Lymphoma
Haematological Neoplasia - Overview
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Leukemias:
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Lymphomas:
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Acute & Chronic,
Myeloid & Lymphoid
Hodgkins & Non-Hodgkins
Premalignant:
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Myeloproliverative - MPS
Myelodysplastic - MDS
Central lymphoreticuular
system is thymus & BM
It is primary malignant
proliferative Tumour arising
from the peripheral
Lymphoreticular system
( nodal and extra nodal)
Hodgkin lymphoma
Thomas Hodgkin
(1798-1866)
Epidemiology of lymphomas
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5th most frequently diagnosed cancer
overall for both males and females
males > females
incidence
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NHL increasing over time
Hodgkin lymphoma stable
less frequent than non-Hodgkin lymphoma
overall M>F = 3 :1
peak incidence in 3rd decade
Associated (etiological?) factors
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EBV infection
smaller family size
higher socio-economic status
caucasian > non-caucasian
possible genetic predisposition
other: HIV? occupation? herbicides?
Hodgkin lymphoma
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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
B-cell development
CLL
MCL
stem
cell
memory
B-cell
mature
naive
B-cell
germinal
center
B-cell
lymphoid
precursor
progenitor-B
LBL, ALL
pre-B
immature
B-cell
MZL
CLL
MM
DLBCL,
FL, BL, HL
plasma cell
A possible model of
pathogenesis
transforming
event(s)
EBV?
loss of apoptosis
cytokines
germinal
centre
B cell
RS cell
inflammatory
response
Lymphoma - Gross
Hodgkins lymphoma
Reed-Sternberg cell
Hodgkins lymphoma cells
Reed-Sternberg cell
The Scream, 1893
Edvard Munch
RS cell and variants
classic RS cell
lacunar cell
popcorn cell
(mixed cellularity)
(nodular sclerosis)
(lymphocyte
predominance)
Hodgkins Lymphoma:
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Painless, firm lymphadenopathy,
Fever* Eosinophilia
Only Reed-Sternberg cells malignant (B cell)
Classification(WHO): Classic Hodgkins:
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Lymphocyte predominant.
Nodular Sclerosis.
Mixed cellularity.
Lymphocyte depleted.
Nodular lymph. predominant (non-classic)
Hodgkin’s Disease
Nodular Sclerosing
 < 80%
 Supraclavicular &
mediastinal
 Stage I&II b
Lymphocyte Predominant
 5 %
 Cervical LN
 Stage I &II a
Hodgkin’s Disease
Mixed Cellularity
 > 20 %
 Retroperitoneal
 Stage II & III
Lymphocyte Depleted
 < 5 %
 Extra nodal system
 Stage III & IV
Hodgkin’s Disease
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Presentation
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Asymmetric lymphadenopathy—90%
Firm, rubbery
 Supraclavicular fossa
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Spleen, liver (extranodal sites relatively
uncommon except in advanced disease
Constitutional symptoms—1/3 of cases
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Fever, night sweats, anorexia, weakness, weight
loss
Lymphadenopathy in HL
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Number one or two
groups
Site mostly cervical
Size usually small
Shape discrete
Consistency india rubbery
or firm
Mobile
No skin involvement
No tenderness
No fixation
Lymphadenopathy in NHL
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Number multiple
Site mostly extra nodal
Size usually large
Shape matted
Consistency hard & cystic
Fixed
skin stretched & red
tender
fixation
Lymphadenopathy in
Lymphoma
HL
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Number one or two
groups
Site mostly cervical
Size usually small
Shape discrete
Consistency india rubbery
or firm
Mobile
No skin involvement
No tenderness
No fixation
NHL
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Number multiple
Site mostly extra nodal
Size usually large
Shape matted
Consistency hard & cystic
Fixed
skin stretched & red
tender
fixation
Extranodal manifestations
(a) SVC compression --dilated Neck veins
(b) RLN ---hoarsness of voice
(3) Mediastinal
(c) Trachea & bronchi--cough& dyspnea
(d) Lung--- Dyspnea & effusion
(5) Hepatomegally--- Ascites dt
•Hepatic dysfunction
•Peritoneal invasion
(6) jaundice
Prehepatic
•hemolytic autoimmune
•hypersplenism
Hepatic–
• cholestatic
• hepatitis
Posthepatic – LN at porta hepatis
(1) Cervical lymphadenopathy
(2) Hilar LN bronchial compression
which cause segmental atelectasis
(4) Splenomegally dt infiltration or
hyperplasia
(7) Stomach & bowel
malabsorption syndromes
(8) Bone deposites
•Sever pain
•Pathological fractures
(9) Neurological
(12)
• cord compression Anaemia
• Cranial nerve palsy Hypersplenism
• Root pains
BM infiltration
Cytotoxic
drugs
(11) Mycosis fungoids
(10) Skin nodules
The challenge of lymphoma
classification
Biologically rational
classification
Clinically useful
classification
Diseases that have distinct
• morphology
• immunophenotype
• genetic features
• clinical features
Diseases that have distinct
• clinical features
• natural history
• prognosis
• treatment
Staging of lymphoma
Stage I
Stage II
Stage III
Stage IV
A: absence of B symptoms
B: fever, night sweats, weight loss
Hodgkin Disease
Lymphoma
Row of
enlarged
lymph nodes
Diagnosis:
Hodgkin’s Disease
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Evaluation
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H&P
Biopsy = Reed-Sternberg
cells
Staging w/u
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Similar to NHL
Laparotomy
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Controversial
From, Principles and Practice of Pediatric
Oncology, Lippincott Williams & Wilkins,
P 640.
Hodgkin’s Disease
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Localized disease
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Extended field XRT
Disseminated disease
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MOPP = nitrogen mustard, vinblastine,
procarbazine, prednisone
ABVD = adriamycin bleomycin, vincristine,
dacarbazine
Laboratory Diagnosis:
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Haematological:
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Bone marrow:
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Normocytic normochromic anemia, High ESR*
Leucocytosis, Eosinophilia, lymphopenia
Leukoerythroblastic picture - BM infiltration*
Normal, or late involvement.
Trephine biopsy- diffuse or follicular infiltration
Biochemical:
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High serum LDH – poor prognosis
Hypercalcemia, Alkaline phosphatase, Uric acid.
Serum transaminases & Bilirubin – Liver
Laboratory Diagnosis:
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Haematological:
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Bone marrow:
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Normocytic normochromic anemia, High ESR*
Leucocytosis, Eosinophilia, lymphopenia
Leukoerythroblastic picture - BM infiltration*
Normal, or late involvement.
Trephine biopsy- diffuse or follicular infiltration
Biochemical:
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High serum LDH – poor prognosis
Hypercalcemia, Alkaline phosphatase, Uric acid.
Serum transaminases & Bilirubin – Liver
Laboratory Diagnosis:
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Immunological:
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Monoclonal gammopathy –B cell NHL,
Myeloma
Low normal gammaglobulins
Autoimmune hemolytic anemia – auto ab.
Karyotypic/Genetic:
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t(14;18) – B cell follicular (14* heavy chain)
t(11;14) – diffuse NHL
Radiological
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Chest x ray
Bone scan
Bone x ray if +ve bone scan or bone pains
CT scan of chest & abdomen & pelvis
Ga 67 scan
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SPRCT
PET to evaluate residuals
Mediastinal Lymph nodes-NHL
LN biopsy
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Must whole LN as
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destruction of the architecture is of
diagnostic value and
also Reed Sternberg in HL id diagnostic
Additional work up in NHL
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Flow cytometry
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Diagnostic spinal tab in
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Peripheral blood
Bone marrow detect haematological
involvement
Lymphoblastic lymphoma
Burkitt’s lymphoma
Upper GIT& small bowel series &
endoscopy in S&S of GIT
Diagnostic laparotomy
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Indicated only in HL stage I&IIa
( as supraclavicular
enlargment = 40% abdominal involvement)
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Technique
1.
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3.
4.
5.
6.
7.
Systemic LN examination
Biopsy from suspicious LN
Splenectomy
Wedge biopsy from liver
Ovariopexy
Appendectomy
Putting silver clips at the site of involved LN
Hodgkin’s Disease
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Localized disease (Stage I & II)
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Extended field XRT
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Recently IFRT + new modality chemotherapy ABVD
Stage III a
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Above diaphragm -------- Mantle
below diaphragm --------Inverted Y
Extended field RT
IFRT + ABVD
Multi agent chemotherapy ABVD or MOPP
Disseminated disease (Stage III b & IV )
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MOPP = nitrogen mustard, vinblastine, procarbazine,
prednisone
ABVD = adriamycin bleomycin, vincristine,
dacarbazine
Radiotherapy
Treatment and Prognosis
Stage
Treatment
I,II
ABVD x 4 &
radiation
III,IV
ABVD x 6
Failurefree
survival
70-80%
Overall 5
year
survival
80-90%
60-70%
70-80%
Hodgkin’s Disease
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Survival
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Stages I, II, and III = 90%
Stage IV = 75-80%
Long term complications of
treatment
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infertility
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secondary malignancy
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MOPP > ABVD; males > females
sperm banking should be discussed
premature menopause
skin, AML, lung, MDS, NHL, thyroid, breast...
cardiac disease
Non-Hodgkins
Lymphoma (NHL)
Mechanisms of lymphomagenesis
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Genetic alterations
Infection
Antigen stimulation
Immuno-suppression
NHL – Classification:
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According to cell type
 T cell, B cell, Histiocytic & Misc. NHL
According to Clinical grade
 Low grade, Intermediate & High grade
NHL.
Histopathological
 Diffuse/Follicular NHL,
 Small, Intermediate & Large cell NHL
Ex: Lennert’s lymphoma is a low grade T cell NHL.
Burkitt’s lymphoma, a high grade B cell NHL
Kiel Classification of NHL
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B Cell NHL:
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T Cell NHL:
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Low Grade: lymphocytic, plasmacytic,
centrocytic, mixed centrocytic centroblastic.
High Grade: Centroblastic, Immunoblastic,
Burkitts, lymphoblastic.
Low Grade: lymphocytic, mycosis, Lennerts
High Grade: immunoblastic, lymphoblastic etc.
Rare types:
NCI – Working Formulation
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Low-grade NHL:
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Intermediate-grade NHL:
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Follicular large cell
Diffuse small cleaved
High-grade NHL:
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Small lymphocytic
Follicular small cleaved
Immunoblastic
Lymphoblastic
Miscellaneous: Histiocytic, Mycosis etc.
Non-Hodgkin lymphoma
Incidence
Diffuse
large B-cell
lymphoma
Follicular
lymphoma
Other NHL
Follicular lymphoma
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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
Diffuse large B-cell lymphoma
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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%
NHL- Histologic types
Diffuse - & - Follicular
NHL- Histologic types
Small – Intermed. – Large
Lymphoma classification
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(based on 2001 WHO)
B-cell neoplasms
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T-cell & NK-cell neoplasms
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Precursor B-cell neoplasms (2 types)
Mature B-cell neoplasms (19)
B-cell proliferations of uncertain malignant potential (2)
Precursor T-cell neoplasms (3)
Mature T-cell and NK-cell neoplasms (14)
T-cell proliferation of uncertain malignant potential (1)
Hodgkin lymphoma
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Classical Hodgkin lymphomas (4)
Nodular lymphocyte predominant Hodgkin lymphoma (1)
Clinical manifestations
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Variable
severity: asymptomatic to extremely ill
 time course: evolution over weeks, months, or
years
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Systemic manifestations
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fever, night sweats, weight loss, anorexia, pruritis
Local manifestations
lymphadenopathy, splenomegaly most common
 any tissue potentially can be infiltrated
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Lymphadenopathy in NHL
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Number multiple
Site mostly extra nodal
Size usually large
Shape matted
Consistency hard & cystic
Fixed
skin stretched & red
tender
fixation
Extranodal manifestations
(a) SVC compression --dilated Neck veins
(b) RLN ---hoarsness of voice
(3) Mediastinal
(c) Trachea & bronchi--cough& dyspnea
(d) Lung--- Dyspnea & effusion
(5) Hepatomegally--- Ascites dt
•Hepatic dysfunction
•Peritoneal invasion
(6) jaundice
Prehepatic
•hemolytic autoimmune
•hypersplenism
Hepatic–
• cholestatic
• hepatitis
Posthepatic – LN at porta hepatis
(1) Cervical lymphadenopathy
(2) Hilar LN bronchial compression
which cause segmental atelectasis
(4) Splenomegally dt infiltration or
hyperplasia
(7) Stomach & bowel
malabsorption syndromes
(8) Bone deposites
•Sever pain
•Pathological fractures
(9) Neurological
(12)
• cord compression Anaemia
• Cranial nerve palsy Hypersplenism
• Root pains
BM infiltration
Cytotoxic
drugs
(11) Mycosis fungoids
(10) Skin nodules
Non Hodgkin
Lymphoma spread to Spleen
Lymphoma Intestine
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
Staging of Lymphoma
Burkitt’s Lymphoma
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Unusual, B-Lymphoblastic high grade
Young african children, jaw bones
Isolated histiocytes, starry sky pattern
EBV infection related. t(8;14)
Chemotherapy – good response
But relapse usual, 30% cure.
Burkitt’s Lymphoma
Burkitt’s Lymphoma
Burkitt’s Lymphoma L.N.
Non specific LN
Tuberculosis of LN
Metastasis LN