Lymphoma

0
Stage:Second grade(A1)
Module:CLS-PATHO
LYMPHOMA
‫اف‬‫رش‬‫اب‬‫ا‬‫تورة‬‫ك‬‫دل‬:‫صاحب‬ ‫هدى‬
‫ال‬:‫طالب‬‫امحد‬ ‫عيل‬ ‫اهمي‬‫ر‬‫اب‬
2018

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CONTENTS
 Introduction………………………………2
 Epidemiology…………………………….3
 Etiology……………………………..........4
 Pathology………………………………....4
 Risk factors………………………..…….12
 Clinical presentation……………….....…12
 Diagnosis…………....……….………….13
 Staging……………...…………,………..14
 Investigations……………………………15
 Management & Treatment……….……...16
 Prognosis…………………….…………..18
 Prevention……...………….…………….18
 References…………………………..……20

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INTRODUCTION
Lymphoma is a group of malignant neoplasms characterized by abnormal
proliferation of lymphoid cells (such as lymphocytes,histiocytes and their precurcers
and derivatives)related to lymphoid tissues and organs such as spleen,thymus,and the
lymph nodes that are distributed through out the body.lymphoma is divided into two
major types which are Hodgkin(HL) and non-Hodgkin lymphoma(NHL)[1].in 1832
the first description of lymphoma was done by the british physician Thomas Hodgkin
so the Hodgkin type of lymphoma was named after him,after a period of time many
other types of lymphoma were described. these early describtions of Hodgkin disease
were focused on macroscopic appearances and distribution of affected lymph
nodes,spleen and visceral organs as observed at post –mortem examination.then the
results of histopathological technique that were done on three cases of patients
suspected to have lymphoma showed that two of them were having typical form of
Hodgkin disease while the last one having leukemia.[2]
EPIDEMIOLOGY
HODGKIN LYMPHOMA(HL)
The incidence is about 4 cases per 100,000 population per year. the sex ratio is
showed to be slight male excess(1.5;1) so the incidence rates showed to be increased
in male rather than females..The epidemiology of Hodgkin lymphoma is
characteristically bimodal age-incidence in the young adults(20-40year old) with the
peak at 25 year old with a few cases occurring among children,thereafter,incidence
rates decline to a plateau through middle age,after which they increase again by
age(50-70year old).the American whites have somewhat higher incidence of Hodgkin
type than the blacks.the geographical distribution show increase rate in highly
developed economic communities as in the united states.[2]

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Fig.1 Incidence rates of HL.[3]
NON-HODGKIN LYMPHOMA(NHL)
The annual incidence rate of NHL from 2007 to 2011 estimated from National
Cancer Institute(NCI) was 19.7 cases per 100,000 individuals.the sex ratio also
showed male predominance,and it increased exponentially with age(9.3 per 100,000
persons under 65 years old and 91.5 per 100,000 persons age 65 and older).the
occurrence also increase in whites than the blacks.Finally,the Geographical
distribution also tend to be increased in the highly developed countries such as the
USA.[4]
Fig.2 Incidence rates of NHL.[5]

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ETIOLOGY
The cause of Hodgkin lymphoma is unknown,and it is more commonly occurring in
patients of well-educated backgrounds with small families and it is three times more
commonly in patients with a past history of infectious mononucleosis but it is not
proved till now that the Epstein-barr virus is the causative agent.[6]
The congenital and acquired states of immunosuppression are the strongest factors to
increase the risk of NHL,These conditions include Wiskott-Aldrich syndrome,X-
Linked Proliferative syndrome and others.the host defects in immune regulation
resulting in uncontrolled infection and proliferation of B-Lymphocytes contribute to
the progression of NHL.Acquired immunodeficiency states such as HIV Tend to
increase the risk of NHL by 75 to 100 times or folds.Several viruses have been
involved in the pathogenesis of NHL,for example,if the immunocompromised
individual (where there is no Equilibrium between latent EBV infection and the host
immune system),However,the control mechanisms are weakened, resulting in EBV-
driven B-cell Proliferation and ultimately the development of NHL.The most common
bacterial infection that is linked to NHL is Chronic Gastritis infection with
H.Pylori.The Life style factors include the use of tobacco,alcohol and the use of
organophosphate insecticides by the farmers.Also numerous studies have assured that
the risk of NHL is linked to genetic variations in several pathways including oxidative
stress and DNA repair pathways.[4]
PATHOLOGY
According to WHO Pathological classification of Hodgkin lymphoma,it comprises
two main types the first one is nodular lymphocyte-predominant HL which accounts
for 5% of the cases.the second one is classical HL which comprises 95% of the cases
Both types share in common that the neoplastic cell population which can be
mononucleated or multinucleated makes up only a small percentage of all cells

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present in the affected lymph node.the second type is further subdivided into nodular
sclerosing(70%),mixed cellularity (20%),lymphocyte-rich(5%) and lymphocyte-
depleted which is rare.[7]
A. Nodular lymphocyte-predominant HL(5%)
In this type of HL the lymphocytes (LP)or histiocytes has one large nucleus that is
usually multilobulated ''popcorn cells''.the number of nucleoli is increased,and these
nucleoli are less prominant and less eosinophilic.the LP cells are found in a nodular or
follicular fashion(pattern) that is dominated by B lymphocytes which carry on IgD on
their surfaces.[7]
Fig.3 Nodular Lymphocyte-Predominant HL.[8]
B.Classical HL is divided to;
1.nodular scelorsing(70%)
The affected lymph nodes show a markedly thickened capsule and a nodular
infiltrate(increase in the number of malignant lymphocytes in the nodules),each
nodule is surrounded by broad collagen fibers or bands which gives the distinct
feature (nodular sclerosing) to this type.Those cells are present in a background of
small lymphocytes and other non-neoplastic cells such as histiocytes and
eosinophils.and the number of the cells differ within a single infiltrated lymph

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node.also those cells can form sheets that can be associated with necrosis and an
extensive fibrohistiocytic reaction.[7]
Fig.4 Nodular Sclerosing HL.[9]
2. mixed cellularity (20%)
HRS cells in this type are distributed randomly in a background that can contain small
lymphocytes,histiocytes,eosinophils,neutrophils,plasma cells.the infiltration way is
diffuse,sometimes,the lymph nodes are partially preserved leading to interfollicular
infiltration.in this type,the formation of collagen fibers is absent.this type of classical
HL is usually referred to as ''wastebasket'' of cHL.[7]
Fig.5 Mixed cellularity HL.[10]

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3.lymphocyte-rich(5%)
In this type of cHL the HRS cells are present in a background rich in lymphocytes that
can be either nodular or rarely diffuse,the most distinct feature of this type is the
abscence of neutrophils and eosinophils in nodular infiltrate,sometimes can only be
found in small numbers in the interfollicular regions and are close to the vascular
zones.[7]
Fig.6 Lymphocyte-rich HL.[11]
4.lymphocyte-depleted(rare )
It is the rarest type of cHL about less than 1%. It is characterized by extensive
increase in the number of HRS cells in the infiltrate and the depletion of small
lymphocytes in the nonneoplastic population.some of the common classification has
put this type of cHL on borderline catagories.[7]

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Fig.7 Lymphocyte-depleted HL.[12]
The World Health Organization (WHO) classification, first introduced in 2001 and
updated in 2008,This classification divides NHL into two groups: those of B-cell
origin and those of T-cell/Natural killer-cell origin.[13]
A.NHL of B-cell origin:
1.Follicular Lymphoma
It is considered as a common B-cell Lymphoma that accounts for 20% of NHL in
USA and Europe.this type erase the nodal architecture with at least a partially
follicular pattern.the cytologic composition is a mixture of centrocytes and
centroblasts in varying proportions.the grading here is based on the number of
cntroblasts per 400x Microscopic field.[4]
Fig.8 Follicular Lymphoma.[14]

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2.Burkitt's lymphoma
These lymphomas usually develop in the states of mild immunodeficiency.patients
with HIV infection may develop classical Burkitt lymphoma.They involve bone
marrow,peripheral blood,and the face and may also manifest with lymphadenopathy.
lymphoma cells are medium-sized,non-cleaved lymphocytes that have a deeply
basophilic cytoplasm,lipid vacuoles,and several nucleoli.[15]
Fig.9 Burkitt's Lymphoma.[16]
3.Diffuse Large B-cell Lymphoma
There are several morphological variants of this lymphoma.They include:
a.centroblastic type composed of centroblasts which have multiple nucleoli
b.immunoblastic type also referred to Immunoblastic Lymphoma(IBL) composed of
immunoblasts which have a single,central,prominent nucleoli.
c.Anaplastic type in which there are large bizarre tumor cells.[15]

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Fig.10 Gastric Diffuse Large B-cell Lymphoma.[17]
4.Plasmablastic Lymphoma
It is a highly aggressive form of large B-cell lymphoma with morphologic and
immunophenotypic features that are indicators of terminal B-cell differentiation,the
disease is usually locally invasive with poor response to therapy and short survival,it
is often associated with infection with AIDS,the neoplastic cells resemble
immunoblasts but show the immunophenotype of plasma cells.The apoptosis is
prominent and the mitotic activity is rapidly occurring.the malignant cells are
large,with clumped chromatin, smooth nuclear boundaries and eccentric
cytoplasm.[18]
Fig.11 Plasmablastic Lymphoma.[19]

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B.NHL of T-cell/Natural killer-cell origin:
1.Adult T-cell Lymphoma
The tumor cells are medium to large,with pleomorphic nuclei that show lobulations or
convolutions,so they are referred to (Flower Cells),the cytoplasm is
Basophilic,Sometimes there may be associated hemophagocytosis,and in the Bone
marrow it may be associated with osteoclastic activity.[20]
Fig.12 Adult T-cell Lymphoma.[21]
2. Anaplatic large T-cell lymphoma,Primary Systemic type
A neoplasm of large lymphoid cells with pleomorphic nuclei and abundant
cytoplasm,it is usually composed of large blastic cells with round or
pleomorphic,often horseshoe-shaped or multiple or single prominent nucleoli and
abundant cytoplasm,which gives the cells an epithelial-like appearance.[22]

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Fig.13 Anaplatic large T-cell lymphoma,Primary Systemic type.[23]
RISK FACTORS
Immune deregulation contributes to most of the pathogenesis of lymphomas.It is
believed that some infectious agents, autoimmune diseases,and immune suppressor
agents represent the most dangerous risk factors for the development and the ongoing
of specific lymphoma types.Researches show a strong association between Human
immune deficiency virus/Acquired immunodeficiency syndrome and several types of
HL and a second correlation between HL and Epstein-Barr virus,,other viruses can
have an impact on lymphomas such as the human retro-virus(e.g AIDS virus) which is
well-known as a causative agent for the development of Adult T-cell Lymphoma.[24]
CLINICAL PRESENTATION
Usually indolent (causing little or no pain) swellings that are confined to the cervical
or supraclavicular region(60-70%) are the first symptoms of the disease;and in 30% of
the early diagnosed patients the axillary lymph nodes are observed,the bone marrow
involvement occurs in less than 10% of the cases.those swellings can further cause
Dry cough and some Breathlessness if the mediastinum is involved.[25]

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Fig.14 Lymphadenopathy of HL.[26]
Most of the patients with NHL come to medical attention because of the
adenopathy,However other problems such as abdominal fullness caused by
splenomegaly ,pain in the involved sites of disease,anemia,skin manifestations,
neurologic symptoms or systemic symptoms such as fever,night sweats or weight loss
are the first signs of the disease.[27]
DIAGNOSIS
The diagnosis of HL is done by surgical excision of the affected lymph node and sent
for histopathological study,sometimes a core needle biopsy is done to provide a less
invasive alternative with a good diagnostic result,when the HL is found in the chest
then the cardiothoracic team should be ready to obtain tissue through
mediastinoscopy or sometimes through endo-bronchial ultrasound (EBUS) guided
biopsy.Histopathological analysis along with immune-histochemistry is very
important for accurate diagnosis.A confirmatory test should be done by experienced
hematopathologist.[28]

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Fig.15 Lymphadenectomy for diagnostic purposes.[29]
The diagnosis of NHL is usually done by lymph node biopsy and certain tests done on
the blood,bone marrow and then the examination.Immunophenotyping of surface
antigens to distinguish T and B cell tumors and this can be done on blood,marrow,or
nodal material. Immunoglobulin determination as some lymphomas are associated
with IgG, IgM paraproteins which are very useful in treatment response. Cases of
NHL were divided into three primary groups B-cell-lineage,T-cell lineage,and
indeterminate lineage based on staining patterns with pan-B and pan-T monoclonal
antibodies. A tumor was considered B-lineage if expression of one or more pan-B
antigens were detected in the absence of T antigens.similarly,A tumor is considered as
T-lineage if one or more pan-T antigens were expressed in the absence of B
antigens.If neither B nor T antigens were convincingly expressed ,then the tumor is
considered as indeterminate or uncertain.[30]
STAGING
The term staging refers to the anatomical distribution of the disease through the
body[28]

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Table.1 Ann Arbor Staging System of HL.[31]
The optimal staging modality in HL is via combined CT of neck,chest ,abdomen,
pelvis, along with functional imaging with F-flourodeoxyglucose-
PET(PET/CT).(PET/CT) upstages for 13-24% of cases compared to CT only.[28]
The same staging system is used for NHL,But NHLis more likely to be stage III or IV
at presentation.[6]
Fig.16 Ann Arbor Staging System of NHL.[32]
INVESTIGATIONS
The goal upon the investigations not only to diagnose the lymphoma but also to
determine the extent(degree of distribution of the disease through out the body). For
example;

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a.FBC(Full Blood Count) if the normochromic or normocytic anemia(decreased
production of RBC from bone marrow)or lymphopenia are present they indicate a bad
prognostic sign.
b.ESR(Erythrocyte Sedementation rate) may be raised.
c.Renal function tests are very important to make sure that the kidneys are in a good
status before the treatment.
d.Liver function test may be abnormal and this abnormality may indicate hepatic
infiltration(e.g TSB )
e.Chest x-ray may show mediastinal mass.
f.CT scan of neck,chest,abdomen and the pelvis is very important in staging and
investigation of the disease(e.g in a bulky disease more than 10 cm in a single lymph
node is considered as a bad prognostic feature).[6]
They are the same as for HL,But in addition it requires:
a.Routine bone marrow aspiration and Trephine.
b.Immunophenotyping of surface antigens to distinguish B and T cell types of
NHL.this may be done on themarrow,blood,or nodal material.
c.Immunoglobulin determination because some lymphomas are associated with IgG
or IgM paraproteins,Which serve as markers for treatment response.
d.Measurement of Uric Acid levels because Some very aggressive high-grade NHL
are associated with very high levels of Uric Acid,which can predispose to Renal
failure when treatment is started.
e.HIV Testing this may be useful if risk factors are present.[6]

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MANAGEMENT AND TREATMENT
Dr.Vera peters was the pioneer of curative radiotherapy of HL.,Therapy should be
performed by well-experienced clinicians in medical centers with appropriate medical
facilities.The treatment of HL is highly dependent on the stage of the disease,Stage I
and Stage II requires localized radiotherapy with no bad prognostic results. fertility is
usually preserved after radiotherapy,Young females receiving breast irradiation of
chest disease-involvement have increased risk of having breast cancer and should
have a screening programmes.The patients who continue to smoke after lung
irradiation have increased risk of having lung cancer. Nowadays,the majority of
patients with HL are treated with chemotherapy along with adjunctive radiotherapy.
The ABVD method (doxorubicin ,vinblastine, bleomycin and decarbazine) is
commonly used in the UK.Treatment response is done clinically and by repeat CT
scan and PET(Positron Emission Tomography).sometimes the ABVD regimen can
cause cardiac and pulmonary toxicity (e.g myocardial infarction,stroke,or second
cancers).patients with advanced stages III & IV are treated by chemotherapy
alone.Moreover,the patients with resistance to therapy are directed to autologous bone
marrow transplantation (BMT).[33] An important note to be considered is that
the Standard treatments have been developed that cure approximately 70% of all
patients who present to most institutions.Physicians should know the treatment
approaches before proceeding with staging methods,because intelligent use of the best
available treatment often bypass the need for staging.[34]
Low-grade NHL patients may not require therapy.The indications for treatment
include systemic symptoms,lymphadenopathy which causes discomfort,the options
include:
a.Radiotherapy.
b.Chemotherapy.
c.Monoclonal Antibody therapy:Humanised monoclonal antibodies can be used to
target surface antigens on tumor cells,and induce Tumor cell Apoptosis directly.

LYMPHOMA
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d.Transplantation.
High-grade NHL patients directly need treatment at the initial presentation the options
include:
a.Chemotherapy.
b.Radiotherapy.
c.Monoclonal antibody therapy.
d.Bone marrow transplantation.[6]
Fig.17 Radiotherapy of Lymphoma.[35]
PROGNOSIS
Doctors often use survival rates as a standard way of discussing a person's prognosis.
These numbers can’t tell you how long you will live, but they might help you better
understand your prognosis.More than 90% of patients with early stages of HL Stage I
& II usually obtain complete recovery when treated with chemotherapy along with
adjunctive radiotherapy.The major challenge is how to reduce the treatment intensity
of radio or chemotherapy with respect to cure possibility of patients.[6]

LYMPHOMA
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PREVENTION
Like other cancers the prevention is done by avoiding the exposure to radiations and
industrial chemicals and quit smoking and alcohol drinking,and maintain an ideal
weight which is an essential point is obtained through balanced diet.Finally,the
prevention programmes in some of the countries can do the job by explaining the risk
of those factors to certain cancer (one of them is lymphoma) can reduce the incidence
or occurrence of Lymphomas.[36] The guidelines for preventive measures include the
immunization after transplantation,antibiotics withdrawl for endocarditis prophylaxis,
assessment of tobacco use and counseling against smoking,assessment of renal
function with BUN(Blood Urea Nitrogen),creatinine and urine protein.[37]

LYMPHOMA
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SUMMARY
 Lymphoma is one of the blood cancers,was first described by the scientist
Thomas Hodgkin,Lymphoma is divided into HL & NHL,The incidence rates
for lymphomas are increasing world wide,many of the studies have assured the
causes of lymphomas but some of them still unknown,Each subtype of HL &
NHL has its own histopathological features.Finally,Lymphomas nowadays are
controllable since they are treated by chemotherapy & radiotherapy that are
available in many of the countries.

LYMPHOMA
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1. W. A. Newman Dorland, '' Dorland's pocket medical dictionary'', Saunders,
Philadelphia, 32nd
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2. Richard T. Hoppe et.la , ''Hodgkin lymphoma SOLUTION'', Wolters
Kluwer/Lippincott,PA 19106 USA, 2nd
ed.(2007), pages 11,chapter2.
3. https://seer.cancer.gov/statfacts/html/hodg.html
4. Andrew M. Evens & Kristie A. Blum'',Non-Hodgkin Lymphoma Pathology
Imaging and Current Therapy'',SPRINGER,Boston USA,(2015),page 3-
4,chapter 2.
5. https://www.slideshare.net/chandanashwin/nonhodgkinslymphoma
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edition
(2010),pages1037-1039,chapter24.
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overview'',SPRINGER,New York USA, 2nd
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3.
8. http://www.pathpedia.com/education/eatlas/histopathology/lymph_node/hodg
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kin_lymphoma_nodular_sclerosis_subtype.aspx
kin_lymphoma_mixed_cellularity_subtype.aspx
11. http://www.humpath.com/spip.php?article1271
kin_lymphoma_lymphocyte_depleted_subtype.aspx
13. Swerdlow SH et.la ,''WHO Classification of tumours of Haematopoietic &
Lymphoid Tissues'',International Agency for research on cancer, Lyon France,
4th
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(2013),pages 26-33,chapter 3.
16. http://www.pathpedia.com/education/eatlas/histopathology/lymph_node/burkit
t_lymphoma.aspx
17. http://www.pathpedia.com/education/eatlas/histopathology/stomach_ge_juncti
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18. Christopher D.M. Fletcher,''Diagnostic Histopathology of
Tumors'',ELSEVIER SAUNDERS,Philadelphia PA 19103-2899,4th
edition(
volume 2)(2013),page 1422,chapter 21.
19. http://atlasgeneticsoncology.org/Anomalies/PlasmablasticLymphomaID1564.h
tml

LYMPHOMA
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20. Toshiki Watanabi .Takuya Fukushima,''Adult T-cell
Leukemia/Lymphoma'',SPRINGER,Japan KK,(2017),page 49,chapter4.
21. https://www.researchgate.net/figure/Section-from-a-lymph-node-of-a-patient-
with-adult-T-cell-leukaemia-lymphoma-showing_fig3_5804598
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WILLIAMS & WILKINS,Philadelphia, 2nd
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10.

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