s lymphomas are characterised by
diffuse or nodular collections of abnormal lymphocytes
(or rarely, histiocytes)
Thus, malignant lymphocytes accumulate in lymph nodes
and cause lymphadenopathy
Usual clinical presentation is with painless asymmetrical
lymphadenopathy
Constitutional symptoms of fever, weight loss, and
sweating are prominent in patients with widespread
disease
 Management
Blood tests may show anaemia, neutrophilia and raised
erythrocyte sedimentation rate (ESR) or lactic
dehydrogenase (LDH)
Diagnosis is made by histological examination of an
excised lymph node
Staging of the disease is important for determining
treatment and prognosis - patient history, examination,
blood tests, radiological findings are used
Treatment is with radiotherapy, chemotherapy or a
combination of both - treatment choice depends on the
stage and grade of the disease
Response to treatment can be monitored by radiological
modalities
Prognosis is excellent, and over 85% of patients can
expect to be cured
Late side effects of treatment are a grave concern
 An Unusual NHL
Burkitt's lymphoma
A very fast-growing NHL that originates from B lymphocytes
Can develop at any age - most common in children and
young adults, particularly males
Unlike other lymphomas, it has a specific geographic
distribution - most common in central Africa
Epstein-Barr virus infection is a risk factor
It is more common in people who have AIDS
Large numbers of lymphoma cells may accumulate in the
lymph nodes and organs of the abdomen, causing swelling
Lymphoma cells may invade the small intestine, resulting in
blockage or bleeding
The neck and jaw may swell, sometimes painfully
Biopsy specimen (and order procedures) done to stage the
disease