Last edited: 6/22/2023
NON-HODGKIN'S LYMPHOMA
Non-Hodgkin's Lymphoma
Medical Editor: Jona Mae M. Frondoso, & Sarah Abimhamed
OUTLINE
I) INTRODUCTION
II) PATHOPHYSIOLOGY
(A) LYMPHOCYTE PATHWAY
(B) CAUSES OF NEOPLASTIC
LYMPHOCYTES (B CELL)
(C) EFFECTS OF NEOPLASTIC
LYMPHOCYTES (B-CELL + T-CELL)
III) DIAGNOSTIC APPROACH TO V) TREATMENT
(A) OTHER TREATMENTS:
NON-HODGKIN’S LYMPHOMA
VI) REVIEW QUESTIONS
(A) LAN 2/2 METS VS. LYMPHOMA
(B) FLOW CYTOMETRY
VII) REFRENCES
(C) CYTOGENETICS/ PCR + HISTOPATHOLOGY
IV) STAGING NON-HODGKIN’S
LYMPHOMA
(A) HOW TO DETECT EXTRANODAL INVOLVEMENT:
(B) ANN-ARBOR STAGING SYSTEM:
(C) SUB-CLASSIFICATION SYSTEM:
I) INTRODUCTION
(1) Lymphoma [USMLE]
● Discrete tumor mass arising from lymph nodes.
● Variable clinical presentation
o Arising in atypical sites
o Leukemic presentation
(2) Types of Lymphoma [USMLE]
(i) Hodgkin
(ii) Non-Hodgkin
• A localized, single group of nodes with
contiguous spread (the stage is the strongest
predictor of prognosis)
• Better prognosis
• Multiple lymph nodes involved
• Extranodal involvement common
• Noncontiguous spread
• Worse prognosis
• Unlike Hodgkin’s lymphoma, it has a lot of
different types
• 85-90% OF NHL
o B-cell NHL
• 10-15% OF NHL
o T-cell NHL
Figure 1. Lymphocyte Pathway.
Non-Hodgkin's Lymphoma
Hematology Pathology: Note #8. .
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II) PATHOPHYSIOLOGY
(A) LYMPHOCYTE PATHWAY
● Non-Hodgkin lymphoma
o Occurs at different points of the lymphocyte pathway (Figure 1)
o Occurs when there is a mutation at a certain point in the pathway resulting in proliferation
 Mantle cell lymphocyte
• Mantle cell lymphoma
 Centroblast
• Diffuse large B cell lymphoma
• Burkitt cell lymphoma
 Centrocyte
• Folllicular cell lymphoma
 Marginal zone lymphocyte
• Marginal zone lymphoma
● In the red bone marrow
o Lymphoid stem cells will differentiate into
 Precursor / Naive T cell
• Naive cells: not exposed to antigens yet
 Precursor / Naïve B cell
(1) T – Cell Lymphoma
(2) B - Cell Lymphoma
● Associated with human T cell lymphotropic virus
(HTLV)
o HTLV can be caused by IV drug abuse
● Precursor / Naïve B cells
o They can move into the different lymph node zones
where they may or may not be exposed to antigens.
o Has B cell receptors that can be attached to antigens
o When there is antigen exposure in the mantle zone,
the exposed B cell can move further to the next zone.
 B cells become bigger with more diverse antigen
receptors
o When there is no antigen exposure in the mantle
zone, the naïve B cell will remain in the mantle zone
● Precursor T cells
o Go to the thymus, where it matures
o In the thymus, it will differentiate into
 T helper cells
• Has CD4+ proteins on its surface
 Cytotoxic T cells
• Has CD8+ proteins on its surface
o T helper cells and cytotoxic T cells can infiltrate the
blood or the lymph nodes.
● T helper cells and Cytotoxic T cells
o When T cells are supposed to come into the lymph
node, they undergo mutation processes →
replication, and proliferation in the lymph node,
blood, and skin tissues.
● Centroblast
o B cell in the germinal zone
o SOMATIC HYPERMUTATION
 Changes in the variable regions of the B cell
receptor
 This leads to CLONAL EXPANSION
• Centroblasts will divide, forming tons of centroblasts
with all types of variable B cell receptors.
o If it has a low affinity to the antigen, it will undergo apoptosis.
o If it has a good affinity for the antigen, then it moves
on to the next stage - centrocyte.
● Mantle cell lymphocyte
o B cell in the mantle zone that has not been exposed
to an antigen
● Centrocyte
o What centroblasts will become if they have good
affinity to receptors
o Centrocytes don’t interact with other cells
o Dendritic cells and T cells in the vicinity will trigger the
centrocytes to undergo class switching.
o CLASS SWITCHING
 The point where the centrocyte decides what
antibodies it will produce
 After class switching, centrocytes will move to the
marginal zone, becoming marginal zone
lymphocytes
● Marginal zone lymphocyte
o It will differentiate into either memory B cell or
plasma cell
 Memory B cells can recognize any type of foreign
antigen
 Plasma cell produces antibodies
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Hematology Pathology: Note #8.
Non-Hodgkin's Lymphoma
(B) CAUSES OF NEOPLASTIC LYMPHOCYTES (B CELL)
(1) Decrease Cell Apoptosis
(2) Increase Cell Proliferation
● R ECALL
o Naïve B cells (no antigen exposure) will stay in the
mantle zone as mantle cell
o Antigen exposure will cause the NBC to move into the
germinal center, becoming centroblast
o Centroblast will undergo somatic hypermutation
o If it doesn’t undergo apoptosis and survives, it will
become a centrocyte.
o Centrocytes will differentiate in the marginal zone
o Marginal zone lymphocyte differentiates into
memory B cell or plasma cells
● R ECALL
o Naïve B cells (no antigen exposure) will stay in the
mantle zone as mantle cells.
 Chronic lymphocytic lymphoma / Small lymphocytic
lymphoma occurs when there is a mutation, hence
hyperproliferation, of the exposed naïve B cell before
entering the germinal center.
o Antigen exposure will cause the NBC to move into the
germinal center, becoming centroblast.
o Centroblast will undergo somatic hypermutation
o If it doesn’t undergo apoptosis and survives, it will
become a centrocyte.
o Centrocytes will differentiate in the marginal zone
o Marginal zone lymphocyte differentiates into
memory B cell or plasma cells
● Decrease cell apoptosis → cells live for a long time, but
they are not hyperproliferating → indolent, slow (Figure
2)
(i) Follicular Lymphoma (FL)
• Increase in the number of centrocytes in the
germinal center
• Due to chromosomal translocation between
chromosomes 14 and 18
• (14;18)t → ↑↑ BCL2 gene expression →
inhibits apoptosis → ↑ cell number
o BCL2: inhibits apoptosis when
hyperactivated
(ii) Marginal Zone Lymphoma (MZL)
• Increase in the number of marginal zone
lymphocytes in the marginal zone
• No obvious chromosomal translocation, but at
some point along the structure, there is a
gene that is hyperexpressed
• ↑↑ BCL10 → ↑NF-Kβ → inhibits apoptosis
→ ↑ cell number
o NF-Kβ: inhibits apoptosis when hyperactivated
● Cells are hyperproliferating → rapid, aggressive (Figure 3)
(i) Mantle Cell Lymphoma (ML)
• Increase in the number of mantle cells in the mantle zone
• Due to chromosomal translocation between
chromosomes 11 and 14
• (11;14)t → ↑↑ Cyclin D → ↑ cell proliferation
→ ↑ cell number
o Cyclin D: Helps cell enter the S phase of cell division
(ii) Burkitt’s Lymphoma (BL)
• Increase in the number of centroblasts in the
germinal center
• Due to chromosomal translocation between
chromosomes 8 and 14
• (8;14)t → ↑↑ C-MYC → ↑ cell proliferation
→ ↑ cell number
o C-MYC: A super hyperactive proto-oncogene
causing massive cellular hyperproliferation
• Associated with EBV and HIV
o At risk, population are African populations
(iii) Diffuse Large B-Cell Lymphoma (DLCBL)
• Increase in the number of centroblasts
o It can also occur in other areas (e.g., plasma cell stage)
• The most common type of NHL
• Chromosome 3
• ↑↑ BCL6 → ↑ cell proliferation → ↑ cell number
o BCL6: proto-oncogene
o BCL2 / P53: can also be mutated, which
inhibits apoptosis
o It can also be a combination
• Associated with EBV and HIV
Figure 2. A decrease in cell apoptosis leads to the formation of
neoplastic lymphocytes.
Figure 3. Increased cell proliferation leads to the production of
neoplastic lymphocytes.
Non-Hodgkin's Lymphoma
Hematology Pathology: Note #8. .
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(C) EFFECTS OF NEOPLASTIC LYMPHOCYTES (B-CELL + T-CELL)
(1) Lymph Nodes
● Lymphadenopathy
o Lymphocytes fill up lymph nodes due to decreased
apoptosis or hyperproliferation.
o Also present in Hodgkin’s lymphoma
o Characteristics
 Painless
 Rubbery
 Noncontiguous
• Versus HL, which is contiguous
● Lymph nodes affected (Figure 4)
o Cervical
o Supraclavicular
o Axillary
o Mediastinal
 HL >> NHL
o Abdominal
 NHL >> HL
Figure 4. Lymph Nodes.
(2) Cytokines
● Lymphocytes release cytokines such as IL1, IL6, TNF-alpha
● Cytokines stimulate the hypothalamus to Increase the hypothalamic
temperature set point leading to the following B-symptoms
(HL>>NHL)
o Fever
o Night sweats
o Weight loss
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Hematology Pathology: Note #8.
Non-Hodgkin's Lymphoma
(3) Extranodal Involvement
● NHL >> HL
● Neoplastic lymphocytes may enter the bloodstream and go to other tissues
(i) CNS
• Primary CNS Lymphoma
o Associated with HIV +
o Higher incidence of DLBCL
• Meningitis
• Seizures
• Spinal Cord Compression
o It may present as cauda equina syndrome
(ii) Red Bone Marrow
• When neoplastic lymphocytes occupy the red
bone marrow, there will be less space for
other cells leading to pancytopenia.
• Pancytopenia
o Low erythrocytes
 Anemia
o Low leukocytes
 Infection
o Low thrombocytes
 Bleeding, bruising
(iii) T – Cell Lymphoma
• T cells love to deposit into the skin
• Mycosis fungicides
o Accumulation of T-cells into the skin
forming plaques
• Neoplastic T cells can enter the bloodstream,
becoming Sézary cells
• Erythroderma (Sézary syndrome)
o Occurs when Sézary cells enter tissues
producing a diffuse red rash
(iv) Glands
• Decrease in saliva
• Decrease in lacrimal fluid
(v) Thyroid
• Thyromegaly (enlarged thyroid)
• Marginal Zone Lymphoma (MZL)
o Decreased saliva + Decreased lacrimal
fluid + thyromegaly
o Conditions that increase BCL10
 PUD
 Hashimoto
 Sjogren
• Gastric MALT Lymphoma
(vi) Stomach
• Gastric MALT Lymphoma
• Also associated with marginal zone lymphoma
•
(vii) Thicken Ilecocal valve
• Small bowel obstruction
• Associated with Burkitt’s lymphoma (sporadic
subtype)
o Not associated with EBV and HIV
(viii) Hepatosplenomegaly
• Associated with Follicular lymphoma
(ix) Bone (Jaw)
• Large jaw mass
• Associated with Burkitt’s lymphoma
• Endemic in African subtype
o Associated with EBV and HIV +
(4) Complications
(i) Hypercalcemia
• Increase in tumor burden
Non-Hodgkin's Lymphoma
(ii) Tumor cell lysis
• Rupture of tumor cells
• Increase in levels of
o Potassium
o Phosphate
o Uric acid
• Decrease in levels of
o Calcium
• Uric acid and formed calcium phosphates may
deposit in the kidneys resulting in acute
kidney injury.
Hematology Pathology: Note #8. .
5 of 10
III) DIAGNOSTIC APPROACH TO NON-HODGKIN’S LYMPHOMA
(A) LAN 2/2 METS VS. LYMPHOMA
● The patient would typically present with:
o Evidence of lymphadenopathy:
 Cervical/ supraclavicular/ axillary/ abdominal/
mediastinal (look for compression symptoms)
o Extranodal features
o B-symptoms (fever, night sweats, weight loss)
● Evaluate the (enlarged) lymph node(s):
Q1: Is it metastatic? Or is it lymphoma?
 Do a lymph node biopsy:-
(B) FLOW CYTOMETRY
● After detecting neoplastic lymphocytes in the L.N.s
o Look at the cluster of differentiation (CD) proteins
 CD3+ → T-cell NHL
 CD20+ → B-cell NHL (85-90% prevalent)
● Note: for T-cell NHL, skin lesions are typically present,
and therefore a skin biopsy is taken, and “Pautrier’s
microabscesses” may be seen.
o In blood smears, Cesari cells may be present
 This is how to look for Mycosis fungicides
Mets (+) (metastasis) ?
o look for primary tumor
Reed-Sternberg cells (+) OR Popcorn cells (+) ?
o Hodgkin’s Lymphoma
RS cells (-); Popcorn cells (-); Mets (-) ?
o likely Non-Hodgkin's Lymphoma
Q2: is it T-cell or B-cell?
• Do a flow cytometry
Figure 6. Flow Cytometry is used to differentiate types of NHL,
whether it's T-cell or B-cell lymphoma, based on the cluster of
differentiation (CD).
o Q3: What type of B-cell NHL is it?
 Determine using Cytogenetics/PCR or
Histopathology.
• Mantle-cell (MCL)
• Diffuse Large B-cell (DLBCL)
• Burkitt’s (BL)
• Follicular (FL)
• Marginal zone (MZL)
Figure 5. Lymphadenopathy can be differentiated with a biopsy,
whether it’s of metastatic origin or whether it’s a lymphoma
6 of 10
Hematology Pathology: Note #8.
Mutation/
Translocation
Extra
MCL
t(11:14)
DLBCL
↑BCL 6
HIV/EBV
BL
t(8:14)
HIV/EBV (African type)
FL
t(14:18)
MZL
↑BCL 10
Hashimoto’s/ Sjogren’s/ Peptic
ulcer disease (H. pylori)
Non-Hodgkin's Lymphoma
(C) CYTOGENETICS/ PCR + HISTOPATHOLOGY
(1) Cytogenetics/PCR
● After detecting the CD to figure out what type of
lymphoma it is, we take the genetic material and look for
the chromosomal abnormality and string out the gene
from the DNA (cytogenetics; CG), then quantify (PCR).
o
Based on mechanisms of increasing
neoplastic lymphocytes, there are:
1.↓ Apoptosis (indolent; slow-growing)
a.Follicular lymphoma (FL)
b.Marginal-zone lymphoma (MZL)
2.↑ Cellular proliferation (rapid/aggressive)
a.Mantle-cell lymphoma (MCL)
b.Burkitt Lymphoma (BL)
Figure 7. Cytogenetics and PCR or Histopathology are used to
differentiate the different types of B-cell NHL
c.Diffuse Large B-cell Lymphoma (DLBCL)
(2) Histopathology
(i) Follicular Lymphoma
(iv) Burkitt Lymphoma “Starry sky appearance.”
(ii) Marginal-zone Lymphoma
(v) Diffuse Large B-cell Lymphoma
(iii) Mantle cell Lymphoma
Non-Hodgkin's Lymphoma
Hematology Pathology: Note #8. .
7 of 10
IV) STAGING NON-HODGKIN’S LYMPHOMA
● It is important to determine whether it has
spread to extranodal tissues.
Extranodal
tissue
Type most likely
associated
GIT, thyroid,
salivary glands
Bone marrow
All types,
but if it affects the jaw
(maxilla & mandible)
→ Burkett’s lymphoma
Brain
Diffuse Large
B-Cell Lymphoma
(Especially if HIV +ve)
Spleen & Liver
Figure 8 Extranodal involvement of Non-Hodgkin’s lymphoma
Follicular Lymphoma
(A) HOW TO DETECT EXTRANODAL INVOLVEMENT:
(i) PET-CT scan
o PET-CT scan is used to detect where the cancer has
spread.
▪ Fluorodeoxyglucose (FDG) is used with the scan.
It provides valuable information about the
metabolic activity of cancer cells and the areas in
which it has spread light up.
(B) ANN-ARBOR STAGING SYSTEM:
●After determining whether there is extranodal involvement
or not, the Anne-Arbor classification system can be used
to determine what stage the lymphoma is.
oIt helps categorize the extent and spread of NHL based on
the involvement of lymph nodes and other organs.
o There are 4 stages, they all have lymph node involvement
Stage
Description
I
II
2 lymph node regions on the same side of
the diaphragm
III
≥2 lymph node regions on both sides of the
diaphragm
IV
≥2 lymph node regions on either same
side/both sides of the diaphragm
+ Extranodal involved
Figure 5.PET-CT using FDG to detect lymphoma spread
(ii) CT scan of CAP w/ contrast
o This is a CT of the Chest, Abdomen, and Pelvis
 Like PET-CT, it helps determine whether the
cancer has spread to other parts of the body.
Figure 9. Anne-Arbor Staging System of Non-Hodgkin’s Lymhpoma
(iii) MRI
o This is only used if cancer has spread to the CNS
 If the patient is HIV positive and has neuro deficit
symptoms
• In this case, an MRI of the brain and LP of the
CSF is done to look for neoplastic lymphocytes.
(iv) Bone marrow biopsy
(C) SUB-CLASSIFICATION SYSTEM:
A: Absence of B-symptoms
B: Presence of B-symptoms
▪ Fever, night sweats, weightless
o This determines whether it has spread to the bone
marrow.
▪ Pancytopenia is also a sign of bone marrow
involvement.
X: Presence of bulky symptoms
▪ Lymph node ≥ 10 cm
Due to the spleen and bone marrow involvement = stage 4
8 of 10
Hematology Pathology: Note #8.
Non-Hodgkin's Lymphoma
V) TREATMENT
●Non-Hodgkin's lymphoma has one systemic chemotherapy regimen
R- CHOP
(A) OTHER TREATMENTS:
(i) Intrathecal chemotherapy
● For patients that are:
o HIV positive (aș a prophylaxis)
o Primary CNS lymphoma (as a treatment)
● Intrathecal methotrexate is injected into the ventricles
of the brain via a lumbar drain or catheter.
(ii) Marginal Zone Lymphoma:
● This is associated with 3 disorders:
o Peptic ulcer diseases (due to H.pylori) → gastric
MALT lymphoma
o Hashimoto’s (thyromegaly)
o Sjogren (lacrimal and salivary gland involvement)
● The underlying disease needs to be treated
o In PUD, the cause of inflammation is H.pylori
▪ By treating the bacteria, there will be ↓
inflammation which means ↓ expression of
BCL10, and so apoptosis will not be inhibited.
●Treatment: CAP
oClarithromycin, Amoxicillin, and PPI
▪ This helps prevent the progression of MALT
lymphoma.
Figure 10. Intrathecal Methotrexate for HIV positive and primary
CNS lymphoma
Remember:
o Gastric MALT lymphoma occurs through ↑↑ inflammation
 This ↑↑ expression of BCL10
 which leads to inhibition of apoptosis
Non-Hodgkin's Lymphoma
Figure 11. Treat underlying cause of MALT lymphoma
Hematology Pathology: Note #8. .
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VI) REVIEW QUESTIONS
1) Which of the following statements is CORRECT?
a) B-cell NHL is more common than T-cell NHL
b) Hodgkin lymphoma has worse prognosis than NonHodgkin
c) Hodgkin lymphoma may have constitutional (“B”)
symptoms but not NHL
d) Non-Hodgkin lymphoma affects a localized, single
group of nodes
2) When the centroblast in the germinal zone has a
good affinity to the antigen, it will move to the next
stage which is called ______.
a) Mantle cell lymphocyte
b) Centrocyte
c) Marginal cell lymphocyte
d) Naïve B-cell
3) Which of the following is CORRECTLY paired?
a) Mantle cell lymphoma: c-myc
b) Burkitt’s Lymphoma: BCL12
c) Follicular Lymphoma: cyclin D
d) DLBCL: BCL6
4) Which of the following is CORRECTLY paired?
a) Mantle cell lymphoma: (11;14)t
b) Burkitt’s Lymphoma: chromosome 3
c) Follicular lymphoma: (8;14)t
d) Marginal zone lymphoma: (14;18)t
5) Which of the following is more common in NonHodgkin lymphoma than in Hodgkin lymphoma
a) Contiguous lymphadenopathy
b) Extranodal involvement
c) B symptoms
d) Mediastinal lymph nodes
6) Which of the following types of NHL is
INCORRECTLY paired with its most common
extranodal involvement?
a) Hepatosplenomagaly: Follicualr lymphoma
b) Small bowel obstruction: Burkitt’s lymphoma
(sporadic subtype)
c) Primary CNS lymphoma: DLBCL
d) Thyromegaly: Mantle cell lymphoma
7) Which of the following methods is used to
differentiate T-cell from B-cell lymphoma?
a) Lymph node biopsy
b) Flow cytometry
c) Cytogenetics
d) Histopathology
10 of 10
Hematology Pathology: Note #8.
8) Which of the following translocations is wrongly
paired with its type of lymphoma?
a) Mantle Cell Lymphoma: t(11:14)
b) Burkitt Lymphoma: t(8:14)
c) Follicular Lymphoma: t(14:18)
d) None (they’re all correctly paired)
9) Which of the following types of B-cell lymphoma is
usually associated with peptic ulcer disease due to
H. pylori?
a) Mantle Cell Lymphoma
b) Burkitt Lymphoma
c) Follicular Lymphoma
d) Marginal-zone Lymphoma
10) Which imaging technique uses fluorodeoxyglucose
(FDG) to provide information about the metabolic
activity of cancer cells in non-Hodgkin's lymphoma
a) PET-CT scan
b) CT scan of CAP w/ contrast
c) MRI
d) Bone marrow biopsy
11) Which subclassification system causes the
presence of fever, night sweats, and weight loss
symptoms in non-Hodgkin's lymphoma?
a. A
b. B
c. X
d. None of the above
12) What stage is assigned to non-Hodgkin's
lymphoma when there is spleen and bone marrow
involvement
a) Stage I
b) Stage II
c) Stage III
d) Stage IV
13) What is the recommended treatment for marginal
zone lymphoma associated with peptic ulcer
disease?
a) R-CHOP
b) CAP
c) Intrathecal chemotherapy
d) None of the above
VII) REFRENCES
● Le, T., Bhushan, V., Sochat, M., Coleman, C., & Qiu, C. (2022).
First Aid for the USMLE Step 1. USA: McGraw Hill.
● Harrison, T. R., & Kasper, D. L. (2015). Harrison's Principles of
Internal Medicine. McGraw-Hill Medical Publ. Division.
Non-Hodgkin's Lymphoma