Lymphoma Dr. Asad 13.7.2023

Lymphoma |1
Lymphoma
Dr.Asad R10
Depertment of Clinical Oncology
BSMMU
Lymphoma |2
Lymphoid organ:
Lymphoid organs are specialized tissues that provide the microenvironment for the
functional maturity (primary lymphoid organs) or activation (secondary lymphoid
organs) of lymphocytes
➢ Lymphocytes both regulate and carry out adaptive immunity.
➢ In adult, lymphocyte production occurs in red bone marrow.
➢ But maturation occurs in Lymphoid organ which are two types:
Primary Lymphoid organ:
▪ Bone marrow, (produces Lymphocyte, matures B cell)
▪ Thymus: (for maturation of T cell)
Then the B-cell and T cell circulates through 2ndary lymphoid organ, through
which final maturation occurs and become functional.
Secondary Lymphoid organ:
▪ MALT,
▪ lymph nodes and
▪ spleen.
Extra lymphatic organ:

✓ Extralymphatic means other than lymph nodes and other lymphatic structures.
✓ These lymphatic structures include
➢ Spleen,
➢ Thymus gland,
➢ Waldeyer's ring (tonsils),
➢ Peyer's patches (ileum) and
➢ lymphoid nodules in the appendix
Lymph nodes:
➢ bean-shaped, encapsulated structures,
➢ generally, only 10 mm by 2.5 cm in size, distributed throughout the body along the
lymphatic vessels
➢ A total of 400 to 450 lymph nodes are present
➢ Lymph node has,
▪ One convex surface: Receiving afferent Lymphatics
▪ One concave surface: Receiving efferent Lymphatics also known as
hilum where an artery, vein, and nerve penetrate the organ
▪ both with valve)
➢ From outside to inside structures are
▪ Capsule
▪ Cortex
▪ Medulla
Description
Capsule → Made of dense collagen tissue
→ extending trabeculae internally through which the blood
vessels branch.
Cortex → Outer peripheral part
→ Inner part of cortex peripheral to medulla is called paracortex
Medulla → Most inner part adjacent to hilum
Dr. Asad R10

Lymphoma |3
How lymph percolates:

1. received by afferent lymphatics into cortex
2. passes through lymphatic sinuses along trabeculae (known as trabecular siunus/cortical
sinus)
3. then interconnected sinus channels in medulla, known as medullary sinuses
In outer cortex there is collection of B cell known as Germinal center/ Lymphatic nodules.
Lymphatic Nodule/Follicle are 2 types:
• primary follicle (don’t have germinal center)
• secondary follicle (when germinal center develops)
A lymphoid follicle is known as a primary follicle until it is not challenged by an antigen. The
primary follicle consists of resting B-cells along with other cells. when lymphatics percolates
through Lymphnode, it comes in contact with primary follicle.
Once a primary follicle is challenged by an antigen, it becomes enlarged and

known/converts as a secondary follicle. It consists of actively dividing B-cells at the center
known as the germinal center surrounded by a ring of B-lymphocytes. So, the germinal center
is present in the secondary follicle (marginal zone)
Dr. Asad R10

Lymphoma |4
This germinal center and Marginal zone of

2ndary follicle contain:
➢ Antigen presenting cell
➢ Follicular dendritic cell
➢ Reticular cell
➢ B cell: as a form of
o Centrocyte
o Centroblast
Antigen presenting cell ✓ Presents Antigen with MHC II molecule to T and

B cell
Dendritic cell ✓ APC with large dendritic projection
Follicular dendritic cells ✓ cells of the immune system found in primary and
(FDC) secondary lymph follicles (lymph nodes) of the B
cell areas of the lymphoid tissue
✓ not derived from the bone-marrow hematopoietic
stem cell, but are of mesenchymal origin.
Reticular cell ✓ Produce Collagen III fiber
❖ Follicular dendritic cells (FDC) are not typical APC. They bind the antigen with
specific antibody and may hold it for days months even years, and consistently
present the antigen to B cell to produce low level of antibody for longer time (?)
Sometimes they are referred as antigen holding cell.
❖ APC, dendritic cell, and are mainly present in marginal zone. (?) when lymph
passes through cortical sinus, they come in contact with antigen, they present the
antigen to B cell, which are mainly present more centrally(?)
❖ Depending on the type of antigen, certain group of B cell will be activated and
starts proliferated, so they will present with larger, pale nucleus, known as
Centroblast. Other lymphocyte will remain resting phase, known as Centrocyte.
❖ Later Centroblast may convert into plasma cell (which is a specialized B cell, with
nucleus having cart wheel appearance). This cell produces large amount of antibody
and remains in Medulla, close to afferent vessels.
In paracortex/Inner Cortex:
➢ Mainly T cell are present here. In case of Viral or Other acute infective condition,
where Cell mediated immunity is mainly activated, antigen comes in contact to T cell
in paracortex, while passing through lymphatics. No FDC
So, cell arrangement in Lymphnode:
➢ In Cortex : B cell, APC, FDC
➢ In Paracortex : T cell
➢ In Medulla : Plasma cell
Dr. Asad R10

Lymphoma |5
Common CD markers:
White blood cells (WBCs) have different subsets with unique functions and characteristics, and
can be identified by different cell surface markers or antigens. Here are some common CD
markers used to classify WBC subsets:
Cluster of Differentiation (CD Markers) Mnemonics:
First, differentiate WBC from RBC, platelet by
CD45 = Leukocyte Common Antigen (LCA)
i.e. expressed in all except erythrocytes and platelets.
Then differentiate Myeloid and Lymphoid group:
CD13, CD33 and CD11b = Pan-myeloid markers
Negative in Pan Lymphoid series
Next: differentiate between T cell and B cell
CD3 = Pan-T cell marker
Additional T cell marker: (tiny number)
CD2
CD4 (T-helper cells)
CD8 (Cytotoxic T cells; i.e. 2 X 4 = 8)
CD28 (Costimulatory molecule needed to activate T cells) – has “2” and “8”
Also: CD1, CD3, CD5 and CD7
CD 30: positive for Th2 cells
In T cell CD positive are 1234578 28
B Cell marker:
CD19: all B cells
CD20: most B cells
CD21: mature B cells with EBV receptor
CD22: mature B cells
CD40: needed for isotype switching and formation of memory cells
CD79a: B-cell receptor
CD10 or CALLA (Common ALL Antigen): Pre-B cells and derivatives
PAX5: B-cell specific transcription factor
Dr. Asad R10

Lymphoma |6
NK Cell Surface Markers (come from lymphocyte precursors, not T cell)

CD3: Negative
CD16: Positive
CD56 Positive
Receptors present in Antigen Presenting Cells (APCs) including B cells:

CD80 (B7-1) and CD86 (B7-2):
Co-simulatory molecules present in Antigen Presenting Cells (APC)
MHC class II
Stem cell markers are CD34, tDT and HLA-DR.
Macrophages : CD14
Neutrophils : CD18
Dendritic cells : CD1 and CD11
B cell development:
➢ From the marrow, naïve B cells migrate through the blood and extravasate into
secondary lymphoid tissues, such as the spleen, lymph nodes, and mucosa-associated
lymphoid tissues (MALTs) in the gut.
➢ The initial commitment to B cell differentiation by lymphoid progenitors in the bone
marrow requires the expression of the master B lineage transcription factor PAX5,
which directly upregulates the expression of early B lineage markers such as CD19
➢ During development, pre-B cells pass through checkpoints that correspond to specific
stages of Ig gene
➢ During the period of Ig gene rearrangement, pre-B cells lack complete surface Ig and
express CD19 and CD10, the latter previously referred to as the common
acute lymphoblastic leukemia antigen (CALLA).
Dr. Asad R10

Lymphoma |7
➢ Cells that express surface Ig upregulate additional B-cell markers such as CD79a,
cytoplasmic and surface CD22, and CD20, as well as prosurvival factors such as
BCL2, and downregulate CD10 and TdT, emerging from the process as mature,
immunologically naïve B cells
➢ Antigen-mediated B-cell activation requires the transcription factor MYC and is
accompanied by an increase in cell size and entry into cell cycle
➢ Once in follicles, the B cells downregulate MYC and BCL2 and upregulate the
transcriptional repressor BCL6, which, like MYC, is essential for secondary B-cell
follicle formation
➢ The key roles of MYC, BCL2, and BCL6 in this process explain why the genes
encoding these factors are commonly mutated in B-cell lymphomas.
➢ mutations involving MYC, BCL2, and BCL6 identical to those found in lymphomas
indicates B cell tumor is from germinal center
At first : PAX5
pre-B cell : CD19 and CD10
later : CD79a, CD22, and CD20
from GC : MYC, BCL2, and BCL6
Dr. Asad R10

Lymphoma |8
Definition of Lymphoma:
➢ Lymphoma is the solid malignancies in the lymphoreticular system
➢ Lymphoid neoplasms are malignancies of B-cells, T-cells, and NK (natural killer) cells
➢ Lymphomas present as solid masses arising in lymph nodes or at extranodal sites
anywhere in the body, whereas leukaemias and multiple myeloma are diseases
primarily of the bone marrow. (walter)s
➢ Traditionally, classifications have distinguished between lymphomas” – i.e., neoplasms
that typically present with an obvious tumor or mass of lymph nodes or extranodal
sites – and “leukemias” – i.e., neoplasms that typically involve the bone marrow and
peripheral blood, without tumor masses. However, we know that many B- and T/NK-
cell neoplasms may have both tissue masses and circulating cells from recent knowledge.
So, the term leukemia and lymphoma merely reflect the usual distribution of each
disease at presentation (walter)
➢ The World Health Organization (WHO) classification of haemato-lymphoid tumors
is the most widely used pathologic classification system for hematopoietic and lymphoid
neoplasms. The current revision, known as the 5th edition, was published in 2022 and
supersedes the 4th edition revised published in 2016.
WHO classification divides hematopoietic and lymphoid neoplasms into 3 major

groups:
Myeloid neoplasms
This group includes neoplasms that arise from cells in the myeloid lineage, such as
✓ myeloid leukemias,
✓ myelodysplastic syndromes,
✓ myeloproliferative neoplasms, and
✓ other rare myeloid neoplasms.
Lymphoid neoplasms
This group includes neoplasms that arise from cells in lymphoid lineage, such as
✓ lymphomas,
✓ leukemias, and
✓ other rare lymphoid neoplasms.
Histocytic and dendritic cell neoplasms
This group includes neoplasms that arise from cells in the histiocytic and dendritic
cell lineages, such as
✓ Langerhans cell histiocytosis and
✓ other rare histocytic and dendritic cell neoplasms.
Dr, Asad R10

Lymphoma |9
WHO classification
Division Includes
Myeloid Neoplasms
Myeloproliferative neoplasms Chronic myeloid leukaemia
Polycythaemia vera
Primary myelofibrosis
Mastocytosis Cutaneous/ Systemic mastocytosis
Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement
Myelodysplastic/myeloproliferative Chronic myelomonocytic leukaemia
neoplasms Atypical chronic myeloid leukaemia,
Myelodysplastic/myeloproliferative neoplasm
with ring sideroblasts and thrombocytosis
Myelodysplastic syndromes
Myeloid neoplasms with germline predisposition
Acute myeloid leukaemia and related precursor Neoplasms
Blastic plasmacytoid dendritic cell neoplasm
Acute leukaemias of ambiguous lineage
Lymphoid Neoplasms
Precursor lymphoid neoplasms B-lymphoblastic leukaemia/lymphoma
T-lymphoblastic leukaemia/iymphoma
NK-lymphoblastic leukaemia/iymphoma
Mature B-cell neoplasms Chronic lymphocytic leukaemia/
B-cell prolymphocytic leukaemia
Splenic marginal zone lymphoma
Nodal marginal zone lymphoma
Follicular lymphoma
Primary cutaneous follicle centre lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Hairy cell leukaemia
Burkitt lymphoma
Lymphoplasmacytic lymphoma
Plasma cell neoplasms: Plasmacytoma
High-grade B-cell lymphoma
Mature T- and NK-cell neoplasms Primary cutaneous peripheral T-cell lymphomas,
Adult T-cell leukaemia/lymphoma
T-cell lymphoma
Mycosis fungoides
Sezary syndrome
Anaplastic large cell lymphoma,
Hodgkin lymphomas
Immunodeficiency-associated
lymphoproliferative disorders
Histiocytic and dendritic cell neoplasms
Dr, Asad R10

L y m p h o m a | 10
Grossly, lymphoma can be classified as

❖ Hodgkin lymohoma
Classic type
→ Nodular sclerosis
→ Lymphocyte rich
→ Lymphocyte depleted
→ Mixed cellularity
Nodular lymphocyte predominant
❖ Non-Hodgkin Lymphoma
Non-Hodgkin Lymphoma includes

Hodgkin lymohoma
Non-Hodgkin Lymphoma
Types of B cell verity of NHL:
High grade NHL Low grade NHL
1. Diffuse large B cell lymphoma (DLBCL)
2. Mantle cell lymphoma
3. Peripheral T cell lymphoma 1. Follicular lymphoma (Grade – 1,2)
4. Follicular lymphoma (grade 3) 2. Marginal Zone lymphoma
5. Burkitt’s lymphoma 3. Mycosis fungoides.
6. Primary CNS lymphoma
7. Lymphoblastic lymphoma
T cell Lymphoma
The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:
➢ T-cell chronic lymphocytic leukemia/prolymphocytic leukemia
➢ T-cell granular lymphocytic leukemia
➢ Mycosis fungoides/Sézary syndrome
➢ Peripheral T-cell lymphoma, not otherwise characterized
➢ Hepatosplenic gamma/delta T-cell lymphoma
➢ Subcutaneous panniculitis-like T-cell lymphoma
➢ Angioimmunoblastic T-cell lymphoma
➢ Extranodal T-/NK-cell lymphoma, nasal type
➢ Enteropathy-type intestinal T-cell lymphoma
➢ Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+)
➢ Anaplastic large cell lymphoma, primary systemic type
➢ Anaplastic large cell lymphoma, primary cutaneous type
➢ Aggressive NK-cell leukemia
Dr, Asad R10

Distribution of various types of lymphoma:

The percentage distribution of various types of lymphoma can vary depending on the population
being studied and the region of the world. However, based on data from the American Cancer
Society, the following is a rough estimate of the percentage distribution of the two main categories
of lymphoma in the United States:
❖ Non-Hodgkin lymphoma (NHL) : approximately 90% of all lymphomas

❖ Hodgkin lymphoma (HL) : approximately 10% of all lymphomas
Within the category of NHL, there are many different subtypes. According to the Lymphoma
Research Foundation, the most common subtypes of NHL in the United States are:
❖ Diffuse large B cell lymphoma (DLBCL) : approximately 22% of NHL cases

❖ Follicular lymphoma : approximately 20% of NHL cases
❖ Marginal zone lymphoma : approximately 12% of NHL cases
❖ Mantle cell lymphoma : approximately 6% of NHL cases
❖ Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
: approximately 5% of NHL cases
Other less common subtypes of NHL include Burkitt lymphoma, lymphoplasmacytic lymphoma,
and anaplastic large cell lymphoma, among others. The distribution of subtypes can vary
depending on factors such as age, sex, and ethnicity.
According to GLOBOCAN 2020

New cases in 2020 Death in 2020
HL About 83,000 About 23,000
NHL About 5,44,000 About 2,60,000
NHL is 11th most common malignancy and 11th most common cause of cancer related death
although both are among the most sensitive malignancies to radiation and cytotoxic therapy, their
cure rates also differ. (dv)
→ About 80% of patients with HLs are cured by regimens employing conventional and
salvage strategies,
→ whereas <50% of patients with NHLs are cured
Dr, Asad R10

Difference between Hodgkin lymphoma and non-Hodgkin lymphoma

Features Hodgkin’s lymphoma Non-Hodgkin’s lymphoma
Bimodal.
1. Age First peak at 20 to 30 years, and Median age 65 to 70 years
second peak at 50 to 70 years
Unifocal,
Multicentric, more frequent
usually localized to a single axial
involvement of peripheral LN
2. LN involvement group (cervical and mediastinal)
Peripheral groups of LN are
Central groups of LN are more
more involvement
involvement
3. Mesenteric LN and
Rarely involved Commonly involved
Waldeyer’s ring
4. Epitrochlear lymph
Rarely involved Commonly involved
node
Noncontiguous spread
5. LN spread Orderly spread by contiguity
(via blood)
6. Extranodal More common,
Less common, occurs late
involvement occurs early(25%)
7. Systemic features or
Common Less common
B symptoms
8. Alcohol induced
discomfort at lymph Present Absent
node site
9. Pel-Ebstein fever May occur Does not occur
10. Pruritus Common Less common
Reed-Sternberg cells
11. Histology Absent
(hallmark)
12. Bone marrow
Early Late
involvement
Low cure rate (low grade
13. Prognosis High cure rate
tumors are incurable
➢ NHL- extranodal at presentation – 25%.

➢ Mycosis fungoides and MALT lymphomas being virtually always extranodal, except in
advanced stages of the diseases.
➢ Follicular lymphoma, B-cell small lymphocytic lymphoma seldom being extranodal,
except for bone marrow involvement
Dr, Asad R10

Overall important clinical examination findings in lymphoma:

History: (cas)
➢ Painless neck swelling: presented as Painless lymphadenopathy, involving any of the
superficial lymph nodes, is the most common chief complaint of patients with Hodgkin
lymphoma (HL) and non-Hodgkin lymphoma (NHL).
➢ Fevers, night sweats, and weight loss are characteristic in advanced presentations of HL
and aggressive NHL
➢ Pel-Ebstein fever is periodic and uncommon but characteristic of HL
➢ Pruritus, often intense, may be the presenting symptom in HL, particularly the nodular
sclerosis subtype, and may antedate diagnosis by months or years.
➢ Pain
o Alcohol-induced pain in areas of involvement is infrequent but is characteristic of
HL.
o Abdominal pain or discomfort may be due to splenomegaly, bowel dysfunction
due to adenopathy or bowel involvement,
o Bone pain may reflect localized areas of bone destruction or invasion or diffuse
marrow infiltration.
o Neurogenic pain is caused by spinal cord compression, plexopathies, nerve root
infiltration, meningeal involvement, and complicating varicella zoster.
o Back pain suggests massive retroperitoneal nodal involvement, often with psoas
muscle invasion
On examination:
Lymph node examination:
➢ Lymph node chains must be carefully examined, including the cervical, supraclavicular,
axillary, epitrochlear, inguinal, femoral, and popliteal nodes.
➢ The lymph nodes are examined for size, multiplicity, consistency, and tenderness.
➢ Lymphomatous involvement typically imparts a rubbery consistency, not the rock-hard
quality
Tonsils and oropharynx
➢ The tonsils and oropharynx are thoroughly examined.
➢ Waldeyer ring involvement mandates complete evaluation of the
nasopharynx, oropharynx, and hypopharynx by endoscopy
Other examination
evaluate for
➢ Hepatosplenomegaly, Important investigations in specific
➢ the presence of Effusions, types of lymphoma is discussed at
➢ evidence of Neuropathy, and the end.
➢ Bony tenderness.
➢ signs of obstruction:
▪ extremity edema,
▪ superior vena cava syndrome,
▪ spinal cord compression,
▪ hollow viscera dysfunction
Dr, Asad R10

Hodgkin Lymphoma
Epidemiology:
➢ 10% of all lymphomas (Ev)
➢ Worldwide, 83,087 cases and 23,376 deaths were reported in 2020. (dv)
➢ 55% of cases occurring in men. (Ev)
➢ Males slightly greater incidence than females (1.3:1)
➢ Bimodal age distribution at presentation: (Ev)
▪ ages 25–30 and
▪ age >55.
➢ The incidence of NHLPL peaks in middle age, but the disease is also seen in pediatric
patients (dv)
➢ incidence rates are highest in Europe, Australia/New Zealand, and North America,
➢ mortality rates highest in Western Asia and Northern Africa. (dv)
➢ In the United States, new cases have decreased in the past 20 years and death rates have
consistently declined since the 1970s
Classification of HL: (dv)

The 2017 World Health Organization classification of lymphoid tumors recognizes two distinct
clinicopathologic entities under the umbrella of HL:
❖ Classical Hodgkin lymphoma (CHL): accounting for 90% of all cases
which includes:
▪ Nodular Sclerosis Classical Hodgkin lymphoma (NSCHL):
most common (70% of CHL)
▪ Mixed Cellularity Classical Hodgkin Lymphoma (MCCHL):
20%–25% of CHL
▪ Lymphocyte-rich classical Hodgkin lymphoma (LRCHL):
5% of CHL
▪ Lymphocyte-Depleted classical Hodgkin lymphoma (LDCHL):
very rare around 1%
❖ Nodular Lymphocyte-Predominant Hodgkin lymphoma (NLPHL)
CHL is characterized by the presence of Reed-Sternberg cells in an inflammatory

background, whereas NLPHL is characterized by the presence of lymphocytic and
histiocytic (LP or “popcorn”) cells.
Risk factors:
EBV:
➢ Epstein-Barr virus (EBV) infection can be detected in Hodgkin/ Reed-Sternberg (HRS)
cells in 20% to 50% of CHL in the developed world, with a higher incidence in
developing countries.(dv)
➢ In the Western world, EBV infection is mostly detected in cases of MCCHL and
LDCHL, and is less frequently detected in the nodular sclerosing and lymphocyte-rich
subtypes.
➢ Conversely, EBV is found in the malignant cells in nearly all cases of CHL occurring
in patients infected with HIV
HIV: associated with mixed cellularity and lymphocyte depleted (Ev)
Dr. Asad R10

Family History:
➢ Close relatives of HL have an increased risk of developing HL, particularly siblings,
who have a sixfold incidence. (dv)
➢ Monozygotic twins have a high risk with a standardized incidence ratio of 99
Reed-Sternberg cells and their variants:

Both CHL and NLPHL originate from mature B cells. The neoplastic cells of CHL,
often referred to as HRS cells
RS cells are giant cells of B cell origin.
Hallmark of classical HL Absent in NLPHL
RS cells and their variants are: (cas)
❖ RS cells
❖ The lacunar cell
❖ L&H cells
❖ RS-like cells
RS cells:
➢ giant cells that have
✓ more than one nucleus and
✓ large, eosinophilic, inclusion-like nuclei.
➢ RS cells are B cells that originate in the germinal centers of lymph nodes.
The lacunar cell /LC cell
➢ variant of the RS cell
➢ has the same immunophenotype.
➢ It characterizes NS HL and is often far more plentiful than classic RS cells in that
subtype.
L&H cells/ Lympho-histiocytic variant
➢ are RS-like but have a different immunophenotype.
➢ L&H cells were identified in nodular LP HL,
➢ Although the L&H cells are believed to be of monoclonal origin, the surrounding
B-cell infiltrates may be polyclonal.
Mentioned as popcorn cell/LP cell in dv (?)
RS-like cells
➢ are found in a variety of infectious, inflammatory, and neoplastic disorder:
▪ infectious mononucleosis,
▪ lymphoid hyperplasia associated with
✓ phenytoin therapy, and
✓ high-grade NHLs.
Other verities (not mentioned in cas, from net):
Mononuclear variants (Classical HL):
➢ Presented with single large nucleus (Not multi nucleated Like Classical HL cell)
➢ Can be found any type of HL
Mummified cell
➢ Strongly indicated HL, not confirmatory
Anaplastic/Pleomorphic variants:
➢ Present in Lymphocyte depleted type
Dr. Asad R10

Common Immuno-phenotyping of RS cell: (cas)

lack many of the mature B-cell markers such as CD19 and CD20 surface proteins, (dv)
but they almost always express the B-cell specific transcription factor PAX5, albeit weakly
Classical RS cell lacunar cell L&H cells
usually express Same immunophenotype like have a different
✓ CD15 and CD30 Classical RS cell immunophenotype
express manifest B-cell markers
✓ CD20 infrequently, ✓ CD20,
✓ but not CD45 ✓ CD45, and
✓ CD79a
but not
✓ CD15 or
✓ CD30.
Typical immunophenotype for CHL: (NCCN)
CD15+, CD30+, PAX-5+ (weak); CD3-, CD20- (majority), CD45-, CD79a-.
Typical immunophenotype for NLPHL:
CD20+, CD45+, CD79a+, BCL6+, PAX-5+; CD3-, CD15-, CD30-
Dr. Asad R10

From Divita:
HRS cells:
➢ HRS cells almost invariably
express CD30 and
transcription factors PAX5
and interferon regulatory
factor 4 (IRF4) (often referred
to as multiple myeloma
oncogene 1 [MUM1] after
the monoclonal antibody clone
recognizing IRF4).
➢ Approximately half of the
cases also express CD15, but
other B-cell markers such as
CD20, CD79a, and CD19 are
either not expressed or
expressed weakly by a subset
of HRS cells
➢ HRS cells do not express
immunoglobulins or
transcription factors that are
required for immunoglobulin
gene transcription such as
OCT-2 or BOB1
➢ Another important
immunophenotypic feature of
HRS cells is the loss of major
histocompatibility complex (MHC) class I and II expression and upregulation of
immune escape molecules such as PD-L1 in most of the cases
LP cells:
➢ LP cells, in contrast to HRS cells, show consistent expression of numerous mature
B-cell markers such as CD20, PAX5, CD19, CD79a, CD75, BCL6, and CD45 in
nearly all cases and aberrant expression of epithelial membrane antigen
➢ In addition, they show intact immunoglobulin production machinery including strong
expression of immunoglobulin transcription regulators OCT-2, BOB1, and PU.1, as
well as immunoglobulin heavy, light, and J chains.
Most Common Genetic Alteration in Classical Hodgkin Lymphoma:(dv)
→ B2M → SOCS1
→ PDL1/2 → PTPN1
→ CIITA → TNFAIP3
→ CD58 → NFKBIA
→ JAK2 → NFKBIE
→ STAT3 → TRAF3
→ STAT6 → CYLD
Dr. Asad R10

→ XPO1
Mode of spread and site of Involvement in HL: (cas)
➢ HL almost always originates in a lymph node.
➢ Whenever a primary diagnosis of HL is made in an extranodal site without contiguous
nodal involvement, the diagnosis should be highly suspected with the exception of
HIV-infected individuals.
➢ For much of its natural history, HL appears to spread in an orderly fashion through
the lymphatic system by contiguity.
➢ Histologic types other than NS, however, often skip the mediastinum, and
disease appears in the neck and upper abdomen.
➢ The axial lymphatic system is almost always affected in HL, whereas distal sites
(e.g., epitrochlear and popliteal nodes) are rarely involved.
➢ Hematogenous dissemination occurs late in the course of disease and is characteristic
of the LD subtype.
Site of involvements in HL:
Site Description
Peripheral Cervical or supraclavicular occurs in >70% of cases
lymph nodes Lymphadenopathy
Axillary and less frequently involved
Inguinal lymph nodes
Generalized Lymphadenopathy atypical of HL
Thorax anterior mediastinum prime location for NS HL
hilar lymph node involvement. May occure
Lung involvement may occur by direct contiguity with
hilar involvement in HL as well as
by hematogenous dissemination.
Pulmonary involvement by HL may
produce discrete nodules and irregular,
interstitial, or even lobar infiltrates.
Pleural effusion may occur
✓ secondary to mediastinal
compression of vascular–
lymphatic drainage and by
✓ direct pleural involvement.
Chylous effusions occasionally occur.
Pericardial involvement may be found on CT scans, but overt
cardiac tamponade is uncommon.
Superior vena cava syndrome more frequent in NHL than in HL.
Abdomen Abdominal LN splenic hilar nodes, and celiac nodes
are the earliest abdominal sites of
involvement
Mesenteric lymph nodes are rarely
involved in HL.
Spleen At least 25% of spleens not clinically
enlarged harbor occult HL
Liver Liver involvement is uncommon at
diagnosis and is almost
Dr. Asad R10

always associated with infiltration of the

spleen
bone marrow rarely involved at the time of diagnosis of HL. (chance 5%)
may involve in Patients with advanced-stage disease, systemic symptoms, and
MC
Other are rarely involved in HL
extranodal Liver or skin involvement is rare and usually a late manifestation of disease.
sites CNS involvement is very uncommon with the exception of extrinsic spinal
cord compression.
➢ Left supraclavicular lymphadenopathy is more strongly associated with
abdominal involvement (specifically, splenic involvement) than is right-sided disease.
➢ Clinical involvement of meninges, brain, Waldeyer ring, GI tract, kidney, and
other extranodal sites usually suggests an alternative diagnosis.
➢ Clinical examination and investigations depend upon this findings
Important Clinical features in HL:

Important History in HL:
➢ Painless Lymphadenopathy
➢ Alcohol induced pain in neck swelling
➢ Presence of B symptoms: fever, night sweet, weight loss
➢ Pel ebstain fever, saddleback fever
Important Clinical examination:
➢ Lymphadenopathy: rubbery, order of contiguity
➢ assessment of Waldeyer ring
➢ Splenomegaly
➢ Hepatomegaly
➢ Bony tenderness
➢ Pleural effusion
➢ Pericardial effusion
Important investigations:
Routine investigations: For staging:
• CBC with ESR • CECT chest/chest Xray
• S creatinine, S electrolyte, SGOT • CT scan of the neck
• S albumin • CECT abdomen pelvis/USG W/A
• S LDH • PET CT scan
Other investigations on special
conditions:
For confirmation: • Bone marrow aspiration and biopsy
• Core biopsy from LN and IHC • Bone scan
• HIV testing
• Pregnancy test and fertility
counseling
Dr. Asad R10

Chest Xray/ CECT chest: (pz)

➢ An upright posterior–anterior chest radiograph is required for assessment
of mediastinal bulk defined as mediastinal adenopathy measuring 33% or more
of the maximum intrathoracic cavity.
➢ Chest radiograph is highly concordant with chest computed tomography (CT), although
chest radiograph is still required to define bulk in the majority of protocols.
➢ Contrast-enhanced CT is recommended for evaluation of the thorax as it can detect
lymphadenopathy involving the subcarinal, hilar, and cardiophrenic angles as well as
extranodal sites including the pleura, chest wall, or pericardium, which may change
management.
PET CT scan: (pz)
➢ Essentially all cases of HL demonstrate (18) fluorine-fluorodeoxyglucose ([18]F-FDG)
avidity, and thus [18]F-FDG positron emission tomography (PET) is included as
standard staging for HL
➢ [18]F-FDG-PET scans lead to a change in stage in 10% to 30% of patients, more often
upstaging.78
➢ [18]F-PETCT is furthermore critical in monitoring treatment response, particularly in
cases with persistent radiographic abnormalities
CECT abdomen and pelvis:
Preferred for identification of hepatosplenomegaly or intraabdominal LN. in case of
retroperitoneal lymphadenopathy, MRI abdomen is more suitable
Bone marrow biopsy:

Traditionally, bone marrow biopsy was standard in lymphoma staging; however, given
the low rate of bone marrow involvement at initial presentation, particularly in the
setting of a negative [18]F-PET-CT for bone marrow involvement, bone marrow
biopsy can be restricted to patients with
→ B symptoms or
→ stage III or IV disease
Bone scan
in the presence of bone pain or elevated serum alkaline phosphatase or calcium level.
HIV testing
should be considered in patients whose disease presentation is primarily extranodal.
Pregnancy test and fertility counseling
in patients of childbearing age should be performed with staging evaluation.
Dr. Asad R10

Staging of Lymphoma
From AJCC:
Ann Arbor Staging:
➢ Anatomic staging of lymphomas traditionally has been based on the Ann Arbor
classification system, which was originally developed more than 30 years ago for
HL.
➢ It was based on the relatively predictable pattern of spread of HL and improved the
ability to determine which patients might be suitable candidates for radiation therapy.
Cotswold system:
➢ Ann Arbor classification system was updated as the “Cotswold system” to address
some of the issues present in the original staging system and to accommodate
newer diagnostic techniques, including computed tomography (CT) scan.
➢ It subsequently was applied to non-Hodgkin lymphoma (NHL) as well, despite the
fact that the pattern of spread is less predictable than that of HL.
Lugano classification:
➢ However, advances in diagnostics and therapy provided the impetus to review
and modernize the evaluation and staging of lymphoma. Workshops were held at the
11th and 12th
➢ International Conference on Malignant Lymphoma to study areas in need of
clarification or updating and then to review the proposed changes.
➢ The Lugano classification was published and forms the basis for revised
recommendations regarding anatomic staging and evaluation of disease before and after
therapy. This staging system is adopted by the AJCC
Lymph Node Regions
➢ The staging classification for lymphoma uses the term lymph node region. The lymph
node regions were defined at the Rye Symposium in 1965 and have been used in the
Ann Arbor classification; this is unchanged in the Lugano classification.
➢ They are not based on any physiologic principles but rather have been agreed
upon by convention.
➢ The currently accepted classification of core nodal regions is as follows:
Dr. Asad R10

Overall LN Regions are:

➢ Right cervical nodes, including ➢ Right hilar lymph nodes
▪ cervical, ➢ Left hilar lymph nodes
▪ supraclavicular, ➢ Para-aortic lymph nodes
▪ occipital, and ➢ Mesenteric lymph nodes
▪ preauricular lymph nodes ➢ Right pelvic lymph nodes
➢ Left cervical nodes ➢ Left pelvic lymph nodes
➢ Right axillary nodes ➢ Right inguinofemoral lymph
➢ Left axillary nodes nodes
➢ Right infraclavicular nodes ➢ Left inguinofemoral lymph
➢ Left infraclavicular lymph nodes nodes
➢ Mediastinal lymph nodes
❖ In addition to these core regions, HL and NHLs may involve epitrochlear lymph nodes,
popliteal lymph nodes, internal mammary lymph nodes (considered mediastinal
by convention), occipital lymph nodes, submental lymph nodes, preauricular lymph
nodes (all considered cervical)
Dr. Asad R10

For the purposes of coding and staging, involved areas are divided as
Nodal site ✓ lymph nodes,

✓ Waldeyer’s ring,
✓ thymus, and
✓ spleen
Extra Nodal site ✓ adrenal glands,
✓ blood,
✓ bone,
✓ bone marrow,
✓ central nervous system
(CNS; leptomeningeal and parenchymal brain disease),
✓ gastrointestinal (GI) tract,
✓ gonads,
✓ kidneys,
✓ liver,
✓ lungs,
✓ skin,
✓ ocular adnexae
(conjunctiva, lacrimal glands, and orbital soft tissue),
✓ skin,
✓ uterus, and
✓ others.
➢ HL rarely presents in an extranodal site alone, but about 25% of NHLs are extranodal at
presentation.
➢ The frequency of extranodal presentation varies dramatically among different lymphomas,
however, with some (e.g., mycosis fungoides and mucosa-associated lymphoid tissue
[MALT] lymphomas) being virtually always extranodal, except in advanced stages of the
diseases,
➢ some (e.g., follicular lymphoma) seldom being extranodal, except for bone marrow
involvement.
Ann arbor staging of HL (Davidson)
Dr. Asad R10

Cotswolds Staging Classification: (cas)
Lugano Classification for Hodgkin and NonHodgkin Lymphoma

Stage Stage description
Limited stage
Involvement of a single lymphatic site
I
(i.e., nodal region, Waldeyer’s ring, thymus, or spleen)
Single extralymphatic site in the absence of nodal involvement
IE
(rare in Hodgkin lymphoma)
Involvement of two or more lymph node regions on the same side
II
of the diaphragm
Contiguous extra lymphatic extension from a nodal site with or
IIE without involvement of other lymph node regions on the same side of
the diaphragm
II bulky* Stage II with disease bulk* *
Advanced stage
Involvement of lymph node regions on both sides of the
III
diaphragm; nodes above the diaphragm with spleen involvement
Diffuse or disseminated involvement of one or more
extralymphatic organs, with or without associated lymph node
involvement;
or
noncontiguous extra-lymphatic organ involvement in conjunction
IV with nodal Stage II disease
or
any extralymphatic organ involvement in nodal Stage III disease
Stage IV includes any involvement of the CSF,
bone marrow, liver, or multiple lung lesions (other than by direct
extension in Stage IIE disease)
Dr. Asad R10

➢ Stage II bulky may be considered either early or advanced stage based on lymphoma
histology and prognostic factors
➢ definition of disease bulk varies according to lymphoma histology. In the Lugano
classification,
➢ bulk in Hodgkin lymphoma is defined as a mass greater than one third of the
thoracic diameter on CT of the chest or a mass >10 cm.
➢ For NHL, the recommended definitions of bulk vary by lymphoma histology.
➢ In follicular lymphoma, 6 cm has been suggested based on the Follicular Lymphoma
International Prognostic Index-2 (FLIPI-2) and its validation.
➢ In DLBCL, cutoffs ranging from 5 to 10 cm have been used, although 10 cm
is recommended.
➢ Hodgkin lymphoma uses A or B designation with stage group. A/B is no longer
used in NHL
A and B Classification (Symptoms):
1. Fevers. Unexplained fever with temperature above 38°C,
frequently in Pel–Ebstein pattern
2. Night sweats. Drenching sweats (e.g., those that require change of bedclothes)
3. Weight loss. Unexplained weight loss of more than 10% of the usual body weight
in the 6 months prior to diagnosis
Difference between ann arbor and Lugano: (AJCC)

➢ The Lugano classification includes an E suffix for lymphomas with either localized
extralymphatic presentation (Stage IE) or by contiguous spread from nodal disease
(Stage IIE). For example, lymphoma presenting in the thyroid gland with cervical
lymph node involvement should be staged as IIE.
➢ However, in a change from the Cotswold modification of the Ann Arbor staging
system, E lesions do not apply to patients with Stage III nodal disease; any patient
with nodal disease above and below the diaphragm with concurrent contiguous
extralymphatic involvement is Stage IV (previously Stage IIIE).
➢ The key point of difference between Lugano and Ann Arbor classification is the
introduction of FDG-PET/CT in the initial evaluation for staging. As PET/CT scan
provides both metabolic and morphological information in the same examination, it is
useful for precise evaluation in the staging of FDG-avid lymphomas. (net)
Special consideration:
Frequently, extensive lymph node involvement is associated with extranodal extension
of disease that also may directly invade other organs. Such extension should be
described with the E suffix if the nodal disease is on one side of the diaphragm. For
example, mediastinal lymph nodes with adjacent lung extension should be classified
as Stage IIE disease
Dr. Asad R10

The International Prognostic Score (IPS) of HL: (Hasenclever- Diehl)

defined by the number of adverse prognostic factors present at diagnosis that helps
to determine the clinical management and predict prognosis for patients with stage
III–IV disease
it includes:
• Albumin <4 g/dL
• Hemoglobin <10.5 g/dL
• Sex: Male
• Age ≥45 years
• Stage: Stage IV disease
• Leukocytosis (white blood cell count ≥15,000/mm3)
• Lymphocytopenia (lymphocyte count <8% of white blood cell count,
and/or lymphocyte count <600/mm3)
1 point per factor
Each point reduced survival rates by 7% to 8% per year (NCCN)
5-year Freedom From Progression (FFP) and Overall Survival (OS):
0 Points: 84% Freedom from progression and 89% overall survival
1 Point: 77% Freedom from progression and 90% overall survival
5 to 7 Points: 42% Freedom from progression and 56% overall survival
(https://www.merckmanuals.com/medical-calculators/IPS.htm)
*** IPS is also applicable for different NHL, with sperate parameter
Unfavorable Risk Factors for Stage I–II Hodgkin Lymphoma
Factor GHSG EORTC NCCN
Age ≥50
Histology
>50 if A; >50 if A; ≥50 or
ESR and B symptoms
>30 if B >30 if B any B symptoms
Mediastinal mass MMR >0.33 MTR >0.35 MMR >0.33
# Nodal sites >2* >3* >3
E lesion any
Bulky >10 cm
✓ GHSG = German Hodgkin Study Group
✓ EORTC = European Organization for Research and Treatment of Cancer
✓ MMR = Mediastinal mass ratio, maximum width of mass/maximum intrathoracic diameter
✓ MTR = Mediastinal thoracic ratio, maximum width of mediastinal mass/intrathoracic diameter at T5–6
* Note that the EORTC includes the infraclavicular/subpectoral area with the axilla while the
GHSG includes it with the cervical. Both EORTC and GHSG combine the mediastinum and
bilateral hila as a single region.
*** This Risk Factors for Stage I–II Hodgkin Lymphoma are important for treatment purpose
Dr. Asad R10

Depending on the presence of Unfavorable risk factors, and staging, Classical Hodgkin
Lymphoma can be classified to favorable or unfavorable or advanced stages:
Bulky Mediastinal Disease ESR >50
Stage or or Type
>10 cm Adenopathy # Sites >3
No No Favorable Disease
Favorable/
IA/IIA No Yes
Unfavorable Disease
Yes Yes/No Unfavorable Disease
IB/IIB Yes/No Yes/No Unfavorable Disease
III–IV Yes/No N/A Advanced Disease
bulk in Hodgkin lymphoma is defined as a mass greater than one third of the thoracic
diameter on CT of the chest or a mass >10 cm
Stage I:
Stage IA No bulky disease Favorable Disease
ESR<50
<3 nodal site involved
Stage IA Presence of bulky disease Favorable/
Or ESR>50 Unfavorable Disease
Or >3 site involved
Stage IB Unfavorable Disease
Stage II:
Stage IIA No bulky disease Favorable Disease
ESR<50
<3 nodal site involved
Stage IIA No bulky disease but, Favorable/
ESR>50 or Unfavorable Disease
>3 site involved
Stage IIA Presence of bulky disease Unfavorable Disease
And/or ESR>50 or
>3 site involved
Stage IIB Unfavorable Disease
Stage III and IV is considered as advanced disease.

N.B:
→ When stage IA is presented with bulky disease or ESR>50 or >3 nodal site involved,
then it can be considered as both favorable or unfavorable. Otherwise it is favorable.
→ When stage IIA is presented with bulky disease ± ESR>50 or >3 nodal site, then it is
unfavorable disease. Otherwise it is favorable.
→ Stage I or II presented with B symptoms is Unfavorable Disease
Dr. Asad R10

Treatment steps of CHL depends on various study result, including

➢ H10F trail of CALGB (Cancer and Leukemia Group B)
(https://pubmed.ncbi.nlm.nih.gov/30049811/)
➢ H10F trail of RAPID (Randomized Phase III Trial to Determine the Role of FDG–
PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease)
(https://www.nejm.org/doi/full/10.1056/nejmoa1408648)
➢ HD16 Trial by GHSG (the German Hodgkin Study Group)
(https://pubmed.ncbi.nlm.nih.gov/31498753/)
➢ RATHL trial (Response-adapted therapy for advanced Hodgkin lymphoma)
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245987/)
➢ H10U trail of EORTC (European Organisation of Research and Treatment of Cancer)
https://ascopubs.org/doi/pdf/10.1200/JCO.2016.68.6394?role=tab
All combined treatment steps are described as per NCCN:
Treatment steps Stage IA/IIA Favorable (Non-bulky) CHL

➢ First: ABVD x 2 cycles (category 1)
dose
A Doxorubicin 25 mg/m2 IV D1, D15
B Bleomycin 10 U/m2 IV D1, D15
V Vinblastine 6 mg/m2 IV D1, D15
D Dacarbazine 375 mg/m2 IV D1, D15
Repeat cycle every 28 days
➢ Next: Restage with FDGPET/CT and assess Deauville score
Score PET/CT Scan Result
1 No uptake
2 Uptake ≤ mediastinum
Negative 3 Uptake > mediastinum but ≤ liver
Uptake moderately higher than liver and
4
visually above adjacent background activity
5 Uptake markedly higher than liver and/or new lesions
Positive
X New areas of uptake unlikely to be related to lymphoma
After 2 cycle of ABVD next treatment options depends on Deauville score

if Deauville score 1-2 after two cycle of ABVD (Uptake ≤ mediastinum):
next treatment options are any of the following
Options are
Chemotherapy alone ABVD x additional 2 cycles (preferred) (CALGB)
[total 4 cycle]
Or
ABVD x additional 1 cycle (RAPID)
[total 3 cycle]
Or
Combined modality Involved-site radiation therapy (ISRT) 20 Gy
therapy (GHSG HD16; if ESR <50, no e-lesions, <3 nodal sites)
Or
ABVD x additional 1 cycle [total 3] + ISRT 30 Gy (RAPID)
Then follow up the patient
Dr. Asad R10

if Deauville score 3 after two cycle of ABVD (mediastinum <Uptake ≤ liver)

Options are
Combined modality Involved-site radiation therapy (ISRT) 20 Gy
therapy (GHSG HD16; if ESR <50, no e-lesions, <3 nodal sites)
Or
ABVD x 2 cycles (total 4) + ISRT 30 Gy (RAPID)
Or
Chemotherapy alone ➢ AVD x 4 cycles (RATHL)
if Deauville score 4 after two cycle of ABVD (uptake>liver)

next treatment options are
➢ ABVD x additional 2 cycles [total 4]
➢ Then, Again, Restage with FDGPET/CT
➢ If Deauville score 1- 3:
ISRT 30 Gy (RAPID)
➢ If Deauville score 4-5:
Repeat Biopsy
• If negative biopsy: ISRT 30 Gy (RAPID) then F/U
• If positive biopsy: Treat as refractory disease
if Deauville score 5 after two cycle of ABVD (new lesions):

➢ Repeat biopsy:
o A Deauville 5 score would warrant a biopsy to inform subsequent therapy.
o If a biopsy is not feasible, treatment should be escalated
➢ If positive biopsy: Treat as refractory disease
If negative biopsy after score 5: (**treat like score 4)

➢ ABVD x additional 2 cycles [total 4]
➢ Then, Again, Restage with FDGPET/CT
ISRT 30 Gy (RAPID)
Repeat Biopsy
• If negative biopsy: ISRT 30 Gy (RAPID) then F/U
Regarding chemotherapy:
→ Several CHT regimens have been used over history of Hodgkin’s lymphoma.
→ Historical regimen MOPP (mustard, vincristine, procarbazine, prednisone) resulted in
sterility (80% of men, age-linked in women) and secondary acute nonlymphocytic
leukemia. (td)
→ Modern regimens are associated with less sterility and secondary malignancy risk and
include ABVD, ABV, AVD, and AV
→ German HD13 study examined if bleomycin, dacarbazine, or both could be omitted
(ABV, AVD, and AV arms) in early-stage HL. All alternative regimens were associated
with inferior outcomes relative to ABVD
Dr. Asad R10

Treatment of Stage I/II Unfavorable CHL

➢ This group include:
▪ Stage I/II CHL with
✓ B symptoms or
✓ bulky mediastinal disease or
✓ >10 cm adenopathy
Treatment steps are
dose
A Doxorubicin 25 mg/m2 IV D1, D15
B Bleomycin 10 U/m2 IV D1, D15
V Vinblastine 6 mg/m2 IV D1, D15
D Dacarbazine 375 mg/m2 IV D1, D15
➢ Next: Restage with FDGPET/CT and assess Deauville score

if Deauville score 1-3 after two cycle of ABVD (Uptake ≤ liver):
Options are
Combined modality Additional ABVD x 2 cycles (total 4) + ISRT 30 Gy
therapy (adapted from H10U EORTC),
Or
Chemotherapy alone AVD x 4 cycles (RATHL)
if Deauville score 4-5 after two cycle of ABVD (Uptake > liver/new lesions):
next treatment option is: Escalated BEACOPP x 2 cycles
BEACOPP Escalated (chu)
Dose
B Bleomycin 10 mg/m2 IV D8
E Etoposide 200 mg/m2 IV D1-D3
A Doxorubicin 35 mg/m2 IV D1
C Cyclophosphamide 1,200 mg/m2 IV D1
O Vincristine 1.4 mg/m2 IV (max2) D8
P Procarbazine 100 mg/m2 PO D1 TO D7
P Prednisone 40 mg/m2 PO D1 TO D14
**Escalated BEACOPP is an option only for those aged <60 y
➢ Then, Again, Restage with FDGPET/CT (after 2 cycle Escalated BEACOPP)
➢ Escalated BEACOPP X additional 2 cycles (RATHL)
Or
➢ ISRT 30 Gy (H10U EORTC)

Repeat Biopsy
• If negative biopsy: ISRT 30 Gy (H10U EORTC) then F/U
Dr. Asad R10

Treatment of Stage III/IV CHL

Different treatment options are available in this stage,
most common steps of Stage III/IV CHL are:
➢ Then: Restage with FDG-PET/ CT
if Deauville score 1-3 after two cycle of ABVD (Uptake ≤ liver):

➢ AVD x 4 cycles (RATHL)
➢ Then F/U the patient
if Deauville score 4-5 after two cycle of ABVD (Uptake > liver/new lesions):
➢ next treatment option is: Escalated BEACOPP x 3 cycles
➢ Then, Again, Restage with FDGPET/CT (after 3 cycle Escalated BEACOPP)
➢ Escalated BEACOPP X additional 1 cycles (RATHL)
And/Or
➢ ISRT 30 Gy (H10U EORTC)
Repeat Biopsy
➢ If negative biopsy:
▪ Escalated BEACOPP X additional 1 cycles (RATHL)
And/Or
• ISRT 30 Gy (H10U EORTC)
Another treatment steps of Stage III/IV CHL:

➢ Brentuximab vedotin (BV) + AVD (category 1) for 6 cycle.
** use with caution in patients aged >60 y; contraindicated in those with
neuropathy
Then: Restage with FDG-PET/ CT
➢ If Deauville score 1- 3: F/U
➢ If Deauville score 4-5: Repeat Biopsy
➢ If negative biopsy: F/U
Another treatment steps of Stage III/IV CHL:

➢ First: Escalated BEACOPP x 2 cycles Last alternative steps are
only applicable for
➢ Then review Deauville score by repeat PET CT
✓ International
If Deauville score 1-3: prognostic score
➢ Escalated BEACOPP x additional 2 cycles (total 4) (IPS) ≥4,
(HD18) ✓ aged <60 y
➢ Or, A(B)VD x 4 cycles (RATHL)
If Deauville score 4-5: Repeat Biopsy.
➢ If biopsy negative:
➢ Escalated BEACOPP x additional 2 cycles (total 4) (AHL) then again
➢ Escalated BEACOPP x additional 2 cycles if score reduces to 1-3 (total 6)
➢ If biopsy positive: treat as refractory disease
Dr. Asad R10

Recapitulations:
Stage Treatment options DS after ABVD (2)/
(any of the following) BEACOPP (2)
Stage IA/IIA ABVD (4) DS 1-2
Favorable ABVD (3) DS 1-2
(Non-bulky) ABVD (2) +ISRT20 DS 1-2
CHL ABVD (4) + ISRT 30 DS 3
ABVD (2) + ADV (4) DS 3
ABVD (4) + ISRT 30 DS 4 [1-3 later]
ABVD (4) + ISRT 30 DS 5. biopsy -
Stage IA/IIA ABVD (4) + ISRT 30 DS 1-3

Un favorable ABVD (2) + ADV (4) DS 1-3
(bulky, B ABVD (2) + BEACOPP (4) DS 4-5 [1-3 later]
symtoms) ABVD (2) + BEACOPP (2) + ISRT 30 DS 4-5 [1-3 later]
CHL ABVD (2) + BEACOPP (2) + ISRT 30 DS 4-5 [4 later, biopsy -]
Stage III/IV ABVD (2) + ADV (4) DS 1-3

ABVD (2) + BEACOPP (4) ± ISRT 30 DS 4-5 [1-3 later]
ABVD (2) + BEACOPP (4) ± ISRT 30 DS 4-5 [4 later, biopsy -]*
BEACOPP (4) DS 1-3
BEACOPP (2) + ABVD (4) DS 1-3
BEACOPP (6) DS 4-5
Brentuximab VD(6)+AVD (6)
*biopsy done at that condition after BEACOPP (3)
Any DS 5 (after ABVD 2/ BEACOPP 2) and biopsy positive is treated as refractory disease
Dr. Asad R10

Treatment of Nodular Lymphocyte Predominant Hodgkin Lymphoma:

Because of the rarity of this disease, it is difficult to perform randomized prospective clinical
trials. However, several well-designed single-arm phase II trials and large retrospective
analyses have been recently reported. (ad)
Treatment options include (NCCN)
Stage IA, ISRT (preferred for stage IA or contiguous stage IIA)
Stage IIA (Non-bulky) Or
Observation: may be an option for stage IA patients with
a completely excised solitary lymph node.
Stage IB, Chemotherapy: ABVD/CHOP/CVbP
Stage IIB or + Rituximab
Stage IA (Bulky)/ + ISRT
Stage IIA (Bulky or
noncontiguous)
Stage Observe, if asymptomatic
III–IV or
Based on clinical judgment, options include:
Chemotherapy +Rituximab ± ISRT
or
Rituximab
or
Local RT (palliation of locally symptomatic disease)
After treatment with ABVD/CHOP/Rituximab/ISRT or during observation

➢ Restage with FDG-PET/ CT:
If there is Response:
➢ Observe, if asymptomatic
or
➢ ISRT (if no prior RT)
In case of Stable or progressive disease:
➢ Observe: if asymptomatic and biopsy negative
➢ If biopsy positive: treat as refractory disease.
It suggests that (ad)

(1) chemotherapy alone is not indicated for patients with NLPHL,
(2) RT alone should be the standard of care for patients with early-stage NLPHL
without bulky disease or B symptoms, and
(3) limited-field RT is appropriate to reduce toxicity and mortality after more
extensive RT.
(4) chemotherapy is the mainstay of treatment for those with stage II or IV
disease
➢ Because at least 70% to 80% of patients with NLPHL are diagnosed with early-stage
disease, defining the optimal treatment regimen for advanced-stage disease is challenging.
However, chemotherapy is the mainstay of treatment for those with stage II or IV disease
➢ Currently, NCCN guidelines list therapeutic options including CVP (cyclophosphamide,
vincristine, and prednisone), CHOP, and ABVD with or without rituximab for patients with
advanced disease
Dr. Asad R10

Management of CHL In Adults Age >60 Year (NCCN)

➢ CHL in older adult patients is associated with poorer disease outcomes.
➢ B symptoms, poor performance status, mixed cellularity, histologic subtype, EBV+
disease, and medical comorbidities are more frequent in this population.
➢ Standard chemotherapy regimens are associated with dose reductions, treatment
toxicity, and treatment-related mortality in older patients.
➢ There are limited prospective data evaluating alternatives to standard therapies for
patients >60 years. Selection of standard versus alternate first-line therapy for a patient
>60 years should be based on clinical judgment, with the goal of minimizing toxicity
while maximizing efficacy.
➢ The regimens listed below should be considered in patients >60 years to
lessen/minimize toxicity. These regimens have not been proven to overcome the poorer
disease outcomes observed in patients >60 years
Options
Stage I–II Favorable A(B)VD (2 cycles) ± AVD (2 cycles) + ISRT (preferred)
Disease Or
CHOP (4 cycles) + ISRT
Stage I–II Unfavorable or A(B)VD (2 cycles) followed by AVD (4 cycles), if FDG-
Stage III–IV Disease PET scan is negative after 2 cycles of ABVD.
Patients with a positive FDG-PET scan after 2 cycles of
ABVD need individualized treatment.
Other options include:
• Brentuximab vedotin followed by AVD,
conditionally followed by brentuximab vedotin in
responding patients with CR or PR
• Brentuximab vedotin + DTIC (dacarbazine)
• CHOP (6 cycles) ± ISRT
Refractory or relapsed Hodgkin lymphoma

➢ Although many patients with HL are cured with frontline therapy,
▪ 10% to 15% of patients with early stage disease with unfavorable risk factors
and
▪ 40% of patients with advanced-stage disease with high risk factors
can develop relapse or refractory disease. (ad)
Refractory or relapse case should be biopsy proven
Treatment of Relapse cases:
Confirm it by biopsy
If biopsy positive, Restage with initial workup
Treatment options depends on Initial stage and previous treatments
When initial stage IA-IIA and previous no RT
o Second-line systemic therapy + RT or
o Second-line systemic therapy followed by HDT/ASCR ± ISRT
➢ Second-line systemic therapy + RT options is alternative HDT/ASCR when patient
previously received abbreviated cycle of CT (3-4 cycle) in stage IA-IIA
All other relapse cases:
o Second-line systemic therapy followed by HDT/ASCR ± ISRT
Dr. Asad R10

From NCCN discussion:

➢ Suspected relapse at any point should be confirmed with biopsy.
➢ Restaging is recommended for patients with positive biopsy
➢ Observation (with short-interval follow-up with FDG-PET/CT) is appropriate if
biopsy is negative.
➢ Most patients require second-line systemic therapy followed by RT or HDT/ASCR
with or without ISRT.
➢ For patients with initial stage I–IIA disease treated initially with abbreviated
chemotherapy alone (3–4 cycles) and relapsed in initial sites of disease, RT alone may
be appropriate.
Treatment of Refractory cases

1st, start the treatment with Second-line systemic therapy
After completion of Second-line systemic therapy Restage with FDG-PET/ CT
Repeat FDG-PET/ Treatment options (any of the following
CT score
Deauville 1–3 High-dose therapy and autologous stem cell rescue
Observe ± RT (if HDT/ ASCR contraindicated)
Deauville 4 HDT/ASCR ± RT
RT
Subsequent systemic therapy ± RT
If response, consider transplant (autologous or allogeneic)
Deauville 5 RT or
Subsequent systemic therapy ± RT
If response, consider transplant (autologous or allogeneic)
** after treatment: Consider brentuximab vedotin maintenance
for patients with high risk of relapse
From NCCN discussion regarding refractory cases of HL:

➢ Second-line systemic therapy followed by response assessment with FDG-PET is
recommended for all patients.
➢ Patients with a Deauville score of 1 to 3 should proceed to HDT/ASCR with or
without RT (category 1). Observation with or without RT can be considered, if
HDT/ASCRis contraindicated.
➢ Maintenance therapy with BV can be considered for patients with high risk of relapse
as defined by the AETHERA trial, defined as those having
✓ primary refractory disease,
✓ duration of first CR <1 year, or
✓ relapse with extranodal or
✓ advanced-stage disease)
➢ An alternative regimen (3rd line) with or without RT or RT alone is recommended
for patients with a Deauville score of 4 or 5 after second-line systemic therapy.
Autologous or allogenic HCT following additional therapy may be considered in
these patients.
Dr. Asad R10

N.B:
➢ Both relapse and refractory cases, start the treatment with 2nd line CT.
➢ after 2nd line CT if DS score reduces to 1-3, it indicates complete response. In that
condition HDT/ASCR is given
➢ Without CR (score 1-3), ASCR is not advised. In that condition RT can be started to
achieve CR.
➢ If CR is not achieved in neither way, start 3rd line CT. after 3rd line therapy ± RT, if
ever response, consider about allogenic/autologous transplantation.
Second-line systemic therapy:

For patients with relapsed or refractory disease after standard frontline management,
additional salvage chemotherapy followed by HDCT plus ASCT is the standard
approach.
One of the key goals of salvage chemotherapy
is to achieve CR before ASCT. (ad)
Second-Line and Subsequent Therapy for
CHL: (in alphabetical order)
• Brentuximab vedotin
• Brentuximab vedotin + bendamustine
• Brentuximab vedotin + nivolumab
• DHAP (dexamethasone, cisplatin, high-
dose cytarabine)
• Gemcitabine/bendamustine/vinorelbine
• GVD (gemcitabine, vinorelbine,
liposomal doxorubicin)
• GVD + pembrolizumab
• ICE (ifosfamide, carboplatin, etoposide)
• ICE + brentuximab vedotin
• ICE + nivolumab
• IGEV (ifosfamide, gemcitabine, vinorelbine)
• Pembrolizumab
the most common salvage chemotherapies outside clinical trials are the platinum-containing
regimens such as ICE or DHAP (cisplatin, cytarabine, dexamethasone).
Second-Line and Subsequent Therapy for NLPHL:

• R (rituximab) + bendamustine
• R + DHAP
• R + ICE
• R+ IGEV
If not previously used:
▪ R + ABVD
▪ R + CHOP
▪ R + CVbP
Dr. Asad R10

Therapy for Disease Refractory to at Least 3 Prior Lines of Therapy (in alphabetical order)
• Bendamustine
• Bendamustine + carboplatin + etoposide
• C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone)
• Everolimus
• GCD (gemcitabine, cisplatin, dexamethasone)
• GEMOX (gemcitabine, oxaliplatin)
• Lenalidomide
• MINE (etoposide, ifosfamide, mesna, mitoxantrone)
• Mini-BEAM (carmustine, cytarabine, etoposide, melphalan)
• Nivolumab (see indications below)
• Vinblastine
Various dose mentioned in Chu:
CVP
C Cyclophosphamide 400mg/m2 D2-D5
800mg/m2 D1
V Vincristine 1.4mg/m2 (max2) D1
P Prednisolone 100mg/m2 D1-D5
CHOP
C Cyclophosphamide 750 mg/m2 D1
H Doxorubicin 50 mg/m2 D1
O Vincristine 1.4 mg/m2 IV D1
P Prednisone 100 mg/m2 PO D1-D5
Add Rituximab 375 mg/m2 IV on day 1 in case of RCHOP
DHAP (salvage regimen):
Cisplatin 100 mg/m2 IV continuous infusion over 24 D1

hours
Cytarabine 2,000 mg/m2 IV over 3 hours every 12 hours D2
for 2 doses on day 2 after completion of
cisplatin infusion
Dexamethasone 40 mg PO or IV D1-D4
ICE (salvage regimen)
I Ifosfamide 5,000 mg/m2 IV continuous infusion for 24 hours D2

C Etoposide 100 mg/m2 IV D1-D3
E Carboplatin AUC of 5 D2
Mesna 5,000 mg/m2 IV in combination with ifosfamide dose
G-CSF support is administered at 5 µg/kg/day on days 5–12
Add Rituximab 375 mg/m2 IV on day 1 in case of RICE
Dr. Asad R10

ESHAP (salvage regimen)
Etoposide 40 mg/m2 IV D1–4

Methylprednisolone 500 mg IV D1–4
Cisplatin 25 mg/m2/day IV continuous infusion D1–4
Cytarabine 2,000 mg/m2 IV on day 5 after D5
completion of cisplatin and etoposide
MINE (salvage regimen)
M Mesna 1,330 mg/m2 IV administered at same D1-D3

time as ifosfamide on days 1–3, then
500 mg IV 4 hours after ifosfamide
I Ifosfamide 1,330 mg/m2 IV D1-D3
N Mitoxantrone 8 mg/m2 IV D1
Brentuximab: 1.8 mg/kg IV on day 1

Repeat cycle every 3 weeks for up to 16 cycles
GVD:
G Gemcitabine 1,000 mg/m2 IV D1-D8

V Vinorelbine 20 mg/m2 IV D1-D8
D Doxil (liposomal 15 mg/m2 IV D1-D8
doxorubicin?)
IGEV
20 mg/m2 IV D1
Vinorelbine
800 mg/m2 IV D1,4
Gemcitabine
2,000 mg/m2 IV D1-4
Ifosfamide
100 mg PO D1-4
Prednisolone
1,200 mg/m2 IV D 1-4
Mesna
IVE
50 mg/m2 IV D1
Epirubicin
200 mg/m2 IV D3
Etoposide
3000 mg/m2 IV D 1-3
Ifosfamide
3000 mg/m2 IV D 1-3
Mesna
Achieving CR before ASCT is the key to better outcomes in patients with relapsed or
refractory HL.
For details of refractory HL management read:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657361/pdf/12885_2020_Article_7561.pdf
Dr. Asad R10

Process of autologous stem cell transplantations:

➢ A procedure in which a patient's healthy stem cells (blood-forming cells) are collected
from the blood or bone marrow before treatment, stored, and then given back to the
patient after treatment.
➢ In autologous stem cell transplantation, the
procedure uses the patient’s own stem cells
for the transplant. steps are shown in pic
➢ Indications:
▪ Refractory/Relapsed case of HL
▪ Refractory/Relapsed case of NHL
▪ Multiple myeloma
➢ For stem cell mobilization,
→ GCSF (filgrastim is most commonly
used. Other agent GMCSF, Plerixafor
etc)
→ Chemotherapy can also be used for stem
cell mobilization: example:
o Cyclophosphamide (CY) in
myeloma patients
o In lymphoma, combination
chemotherapy is commonly used for
stem cell mobilization in autologous
stem cell transplantation setting.
Regimens include DHAP, ESHAP,
combination of CY, G-CSF, and
etoposide 108 and a combination of
ifosphamide, epirubicin and
etoposide,109 among others.
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068706/)
Target of ASCT:
✓ An autologous stem cell transplant's goal is to restore the body's ability to make
normal blood cells after high-dose chemotherapy or radiation.
✓ Such intensive treatments usually destroy cancer cells better than standard treatments,
but these high-dose treatments are toxic and also destroy the blood-producing stem cells
in the bone marrow.
✓ That is why the stem cells are removed before the treatment, so they can be treated
outside of the body and reinfused after the treatment to make new blood cells in the
bone marrow. This is called “engraftment.
Unlike allogeneic stem cell transplant, this procedure:
✓ Doesn't offer the benefits of graft versus tumor (GVL) effect when healthy donor
cells attack cancer cells. As a result, there is a higher risk of relapse of the disease
✓ Doesn't carry the risk of graft-versus-host-disease
https://www.lls.org/treatment/types-treatment/stem-cell-transplantation/autologous-stem-cell-
transplantation#:~:text=This%20type%20of%20transplant%20is,high%2Ddose%20chemothe
rapy%20or%20radiation.
Dr. Asad R10

Brentuximab Vedotin:
➢ Anti CD30 monoclonal antibody
➢ Can be used as
▪ 1st line therapy in advanced CD30-positive cHL
▪ 2nd line therapy in refractory/relapse cases
▪ 3rd line therapy
▪ maintenance for patients with high risk of relapse after 2nd/3rd line therapy (?)
❖ Practically, it is better to keep it as a reserve for 3rd line therapy after ASCT, or when
ASCT not possible (?)
** Brentuximab vedotin is currently approved as a monotherapy for adult patients

with R/R CD30-positive cHL following ASCT or following ≥ 2 prior therapies
when ASCT or multi-agent chemotherapy is not a treatment option (net)
Indication of Brentuximab maintenance therapy: (NCCN)

Patients with 2 or more of the following risk factors are considered high risk:
✓ Remission duration <1 year,
✓ extranodal involvement,
✓ FDG-PET–positive response at time of transplant,
✓ B symptoms, and/or >1 second-line/subsequent therapy regimen.
The most common treatment-related side effects were (dv)
✓ peripheral neuropathy (42%),
✓ nausea (35%), and
✓ fatigue (34%).
Grade 3 or higher neuropathy was seen in 8% of patients and was the most common
reason for the discontinuation of brentuximab vedotin.
Immune Checkpoint Inhibitors in Patients with Relapsed Classical Hodgkin
✓ CPI (Checkpoint Inhibitors) are recommended for any patients with CHL that has
relapsed or progressed after HDT/ASCR ± brentuximab vedotin. (NCCN)
✓ CPI are also an option for patients with relapsed or refractory CHL who are transplant
ineligible based on
comorbidity or failure of
second-line chemotherapy.
✓ Post-allogeneic transplant,
patients can receive either
nivolumab or
pembrolizumab. There are
limited data regarding the use
of CPI following allogeneic
transplantation. If a CPI is
used, the transplant regimen
will need to be carefully
considered.
Dr. Asad R10

Radiotherapy in Hodgkin Lymphoma

Radiation Fields in HL is important, which is evolving. Various radiation field are:
▪ Extended fields: mantle and inverted Y configurations
▪ IFRT
▪ ISRT
▪ INRT
Evolution of Radiation Fields for Lymphoma
Extended fields Radiotherapy: (Nc)
➢ Historically, HD and NHL were managed with RT alone using extended fields such as
mantle and inverted Y configurations, with higher rates of late toxicity
associated with larger field size
➢ This extended fields had better chance of toxicities (specially, cardiac toxicities and 2nd
malignancy)
➢ By the 1990s, combined modality therapy became a mainstay of lymphoma
management.
➢ With the addition of increasingly successful chemotherapies and advancements in
target localization such as 3D simulation, RT fields have become progressively smaller.
At first IFRT was introduced in exchange of Extended fields
Involved field Radiotherapy:

➢ IFRT includes not just the involved lymph nodes but also the entire lymph node
region containing the involved nodes and adjacent uninvolved lymph nodes. (pz)
➢ based on 2-D treatment planning and bony anatomy.
➢ For extra-nodal sites – the organ alone (if no evidence for lymph node involvement
Involved Node Radiotherapy (INRT)

➢ In 2006, Girinsky et al. proposed a major change in practice, which was subsequently
incorporated into the EORTC-GELA guidelines with the concept of involved node
radiotherapy (INRT).
➢ INRT is based on treating ONLY initially involved lymph nodes and excluding
adjacent uninvolved nodal areas.
➢ This version of INRT required the acquisition of a
i. pre-chemotherapy FDG-positron emission tomography-computed
tomography scan in the radiotherapy treatment position,
ii. with subsequent rigid coregistration to the post-chemotherapy
planning computed tomography scan.
❖ Problems in INRT:
✓ In most centers, pre-chemotherapy positron emission tomography-computed
tomography scans are not carried out in the radiotherapy treatment position with
immobilisation devices as required for INRT;
✓ in addition, lymphoma masses regress during chemotherapy, leading to anatomical
and positional changes, leading to uncertainties in the reconstruction of the pre-
chemotherapy disease extent
Dr. Asad R10

❖ In order to account for these difficulties, the UK National Cancer Research Institute
(NCRI) Lymphoma Radiotherapy Group developed guidelines for a concept termed
‘involved site radiotherapy’ (ISRT) to address this issue.
Involved Site Radiotherapy (ISRT)

➢ ISRT includes an additional margin of 1.5 cm craniocaudally in the direction of
lymphatic spread from the pre-chemotherapy extent of nodal disease.
➢ International Lymphoma Radiation Oncology Group (ILROG) has subsequently
published guidelines has ultimately supported the use of ISRT for RT in HL and nodal
NHL.
(https://www.sciencedirect.com/science/article/abs/pii/S0936655515001065)
Difference between IFRT and INRT/ISRT: (nc)

➢ Unlike traditional IFRT fields that treat adjacent uninvolved lymph nodes, INRT limits
treatment to only preand post-chemotherapy involved nodal volumes plus margin.
➢ Whereas IFRT traditionally uses bony landmarks to identify field borders, INRT
volumes are delineated using definitions of gross tumor volume (GTV), clinical target
volume (CTV), and planning target volume (PTV) per the International Commission
on Radiation Units and Measurements (ICRU) Report 83.
➢ ISRT and IFRT has less OAR dose and toxicities and less chance of 2nd malignancy
comparing with IFRT.
Difference between INRT and ISRT: (nc)

➢ INRT requires precisely fused pre- and postchemotherapy imaging performed in the
treatment position, which is often unattainable in clinical practice.
➢ To avoid this limitation ILROG introduced ISRT that targets the sites of pre- and post-
chemotherapy disease involvement but also offers less stringent treatment volume
definitions than INRT to allow for uncertainties associated with less than optimal
imaging (Nc)
➢ The CTV for ISRT will generally be larger than that for INRT because of the lack of
optimal imaging information. (pz)
➢ As ISRT and IFRT has same chance of OAR toxicities and less chance of 2nd
malignancy, now ISRT is commonly practiced (?)
Dr. Asad R10

In short: (?)
In case of right sided cervical LN at level II HL, stage IA:
✓ When Rt level I-X is involved, it is IFRT
✓ When only level II is involved, it is INRT
✓ When level II+1.5 cm margin is added, it is ISRT
Modalities of treatment:
➢ Treatment with photons, electrons, or protons may all be appropriate, depending on
clinical circumstances.
➢ Advanced RT technologies such as
✓ Intensity-modulated RT (IMRT)/
✓ Volumetric modulated arc therapy (VMAT),
✓ Breath hold or respiratory gating, and/or
✓ Image-guided RT (IGRT), or
✓ Proton therapy
➢ may offer significant and clinically relevant advantages in specific instances to spare
important OAR
Simulation and Field Design: (ev)

➢ 3D simulation (CT, PET/CT, or MRI) is always recommended, when possible in the
same position as in pre-chemo imaging, with appropriate immobilization. (ev) (if
PET CT is done in neck normal position then don’t extend it in CT simulation if
comparison needed)
➢ Fuse pre- and post-chemotherapy imaging studies when available.
➢ Contour pre-chemo GTV on pre-chemo CT and/or PET/CT.
➢ When image fusion is not available, contour the target volumes on the planning CT
scan with larger CTV to account for uncertainties and differences of patient
positioning.(ev)
General Considerations for Cervical/ Supraclavicular Nodal ISRT (Nc)

✓ The patient should be simulated in the supine position with hyperextension of the
neck and the use of a long thermoplastic mask extending to the shoulder region
for immobilization.
✓ 3D simulation should be performed with IV contrast
General Considerations for Axillary Nodal ISRT (Nc)

✓ The patient should be simulated in the supine position with a custom mold for
immobilization. In adults, treatment with arms above the head shifts axillary nodes
away from the chest wall and improves the ability to block the lungs.
✓ In children, treatment with arms akimbo allows for improved blocking of the
humeral heads, which protects sensitive epiphyseal growth plates
General Considerations for Mediastinal Nodal ISRT

immobilization. Arms may be placed at the sides, akimbo, or above the head.
Dr. Asad R10

General Considerations for Para-aortic Nodal ISRT

immobilization. Arms may be placed on the chest or at the sides.
✓ 3D simulation should be performed with IV and PO contrast. As target movement
with respiration may be seen, a 4DCT or fluoroscopy should be considered to allow
for creation of an ITV
ILROG planning definitions for ISRT in lymphoma
Dr. Asad R10

❖ In both involved-node RT (INRT) and involved-site RT (ISRT), the pre-chemo GTV

determines CTV.
❖ CTV encompasses all pre-chemotherapy lymphoma involvement, modified for normal
tissue boundaries, tumor shrinkage, and other anatomic changes. (applicable for
INRT?) (ev)
❖ More generous margins should be used for early-stage NLPHL when RT is used as the sole
treatment modality, including as a minimum adjacent lymph node to the originally involved
GTV
In case of ISRT:
GTV: prechemotherapy volume of involvement.
CTV: GTV to CTV margin should be at least 1 cm. (nc)
In some article it is mentioned as 1.5cm margin
From dobbs:
GTV to CTV margin depends on location:
GTV-CTV margin
neck, mediastinum and 20 mm in the cranio-caudal and
para-aortic nodes 10 mm in other dimensions
hilar, SCF and 10 mm in the anteroposterior (AP)
common iliac nodes and 20 mm in other directions is used
axillary, external and internal iliac, 20 mm is used in all directions
inguinal and femoral nodes
These variable margins are based on observation and designed to exclude initially
displaced normal structures which have returned to their usual position.
❖ The CTV for ISRT will generally be larger than that for INRT because of the lack
of optimal imaging information. (pz)
ITV:
Target motion should be accounted for using an ITV as defined in the ICRU Report 62
as the CTV with a margin to consider organ motion for an individual patient.
A 4-D CT simulation can be useful to obtain the ITV margins.
If unavailable, 1.5- to 2-cm margins may be necessary in the chest or upper
abdomen where respiratory movements are significant. (pz)
(may be in dobbs this ITV margin is incorporated within GTV-CTV margin ?)
GTV to CTV/ITV margin should be at least 1–2 cm in gastric NHL (nc)
PTV:
Additional 5mm (nc)
CTV-PTV margin of 5–10 mm in 3D is added according to anatomical site and
departmental set-up error measurements. (dobbs)
Dr. Asad R10

For NLPHL: (nc)

➢ Patients with nodular lymphocyte-predominant Hodgkin lymphoma NOT receiving
chemotherapy represent a unique group.
➢ Involved lymph nodes should still be present and contoured as GTV.
➢ The lymph node chain where the involved nodes are located should be contoured on
the axial image as the CTV (to include the GTV) and should be extended to include
interruptions between the involved nodes and extended superiorly and inferiorly 2–
4 cm.
➢ In a recent poll of radiation oncology lymphoma experts, the majority (>60 %) felt
the extension should be 4 cm
Irradiation of residual mass after chemotherapy for advanced disease: (ev)

➢ GTV is the residual mass after chemotherapy.
➢ CTV encompasses all pre-chemotherapy lymphoma involvement
➢ Usually 1 cm margin is sufficient, but in the chest and upper abdomen, a larger margin
in the superior-inferior direction may be needed to compensate for respiratory motion.
Mantle RT
Included area:
➢ Bilateral cervical,
➢ supraclavicular,
➢ infraclavicular,
➢ hilar,
➢ mediastinal
➢ axilla lymphatics
Dr. Asad R10

❖ Mini mantle : mediastinal and hilar regions are not included.

❖ Modified mantle : axillary lymph nodes are not included.
Simulation
✓ performed in the supine position with maximum extension of the head and arms above
the head or arms at a 90° angle towards the side, or in the anatomical position with
hands on the waist (akimbo position)
✓ Neck should be at maximum extension.
✓ Extension should be in a position where the chin is in the
same plane as the mastoid process and external occipital
protuberance
✓ This ensures the exclusion of the oral cavity and teeth
from the RT fields, and decreases the dose to the mandible
Borders of Mantle RT:

➢ Superior : chin–mastoid process tip line
➢ Inferior : T9–10 or T10–11 intervertebral space (diaphragmatic dome)
[pericardial involvement or epicardial LAP (+) → T11–T12
intervertebral space]
➢ Lateral : includes axilla
→ All palpable lymph nodes should be marked with wires.
→ Planning is usually performed at SSD=100 cm. However, if the field size is more than
the maximum field size of the treatment machine, the SSD can be increased during
simulation
→ Central axis is usually at the sternal notch or close to it.
→ Central axis and the points 10 cm to the right and left of it and the inferior border should
be marked with a tattoo to check during the daily set-up and to allow for the possibility
of infradiaphragmatic RT at later stages.
Dr. Asad R10

Mantle RT field shielding blocks

✓ Lung blocks: made separately for anterior and posterior
✓ Humeral heads are shielded both anteriorly and posteriorly.
✓ Larynx is shielded.
✓ Heart below hilar level is shielded without including the mediastinal region both
anteriorly and posteriorly.
✓ Spinal cord is shielded in the midline.
✓ A small block is put at the inferior border to the spinal cord posteriorly.
✓ Oral cavity is protected if the superior border includes the oral cavity
Inverse Y R T
Dr. Asad R10

Dose and indication of radiotherapy in Hodgkin lymphoma:

Combined Modality Therapy (CMT)
Non-bulky disease (stage I–II):
20–30 Gy (if treated with ABVD);
1.5–2.0 Gy per fraction
Non-bulky disease (stage IB–IIB):

30 Gy; 1.5–2.0 Gy per fraction
Bulky disease sites (all stages):

30–36 Gy; 1.5–2.0 Gy per fraction
Sites of Deauville 4–5 and partial response (PR) to chemotherapy:

36–45 Gy
ISRT Alone (uncommon, except)

Involved regions:
30–36 Gy (the dose of 30 Gy is mainly used for NLPHL);
1.5–2.0 Gy per fraction
Uninvolved regions:
25–30 Gy; 1.5–2.0 Gy per fraction.
ISRT for NLPHL
includes extension to clinically relevant initially uninvolved
nodes.
Palliative RT: 4–30 Gy
From Nancy:
Condition Dose of RT
Pediatric patients slow response 21 Gy
or bulky mediastinal mass
early stage (I–IIA) non- with a complete response (by may do well with an
bulky disease CT scan criteria) after 2 cycles additional 2 cycles
of ABVD of ABVD without any
radiation
Other stages Patients who do not meet the should receive 30–36 Gy
entry criteria for GHSG (1.8–2 Gy/fraction) as
protocol consolidation following
chemotherapy
Patients with residual PET higher doses of radiation to
avid disease > background 39.6–45 Gy
level of the liver
(Deauville criteria 4 or 5)
NLPHL As definite RT 30–36 Gy
Dr. Asad R10

OAR doses and toxicities for ISRT(NCCN)

Dose Recommendation
OAR Toxicity
(1.5–2 Gy/fraction)
Mean <8 Gy (recommended) Major adverse cardiac
Heart
Mean <15 Gy (acceptable) events
Aortic and mitral valves Dmax <25 Gy Valvular heart disease
Tricuspid and pulmonic
Dmax <30 Gy
valves
Mean <8 Gy (recommended)
Left ventricle Heart failure
Mean <15 Gy (acceptable)
Pericardium
D100 (heart) <5 Gy Pericarditis
Thorax Coronary vessels
LAD V15 Gy <10%
including the left main,
LCx V15 Gy <14%
left anterior
Coronary vessels (total)- Mean <7 Major adverse cardiac
descending (LAD), left
Gy events
circumflex (LCx), and
Minimize the maximum dose to
right
individual coronary arteries
coronary artery (RCA)
Mean dose <13.5 Gy
Lungs V20 <30% Pneumonitis
V5 <55%
Mean <15 Gy
Liver V20 <30% Hepatic toxicity
V30 <20%
Stomach Dmax <45 Gy Ulceration
Mean <10 Gy
Late infections
Spleen V5 ≤30%
Lymphopenia
V15 ≤20%
Abdomen Minimize volume >36 Gy

Pancreas Diabetes
(especially to pancreatic tail)
Diarrhea
V15 <120 cc
Small bowel Obstruction,
Dmax <45 Gy
ulceration, fistula
Mean <8 Gy
V10 <30%
Kidneys Renal insufficiency
V20 <15% (recommended); <25%
(acceptable)
V5: ALARAc Acute cytopenias

Bone marrow V10 <50% Chronic cytopenias
Others V25 <25%
Long bone V40 <64% Fracture
Active bone marrow can be delineated using various imaging modalities and is most
abundant in the pelvic bones, thoracic-lumbar spine, and sacrum.
Dr. Asad R10

Chance of 2nd malignancy after HL radiotherapy: (NCCN)

Dose Recommendation
OAR Secondary Malignancy
(1.8–2 Gy/fraction)
Minimize volume >4 Gy Breast cancer
Breast
(ideally <10%) (adenocarcinoma)
Esophagus Minimize volume >30 Gy Esophageal cancer
Stomach Minimize volume >25 Gy Gastric cancer
Pancreas Minimize volume >5–10 Gy Pancreatic cancer
A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold
increased riskRisk increased to 8-fold with a dose of more than 40 Gy
Secondary cancers:
✓ MOPP regimen and mantle RT causes secondary leukemias and solid tumors.
✓ The most common secondary malignancy following HL is lung cancer. Both CT withm
alkylating agents and RT are associated with a 10-fold increased relative risk of lung
✓ cancer. Smoking can further increase the risk.
✓ MDS/AML(Myelodysplastic syndromes / acute myelogenous leukemia) is usually
seen in the first 3-8 years following treatment for Hodgkin lymphoma. MOPP
(mechlorethamine) incidence 5%, ABVD <1%.
✓ Exposure to epipodophyllotoxins (etoposide and teniposide) may causes AML,
develops within 3 years.
✓ Mantle RT with < 30 yrs of age – 19 fold increase risk of ca breast. If RT to chest in <
15 yrs age, risk increases to 136.
✓ MOPP regimen – increase risk for ca breast.
✓ Stanford regimen -- increased risks of developing melanoma, non-Hodgkin
lymphoma,
✓ soft-tissue sarcoma, salivary gland cancers, pancreatic cancers, and thyroid cancers.
✓ Risk of second malignancy from CT alone is lower and affects fewer anatomic sites
than combined treatment modalities.
Fertility:
Pelvic radiotherapy with lymphoma doses will cause infertility in most young people:
for males sperm banking is effective but for women surgical oophoropexy and,
if possible, cryopreservation of ovarian tissue are advised.
Growth:
Growth retardation in children after radiotherapy includes limited height but also, for
instance, thinning of the neck muscles and shortening of the clavicles from
neck treatment
Lhermitte’s syndrome
is a transient numbness, tingling (paresthesia) or an ‘electric shock’-like sensation in
the arms or legs upon flexion of the neck following mantle or neck irradiation from 2
to 4 months afterwards. It may be due to transient demyelination of the spinal cord due
to damage to oligodendrocytes but does not lead to permanent damage / radiation
myelitis, and it does not require treatment.
Depending upon site of RT other common chronic complication are
coronary artery disease, chronic pericarditis, pancarditis, valvular heart disease,
avascular necrosis of bone
Dr. Asad R10

Follow-up After Completion of Treatment Up to 5 Years:

✓ It is recommended that the patient be provided with a treatment summary at the
completion of therapy, including details of RT, organs at risk (OAR), and cumulative
anthracycline dosage given.
✓ Follow-up with an oncologist is recommended and should be coordinated with the
primary care physician (PCP), especially during the first 5 y after treatment to detect
recurrence, and then annually due to the risk of late complications including second
cancers and cardiovascular disease.
✓ Late relapse or transformation to large cell lymphoma may occur in NLPHL.
Interval Duration
History and Every 3–6 months for 1–2 years, then
physical examination Every 6-12 months until year 3, then
Annually Continue
CBC, platelets, ESR as clinically indicated
(if elevated at time of initial
diagnosis), chemistry profile
TSH If neck irradiated at least annually
neck/chest/abdomen/pelvis Consider no more often than every 6 for the first 2 years
CT scan with contrast months
as clinically indicated After 2 years
FDG-PET/CT only if last FDG-PET was
Deauville 4–5, to confirm complete
response
FDG-PET should not be done routinely due to risk for false positives.
Management decisions should not be based on FDG-PET scan alone; clinical or pathologic
correlation is needed
Counseling:
✓ Reproduction, ✓ breast self-examination,
✓ health habits, ✓ skin cancer risk, end-of-
✓ psychosocial, treatment discussion.
✓ cardiovascular,
*** Infection control after treatment:

✓ Patients undergone splenectomy are predisposed to bacterial sepsis secondary
to encapsulated microorganisms (especially Streptococcus pneumoniae).
✓ Empiric antibiotic therapy should be given. Influenza vaccination annually may help
to reduce the incidence and/or complications of influenza in patients who have received
bleomycin or chest radiation therapy
CT induced Infertility:
MOPP regimen causes
✓ permanent infertility in at least 80% of males and
✓ approximately 50% of females;
Escalated BEACOPP regimen -- 100% of patients treated.
ABVD and Stanford V regimens -- lower risk of permanent sterility.
Dr. Asad R10

Toxicity of ABVD regimen-

Acute toxicity is marked (alopecia is usual, nausea, myelosuppression, constipation,
painful veins, pulmonary fibrosis from bleomycin which is fatal in 1–30%, highest in
elderly patients), but there is minimal risk of infertility or leukemia with ABVD, so this
is standard treatment.
HL during pregnancy:
❖ 4th most common cancer occurs during pregnancy
For staging:
Staging should avoid exposure to ionizing radiation, using MRI or USG in preference
Treatment:
→ RT is potentially teratogenic during the first trimester. Above a dose of 0.1 Gy to the
fetus there is a risk of inducing an abnormality.
→ Chemotherapy has an unquantified risk of teratogenesis or carcinogenesis to the fetus.
Treatment options
1st trimester Immediate therapeutic terminations of pregnancy and then,
start treatment.
If patient wants to continue pregnancy:

Low dose localized radiotherapy (10-36 Gy) above the
diaphragm with abdominal shielding and
single agent chemotherapy (vinblastine)
may control symptoms for a few weeks.
2nd trimester and Treatment is postponed until delivery is induced at 32–34

3rd trimester weeks
If the disease is life threatening (advanced stage, infra

diaphragmatic lymphadenopathy), then
combination chemotherapy with ABVD is the best option,
the risk of carcinogenesis or infertility in the child should be
low with ABVD
RT after delivery
Patients who have been successfully treated for Hodgkin’s disease should be advised
to avoid pregnancy for 2 years after the end of treatment, because after this the risk
of relapse falls markedly. Subsequent pregnancy does not increase the risk of relapse.
Mothers are advised not to breast feed during treatment.
Dr. Asad R10

Non-Hodgkin Lymphoma
➢ Non-Hodgkin lymphomas (NHLs) are neoplastic transformations of B, T, and
natural killer (NK) cells.
➢ Although NHLs and Hodgkin lymphoma (HL) both frequently involve
lymphohematopoietic tissues, their biologic and clinical behaviors are distinct
➢ furthermore, although both are among the most sensitive malignancies to radiation and
cytotoxic therapy, their cure rates also differ.
Incidence and epidemiology:

➢ According to GLOBOCAN 2020:
➢ NHL is
✓ 11th most common malignancy and
✓ 11th most common cause of cancer related death
➢ Responsible for About 5,44,000 new cases and About 2,60,000 cancer related death
➢ In USA there is 77000 new cases and 4% are females and 5% are males
➢ This is more than eight times the incidence of HL.
➢ There is a male predominance and a higher incidence for Caucasians than for African
Americans
➢ There are striking differences in the age-dependent incidence of NHL by histologic
subtype:
→ In children, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL),
and lymphoblastic lymphoma (the tissue equivalent of acute lymphoblastic
leukemia) are most common.
→ Although DLBCL is also the most common histologic subtype in adults, the
indolent lymphomas (small lymphocytic lymphomas [SLLs] and follicular
lymphomas [FLs]) are extremely rare in children
According to WHO:
There are five main categories of lymphoid neoplasms defined by the WHO:
1. precursor B- and T-cell neoplasms,
2. mature B-cell neoplasms,
3. mature T-/NK-cell neoplasms,
4. HL, and
5. immunodeficiency-associated lymphoproliferative disorders
Each category includes what are considered to be unique biologic entities; unlike solid
tumors, they are not further classified or grouped by grade, prognosis, or clinical
behavior
But, traditionally (?) B cell or T cell NHL can be classified as

➢ Indolent/Low grade
➢ Aggressive/High grade
➢ Very Aggressive
based on several factors, including (net)
Indolent/Low grade Aggressive/High grade
Symptoms often causes few symptoms, and cause more severe
these may be mild symptoms, such as fever,
night sweats, and weight
loss.
Dr. Asad R10

Growth rate grows slowly over a period of years,grows more rapidly,

sometimes over a period of
weeks or months.
Size and typically causes enlargement of the often affects multiple lymph
location of the lymph nodes in a limited number of nodes throughout the body.
lymph nodes locations,
Spread to other tends to stay localized to the lymph can spread to other organs,
organs nodes such as the bone marrow,
liver, or lungs.
Indolent/Low grade Aggressive/High grade

Prognosis better prognosis than aggressive Aggressive NHL requires
NHL, with many patients living for prompt and aggressive
many years with minimal treatment. treatment, and the prognosis
can be more uncertain.
KI 67 Less then 30-45% More then 30-45%
Low grade NHL High grade NHL

1. Diffuse large B cell lymphoma
(DLBCL)
2. Mantle cell lymphoma
1. Follicular lymphoma (Grade – 1,2)
3. Peripheral T cell lymphoma
2. Marginal Zone lymphoma
4. Follicular lymphoma (grade 3)
3. Mycosis fungoides.
5. Burkitt’s lymphoma
6. Primary CNS lymphoma
7. Lymphoblastic lymphoma
From Nancy:
Indolent Aggressive Highly aggressive
Follicular lymphoma Follicular lymphoma Burkitt’s Lymphoma
(grades I and II) (grade III)
Marginal zone B-cell Diffuse large B-cell Precursor B-cell or T-
lymphoma: extra-nodal lymphoma (DLBCL) cell Lymphoblastic
(MALT lymphoma), lymphoma/
nodal (monocytoid), Splenic leukemia
Small lymphocytic Mantle cell lymphoma
Lymphoma
T-cell
granular lymphocytic lymphoma
From evidenced base:

Low grade Intermediate grade High grade
Follicular (grade 1–2), Follicular (grade 3), Burkitt’s lymphoma,
CLL, Mantle cell, lymphoblastic
MALT, DLBCL,
Mycosis fungoides T/NK cell,
Peripheral T-cell lymphoma,
Anaplastic large cell.
Dr. Asad R10

B- and T-cell development and cell of origin of lymphomas:
T cell Lymphoma
The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:
➢ T-cell chronic lymphocytic leukemia/prolymphocytic leukemia
➢ T-cell granular lymphocytic leukemia
➢ Mycosis fungoides/Sézary syndrome
➢ Peripheral T-cell lymphoma, not otherwise characterized
➢ Hepatosplenic gamma/delta T-cell lymphoma
➢ Subcutaneous panniculitis-like T-cell lymphoma
➢ Angioimmunoblastic T-cell lymphoma
➢ Extranodal T-/NK-cell lymphoma, nasal type
➢ Enteropathy-type intestinal T-cell lymphoma
➢ Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+)
➢ Anaplastic large cell lymphoma, primary systemic type
➢ Anaplastic large cell lymphoma, primary cutaneous type
➢ Aggressive NK-cell leukemia
Dr. Asad R10

Most cases of aggressive B-cell NHL do not have a well-defned etiology.

Recent work has shown that the lifetime risk for many cancers correlates with the
total number of divisions of normal self-renewing cells (ad)
Exposures and Diseases (Risk factors) Associated with Non-Hodgkin Lymphoma
➢ Infectious agents
➢ Environmental exposures
➢ Occupational exposures:
➢ Prior chemotherapy and/or radiation therapy
➢ Inherited Immunodeficiency States
➢ Acquired Immunodeficiency States
➢ Autoimmune and Inflammatory Disorders
➢ Family History
Infectious agents:(dv)
Associated NHL
Virus Epstein-Barr virus (EBV) most commonly associated with a variety of B-cell
NHLs, including
✓ endemic, sporadic, and AIDS-associated
Burkitt’s Lymphoma;
✓ lymphomas that arise in the setting of
immunosuppression, including after organ
transplantation and treatment of
autoimmune diseases;
✓ extranodal NK cell and T-cell lymphomas
that involve the upper aerodigestive tract,
✓ small number of other unusual and
uncommon T-cell malignancies
human T-cell adult T-cell leukemia-lymphoma (ATLL) seen in
lymphotropic virus type 1 the Caribbean and Japan
(HTLV-1)
Human herpes virus 8 primary effusion lymphoma (PEL), where the
(HHV-8) viral genome is found within tumor cells in virtually
100% of cases
Bacterial Chronic hepatitis B increased risk of NHL
infection weak association with splenic MZL
Helicobacter pylori Gastric extranodal MZLs
Chlamydia psittaci Ocular adnexal MZL
Campylobacter jejuni Mediterranean lymphoma,
Alpha heavy chain diseas
The NHLs that occur in the context of immunosuppression or immunodeficiency, including

HIV-1 infection, are frequently associated with EBV
Dr. Asad R10

Environmental exposures:
✓ There is controversial evidence that certain chemical exposures, specifically the
herbicide phenoxyacetic acid, increase the risk of NHL.
✓ Other potential environmental associations include exposure to (dv)
▪ arsenic,
▪ pesticides,
▪ fungicides,
▪ chlorophenols,
▪ organic solvents,
▪ halomethane,
▪ lead,
▪ vinyl chloride, and
▪ asbestos.
Occupational exposures:
associated with an increased risk include
✓ agricultural work,
✓ welding, and
✓ work in the lumber industry
Prior chemotherapy and/or radiation therapy:

➢ NHL has been observed as a late complication of
prior chemotherapy and/or radiation therapy.
➢ Specifically, patients with HL treated with
radiation therapy and chemotherapy exhibit an
increased risk of developing secondary DLBCL.
Inherited Immunodeficiency States (dv)

➢ Klinefelter syndrome
➢ Chédiak-Higashi syndrome
➢ Ataxia telangiectasia
➢ Wiskott-Aldrich syndrome
➢ Common variable immunodeficiency
➢ X-linked lymphoproliferative diseases
➢ Autoimmune lymphoproliferative disease
➢ Bloom syndrome
The rare inherited immunodeficiency diseases (X-linked lymphoproliferative syndrome,
Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia,
and common variable immunodeficiency syndrome) are complicated by highly aggressive
lymphomas
Acquired Immunodeficiency States

➢ Acquired agammaglobulinemia
➢ HIV-1 infection
➢ Iatrogenic
➢ Multicentric Castleman disease
Dr. Asad R10

** Theincidence of NHL is nearly 100-fold increased for patients undergoing organ

transplantation necessitating chronic immunosuppression and is greatest in the first
year posttransplant.
*** The NHLs that occur in the context of immunosuppression or immunodeficiency,
including HIV-1 infection, are frequently associated with EBV
Autoimmune and Inflammatory Disorders
➢ Rheumatoid arthritis
➢ Autoimmune hemolytic anemia
➢ Systemic lupus erythematosus
➢ Sjögren syndrome
➢ Hashimoto thyroiditis
➢ Acquired angioedema
➢ Inflammatory bowel disease
➢ Celiac disease
Histologically, DLBCLs are most frequently associated with immunosuppression and

autoimmune diseases, although almost all histologies can be seen.
Family History:
✓ An increased risk of NHL has been observed in first-degree relatives with NHL, HL, or
chronic lymphocytic leukemia (CLL).
✓ In large database studies, about 9% of patients with lymphoma or CLL have a first-
degree relative with a lymphoproliferative disorder.
Chromosomal Translocations and Oncogene Rearrangements

➢ lymphomas frequently have chromosomal rearrangements that join these sites of DNA
breakage to a proto-oncogene (Table 67.3), converting it to an oncogene under the
control of Ig or TCR gene enhancer/ promoter elements that are highly active in
lymphoid cells.
➢ Examples of this type of event include
❖ the (8;14)(q24;q32) translocation in BL, involving the MYC proto-
oncogene and the IgH gene;
❖ the (14;18)(q32;q32) translocation in FL, involving the BCL2 proto-
oncogene and the IgH gene; and
❖ the (11;14)(q13;q32) translocation in mantle cell lymphoma (MCL),
involving the cyclin D1 (CCDN1) protooncogene and the IgH gene.
Dr. Asad R10

Genetic Features of B- and T-cell Lymphomas

Genetic Feature Genes Lymphoma
t(8;14) MYC/IgH
t(2;8) MYC/Igκ Burkitt lymphoma
t(8;22) MYC/Igλ
Mantle cell lymphoma;
t(11;14) BCL1 (CCND1)/IgH
Multiple myeloma
t(14;18) BCL2/IgH Follicular lymphoma;
t(3;14) BCL6/IgH Diffuse large B-cell lymphoma
t(11;18) API2/MALT1
t(1;14) BCL10/IgH
MALT lymphoma
t(14;18) MALT1/IgH
t(3;14) FOXP1/IgH
Trisomy 3 Unknown
Splenic marginal zone lymphoma
7q21 deletion CDK6
Chronic lymphocytic
leukemia/small lym
11q23 deletion ATM
phocytic lymphoma;
13q14 deletion MIR15A/MIR16-1
del(17p) and del(13q)
17p13 deletion TP53
also in multiple
Trisomy 12 Unknown
myeloma; del(11q) also
in T-PLL
Lymphoplasmacytic
6q21 deletion Unknown
lymphoma
Mediastinal large B-cell
9p gain JAK2, PD-L1, PD-L2
lymphoma
inv(14)
TCRα/TCL1 T-PLL
t(14;14)
t(2;5) NPM1/ALK
t(1;2) TPM3/ALK
t(2;3) TFG/ALK ALCL-ALK-positive
t(2;17) CTLC/ALK
inv(2) ATIC/ALK
inv(3) TBL1XR1/TP63 ALCL-ALK-negative
DUSP22/FRA7H
t(6;7)
DUSP22-IRF4 ALCL, cutaneous
Trisomy 3 Unknown Angioimmunoblastic
Trisomy 5 Unknown T-cell lymphoma
Isochromosome Hepatosplenic T-cell
Unknown
7q lymphoma
Dr. Asad R10

Disease presentation of NHL: (dv)

lymphadenopathy:
➢ More than two-thirds of patients with NHL present with persistent painless peripheral
lymphadenopathy.
➢ At the time of presentation, a differential diagnosis of generalized lymphadenopathy
necessitates the exclusion of infectious etiologies such as
▪ bacteria (including mycobacteria),
✓ viruses (e.g., infectious mononucleosis, cytomegalovirus, hepatitis
B, HIV), and
✓ parasites (toxoplasmosis);
▪ inflammatory and autoimmune diseases; and
▪ metastatic malignancies.
➢ It is generally agreed that a lymph node larger than 1.5 cm × 1.5 cm that is not
associated with a documented infection and that persists longer than 4 weeks
should be considered for a biopsy
➢ A biopsy should be performed immediately for patients with other
findings suggesting malignancy (e.g., systemic complaints or B symptoms, such as
fever, night sweats, weight loss).
➢ The involvement of Waldeyer ring, epitrochlear, and mesenteric nodes are more
frequently observed in patients with NHL than in patients with HL.
Systemic complaints
➢ About 40% of all patients with NHL present with systemic complaints.
➢ Includes fever, night sweats, weight loss
➢ B symptoms are more common in patients with aggressive histologies, with frequencies
approaching 50%. Less common presenting symptoms, occurring in <20% of patients,
include fatigue, malaise, and pruritus.
Thoracic, abdominal, and/or extranodal symptoms.

➢ These symptoms are presented on the basis of site of involvement and presented as:
▪ mediastinal adenopathy: persistent cough, chest discomfort,
▪ organomegaly
▪ primary cutaneous lesions,
▪ testicular masses,
▪ acute spinal cord compression,
▪ solitary bone lesions,
▪ headache, lethargy, focal neurologic symptoms, seizures, and paralysis.
▪ Rarely, do patients present with unexplained anemia and associated
symptoms
Dr. Asad R10

Investigations of NHL:
➢ Biopsy of any palpable LN/mass/skin lesion and IHC
biopsies in conjunction with appropriate ancillary techniques for the differential
diagnosis including: (NCCN)
→ immunohistochemistry [IHC],
→ flow cytometry,
→ molecular analysis to detect immunoglobulin (Ig) gene rearrangements,
karyotype or
→ fluorescence in situ hybridization [FISH] for major
translocationsa) may be sufficient for diagnosis
➢ Laboratory studies should be obtained, including
▪ Complete blood count,
▪ routine chemistries,
▪ liver function tests, and
➢ serum protein electrophoresis to assess the presence of monoclonal paraproteins.
➢ serum β2-microglobulin level and
➢ serum lactate dehydrogenase (LDH)
As independent prognostic factors
➢ A bone marrow biopsy
should be considered for staging and prognostic purposes depending on the
disease histology and the results of other laboratory and staging studies.
➢ Imaging studies depend on the NHL subtype and the clinical presentation. Chest,
abdominal, and pelvic computed tomography (CT) scans are essential for accurate
staging to assess lymphadenopathy for indolent lymphomas.
➢ FDG-PET scanning
✓ is highly sensitive for detecting both nodal and extranodal sites involved by
NHL.
✓ PET scanning is particularly useful for aggressive lymphomas, including BL,
▪ DLBCL,
▪ plasmablastic lymphoma, and the
▪ aggressive T-cell lymphomas,
✓ but is less reliable in lower grade histologies specifically MZLs.
✓ PET has been utilized more in follicular NHL, where bone marrow
involvement is detected and may impact PFS and OS
➢ CSF examination:
May need if there is neurologic signs or symptoms or a form of NHL. May
also require in NHL involving the paranasal sinuses, testes, epidural space,
and highly aggressive histologies like Burkitt’s lymphoma
Dr. Asad R10

Staging and Prognostic Systems in NHL: (dv)

➢ The Ann Arbor staging
system developed in 1971 for
HL was adapted for staging
NHLs
➢ The concept of staging has
less impact in NHL than in
HL.
➢ Only a minority of patients
with indolent and aggressive
NHL have localized disease
at diagnosis,
➢ there is little therapeutic
benefit to distinguishing
between stage III and stage IV
disease because the treatment
options are identical.
➢ Staging in NHLs, therefore,
is done to identify the
minority of patients who can be treated with local therapy or combined modality
treatment, and to stratify within histologic subtypes to determine the prognosis and
assess the impact of treatment.
➢ Given the similarities in treatment and outcome, in the Lugano Classification.
✓ stage I and II disease have been combined under the title “limited” stage disease,
✓ stage III and IV have been combined under the title of “advanced” disease
***for details of Lugano Classification please see Hodgkin Lymphoma part.
International Prognostic Index (IPI) in NHL: (dv)

Probably more important than staging is the International Prognostic Index (IPI), which
provides risk stratification
International Prognostic Index for NHL:
Factors
Age older than 60 y
LDH >upper limit normal
ECOG performance status ≥2
Ann Arbor stage stage III or IV
Number of extranodal disease sites greater than one
No. of Factors Risk Group 3-y EFS (%) 3-y PFS (%) 3-y OS (%)
0–1 Low 81 87 91
2 Low Intermediate 69 75 81
3 High Intermediate 53 59 65
4–5 High 50 50 59
Dr. Asad R10

International Prognostic Index (IPI) in Follicular Lymphoma: (dv)

A similar predictive model has been developed for FL based on the analysis of over 4,000
patients with follicular NHL, known as the Follicular Lymphoma International Prognostic
Index or FLIPI
Factors
Age older than 60 y
Hb level <12 g/dL
Number of extranodal disease sites greater than FOUR
** Hb level is included instead of ECOG, number of extra nodal site is four here.
No. of Factors Risk Group 5-y OS (%) 10-y OS (%)

0–1 Low 91 71
2 Intermediate 78 51
3–5 High 52 59
✓ Similar disease-specific IPIs have been developed for MCL and peripheral T-cell
lymphoma (PTCL). These prognostic indices take into account the proliferative index
and cell surface markers, respectively
✓ Restaging after treatment is typically done 6 to 8 weeks following the completion of
chemotherapy (or chemoimmunotherapy), or 8 to 12 weeks after the completion of
radiotherapy (RT) or combination chemotherapy and RT, to assess disease response to
treatment.
In next part, various types of NHL treatment and their special features are discussed.
Information collected from NCCN, devita12th etc
Dr. Asad R10

Follicular Lymphoma
➢ Follicular lymphoma (FL) is a neoplasm composed of centrocytes and centroblasts
that are derived from the germinal center of lymphoid follicles (ad)
➢ FLs are malignant counterparts of normal GCBs (Germinal Center of B cell). (dv)
➢ FL recapitulates the architecture of normal GCs of secondary lymphoid follicles.
➢ The neoplastic cells consist of a mixture of (dv)
▪ Centrocytes: small- to medium-sized cells with irregular or cleaved
nuclei and scant cytoplasm
▪ Centroblasts: large cells with oval nuclei, several nucleoli, and
moderate amounts of cytoplasm.
Other points of FL: (dv)

➢ Akin to normal GCs, T cells and follicular dendritic cells are also present in the
malignant follicles;
➢ however, tingible body macrophages, cells that have ingested apoptotic cells that are
common in reactive GCs, are usually absent.
➢ Low-level involvement of the peripheral blood with malignant cells is common;
and morphologically, the nuclei of these cells have notches or cleaves, producing an
appearance that has been referred to as buttock cells
➢ Bone marrow involvement is exceedingly common in FL patients, usually
taking the form of paratrabecular lymphoid aggregates.
Grading of Follicular lymphoma:

➢ The clinical aggressiveness of the tumor correlates with the number of centroblasts
that are present.
➢ The WHO classification grades FL from I to III based on the number of centroblasts
counted per high-power field (hpf): (dv)
❖ Grade I : 0 to 5 centroblasts per hpf;
❖ Grade II : 6 to 15 centroblasts per hpf;
❖ Grade III : >15 centroblasts per hpf.
Grade III has been subdivided into
▪ Grade IIIa : in which centrocytes predominate, and
▪ Grade IIIb : in which there are sheets of centroblasts.
❖ Although the grading system remains in place, clinically, grade I and II and many cases
of grade IIIa FLs are approached similarly
❖ FL grade IIIb is an aggressive disease grouped with DLBCL.
❖ FL grade 3b (ICC)/follicular large B-cell lymphoma (FLBL; WHO) is commonly treated as
DLBCL (BCEL-1). (NCCN)
❖ The management of FL grade 3a is controversial and treatment should be individualized.
❖ Any area of DLBCL in an FL of any grade should be diagnosed and treated as a DLBCL
❖ Differences in molecular genetics, as well as clinical behavior, suggest that FL grade IIIa is
more commonly an indolent disease, whereas grade IIIb is an aggressive disease (dv)
Dr. Asad R10

Large B-cell lymphoma (LBCL) with IRF4/MUM1 rearrangement

➢ It is special subtype of follicular lymphoma. (?)
➢ LBCL with IRF4/MUM1 rearrangement are usually DLBCL but occasionally
are purely FL grade 3b (ICC/FLBL [WHO]) and often DLBCL with FL grade 3b.
(NCCN)
➢ Patients typically present with Waldeyer’s ring involvement and are often
children/young adults.
➢ These lymphomas are locally aggressive but respond well to chemotherapy ± radiation
therapy (RT). They do not have a BCL2 rearrangement and should not be treated as
low-grade FL (NCCN)
Immunophenotype and Genetics:

➢ FL cells typically express
▪ monoclonal Ig light chain,
▪ CD19, CD20, CD10, and BCL6, and
➢ In virtually all cases, FL cells overexpress BCL2.
➢ negative for CD5 and CD23.
From NCCN:
Typical immunophenotype:
✓ CD10+, BCL2+, BCL6+
✓ CD20+,
✓ CD23+/-,
✓ CD43-, CD5-,
✓ Rare cases of FL may be CD10- or BCL2-.
Cytogenetics.
→ Follicular lymphomas bear the t(14;18) translocation that results in up-regulation of
BCL-2 expression. The BCL-2 gene product is considered a potent inhibitor
of apoptosis. (cas)
→ Approximately 85% of FLs have the t(14;18), which drives overexpression of BCL2,
a member of a family of proteins that blocks apoptosis. (dv)
Incidence and etiology:

➢ FL is the second most common lymphoma diagnosed in the United States and
Western Europe, making up
▪ approximately 20% of all NHLs and
▪ 70% of indolent lymphomas.
➢ The median age at diagnosis is 64 years,
➢ there is a slight female predominance.
➢ The incidence is increased among relatives of persons with FL
Risk of FL increased in persons who have (ad)
✓ a first-degree relative with NHL or
✓ who worked as a spray painter and
✓ among women with Sjögren syndrome
Dr. Asad R10

Clinical Features:
➢ Patients with FL generally present with asymptomatic lymphadenopathy, which
often waxes and wanes over years
➢ Less than 20% of patients present with B symptoms or an increased serum LDH.
➢ involvement of other nonlymphoid organs is uncommon.
➢ Central nervous system (CNS) disease is rare. Urgent situations, such as superior vena
cava syndrome or spinal cord compression, are rare (ad)
➢ Bone marrow involvement is present in 70% of patients (dv)
➢ In a small subset of patients, the disease presents in the intestine, particularly the
duodenum; such tumors usually present at an early stage and have a favorable prognosis
➢ At diagnosis, approximately 15% to 20% of patients with FL have early-stage disease
(stages I and II). (ad)
➢ Approximately 80% to 90% of patients with FL present with advanced-stage
disease (stage III or IV) with generalized lymphadenopathy. (ad)
Transformation to aggressive lymphoma:
❖ About 2% to 3% of patients with FL per year undergo transformation to aggressive
B-cell lymphoma, usually diffuse large B-cell lymphoma (DLBCL), with a life-time
risk of 11%. (ad)
❖ However not all cases are typically biopsy-proven, diagnosis of transformation being
sometimes based on clinical, laboratory and radiological features:
❖ Histologic transformation (HT) of FL to DLBCL occurs in 10% to 70% of patients at a
rate of 1% to 3% per year and is associated with (dv)
➢ the rapid progression of lymphadenopathy,
➢ extranodal disease (besides the marrow),
➢ B symptoms,
➢ elevated serum LDH, and
➢ hypercalcemia
• Spontaneous regression of lymphadenopathy can occur in FL patients. Such

regressions, however, are usually partial and are typically short-lived.
Prognosis of FL:
A prognostic model based on clinical features is the FLIPI (as discussed earlier):
Factors
Age older than 60 y
Hb level <12 g/dL
Number of extranodal disease greater than FOUR
sites
FLIPI Pre-Rituximab
No. of Factors Risk Group 5-y OS (%) 10-y OS (%)
0–1 Low 91 71
2 Intermediate 78 51
3–5 High 52 59
**FLIPI was designed pre-rituximab but remained prognostic in rituximab era. (td)
Dr. Asad R10

A modified version of this score, the FLIPI2, evaluated five parameters, with some
overlap of the FLIPI
Factors
Age older than 60 y
Serum b-2 microglobulin elevated
Hb level <12 g/dL
Bone marrow involvement Present
Maximal diameter of lymph node > 6 cm
** in FLIPI2, Serum b-2 microglobulin is replaced with LDH, Bone marrow study and
LN size is included.
FLIPI Pre-Rituximab
No. of Factors Risk Group 5-y OS (%)
0–1 Low 81
2 Intermediate 51
3–5 High 19
➢ The utility of the FLIPI2 model remains uncertain, and it is not used in routine
practice. (dv)
➢ Since the incorporation of rituximab into the mainstream therapy of FL, the FLIPI has
continued to be a useful prognostic model (dv)
M7-FLIPI:
➢ Combining the FLIPI with mutational analysis (known as the M7-FLIPI) has been
examined in a large cohort of FL patients treated with either RCHOP or RCVP.
➢ The mutation status of seven genes—EZH2, ARID1A, MEF2, EP300, FOXO1,
CREBBP, and CARD11—when combined with FLIPI score, identifies high-
and low-risk groups in terms of 5-year failure-free survival.
➢ The failure-free survival for the low-risk patients is 78% at 5 years versus 22% for the
higher-risk patients.
➢ The M7-FLIPI was also able to identify patients at risk for early progression.
Role of PET CT in prognosis: (ad)

➢ PET-CT scan performed at the end of chemoimmunotherapy is considered prognostic.
➢ Response to frontline therapy may inform pursuit of maintenance therapy
given retrospective data suggesting the largest impact of maintenance rituximab
observed among those achieving a partial response to frontline chemoimmunotherapy
Role of grading in prognosis: (dv)

FL tumors are graded from I to III, but grade has limited prognostic utility.
Diagnosis and Investigation of FP:

As mentioned in NHL part, common investigations are
➢ Biopsy and IHC: either ny excision or core
➢ PET CT scan
➢ Imaging
Serum LDH: prognostic significance.
Dr. Asad R10

Serum β2-microglobulin (B2M): prognostic significance.
Bone marrow biopsies:

➢ Bilateral bone marrow biopsies with unilateral aspiration are recommended for
the staging workup because of the patchy nature of involvement.
➢ In FL, the bone marrow characteristically shows a paratrabecular pattern of
involvement. Because the lymphoma cells are associated with stroma and are not easily
aspirated, bone marrow aspirate smears assessed by routine light microscopy may
not be informative.
➢ Flow cytometry and molecular assessment (eg, polymerase chain reaction
[PCR]) of aspirate material can increase the sensitivity of bone marrow
assessment, but in the absence of morphologic abnormalities, positive PCR or flow
findings are traditionally not taken as evidence to warrant assignment of stage IV.
GELF criteria:
High tumor burden in patients with FL is defined by the presence of one or more
Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria; these include:
✓ any nodal, extra nodal mass size >7cm
✓ more then 3 nodal site involvement, each >3cm size
✓ B symptoms
✓ splenomegaly,
✓ pleural effusion,
✓ Ascites
✓ WBC <1000/cumm, platelet >100000/cumm
✓ Lekaemia (malignant cell >5,000/cumm)
*** GELF criteria not important for prognosis, important for treatment decision (?)
Dr. Asad R10

Treatment of Follicular Lymphoma:

❖ Depends on stage, Contiguity, grade
➢ In this section we are discussing about grade I, II, IIIa FL, as grade IIIb is treated as
DLBCL
➢ BCL2-R negative, CD23-positive follicle center lymphoma is not treated as DLBCL
➢ Large B-cell lymphoma (LBCL) with IRF4/MUM1 rearrangement is treated as
DLBCL
Treatment of Early-stage Disease
➢ This group includes Stage I, Stage II
➢ Less than 10% of total case of FL
According to NCCN treatment options are:

Treatment options mentioned in NCCN
Stage I or ISRT (preferred)
Contiguous stage II Or
ISRT
+ anti-CD20 monoclonal antibody (mAb)
± chemotherapy
Or
Anti-CD20 mAb
± chemotherapy in certain circumstances
(for patients with bulky intra-abdominal or mesenteric
>7cm size in stage I disease)
Noncontiguous Anti-CD20 mAbl
stage II ± chemotherapy
± ISRT
Or
Observation
Overall treatment options for early stage FL (Stage I, II) is :

❖ ISRT
❖ combined modality of treatment (CT+ antiCD 20) ± ISRT
❖ Observation
Radiation therapy (ISRT):

➢ Radiation therapy is the treatment of choice for limited-stage FL and results in a 5-
, 10-, and 15-year freedom from treatment failure of 72%, 46%, and 39%, and a 5-, 10-
, and 15-year OS rates of 93%, 75%, and 62%, respectively, with a median survival
of approximately 19 years. (dv)
➢ Several series have reported long-term disease-free survival rates of approximately
35% to 50% for stage I to II patients treated with involved-field radiotherapy (RT), so
it appears that many of these patients are cured, particularly patients with stage I
disease and small disease size (<3 cm). (ad)
➢ The current standard RT dose is 24 Gy with no evidence of benefit for higher doses
as shown in a randomized trial. (dv) [in Nancy this dose mentioned as 24-30 Gy as
indolent variety)
Dr. Asad R10

➢ Adjuvant chemoimmunotherapy or immunotherapy after local RT has been shown

to improve PFS but not OS. (dv)
ISRT is not considered in early stage:

➢ for patients with bulky (>7cm) intra-abdominal or mesenteric stage I disease
(according to GELF criteria)
➢ for elderly patient considering toxicity
➢ for Noncontiguous stage II ISRT can be considered as an additional option after
Rituximab± chemotherapy
AntiCD20mab± chemotherapy:
➢ The integration of chemotherapy with involved- field RT has shown promising results
in some trials. (ad)
➢ Investigators at MDACC prospectively treated 85 patients with stage I or II FL with 10
cycles of COPBleo (cyclophosphamide, vincristine, prednisone, and bleomycin) or
CHOP-Bleo (COP-Bleo plus doxorubicin) and involved-field RT “sandwiched”
after the third cycle. The disease-free survival at 5 and 10 years was 80% and 72%,
respectively—an apparent improvement over results with RT alone (ad)
➢ In addition, a recently published randomized trial showed that systemic therapy with R-
CVP after RT reduced relapse outside radiation fields and significantly improved PFS
in early-stage FL.
➢ Anti-CD20 mAbs include rituximab or obinutuzumab. Obinutuzumab is not
indicated as single-agent therapy (NCCN)
** N.B:
ISRT is the main treatment option in this stage. But in case of bulky (>7cm size) or
non-contagious stage II, ISRT alone is suitable, in this condition start R± CT, then
consider about ISRT later.
Observation:
✓ Observation in early stage FL may be appropriate in circumstances where
potential toxicity of ISRT or systemic therapy outweighs potential clinical benefit
in consultation with a radiation oncologist
✓ this approach is usually reserved for elderly or comorbid patients unable to tolerate
treatment, in light of the limited toxicity of available treatment options.
Dr. Asad R10

Treatment of Advanced-stage Disease

➢ This group include stage III, stage IV
➢ Covers around 90% of total FL patients
Treatment options according to NCCN:

➢ First: Evaluate the indications for treatment according to GELF criteria:
If there is presence of
• any nodal, extra nodal mass size >7cm (Clinically significant bulky
disease)
• more than 3 nodal site involvement, each >3cm size
• B symptoms
• splenomegaly,
• pleural effusion,
• Ascites
• WBC <1000/cumm, platelet >100000/cumm (Clinically significant or
progressive cytopenia secondary to lymphoma)
• Leukemia (malignant cell >5,000/cumm)
If these features are absent:
only observation is enough (as mentioned earlier)
If these features are present:
Systemic chemotherapy
Patients with FL do not require immediate treatment unless they have (dv)
✓ symptomatic nodal disease,
✓ compromised end-organ function,
✓ B symptoms,
✓ symptomatic extranodal disease, or
✓ cytopenias.
Observation done with: (NCCN)

Interval Duration
History and Every 3–6 months for 5 years, then
physical examination and Then Annually As clinically indicated
routine lab investigation
Surveillance imaging with Consider no more often than for the first 2 years
chest/abdomen/pelvis CT every 6 months
scan with contrast No more then annually After 2 years
Surveillance imaging is used for monitoring asymptomatic patients. When a site of
disease can only be visualized on PET-CT scan (eg, bone), it is appropriate to proceed
with PET-CT scans for surveillance
Dr. Asad R10

Rituximab monotherapy vs observation:

➢ In some studies, it is found that
▪ Rituximab induction therapy 375mg/m2 weekly for 4 doses
followed by
▪ maintenance therapy of Rituximab 375mg/m2 2 monthly for 2 weekly
➢ may have better outcome in advanced stage, asymptomatic low-tumor-burden FL [PS
may be improved, OS was same.]
➢ Other studies found no difference in between observation and Rituximab monotherapy.
From NCCN:
➢ Collectively, findings from clinical studies suggest that immediate initial therapy with
rituximab in patients not meeting the modified GELF criteria does not improve OS
and outside the context of clinical trials, observation is still the standard practice for
patients with advanced stage low-tumor-burden FL.
➢ The modified criteria used to determine treatment initiation include:
▪ symptoms attributable to FL (not limited to B symptoms);
▪ threatened end-organ function;
▪ cytopenia secondary to lymphoma;
▪ bulky disease (single mass >7 cm or 3 or more masses >3 cm),
▪ splenomegaly; and
▪ steady progression over at least 6 months
** ascites, pleural effusion is removed from GELF and progression is
added.
❖ Rituximab may be appropriate in patients initially observed and with progression

of low tumor burden disease not meeting GELF criteria. Immediate initial therapy
with rituximab in patients not meeting GELF criteria has not improved overall survival.
Dose: Rituximab mono therapy 375mg/m2 weekly for 4 doses
N.B:
In NCCN, modified GELF criteria is useful to assess if Rituximab monotherapy can be
advised during observation. During the time of observation, if the low grade stage III,
IV low tumor barden follicular lymphoma progresses within 6 month, better to
start Rituximab monotherapy for 4 dose. (?) No need for 2 year maintenance if it is
low tumor burden.
Systemic chemotherapy in advanced stage FL:

❖ When it meets GELF criteria: mainly in case of high tumor burden > 7cm, cytopenia
First-Line Therapy includes:
Preferred regimens (in alphabetical order)
• Bendamustine + obinutuzumab or rituximab
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + obinutuzumabe
or rituximab
• CVP (cyclophosphamide, vincristine, prednisone) + obinutuzumab or rituximab
• Lenalidomide + rituximab
Other recommended regimens
• Lenalidomide + obinutuzumab (category 2B)
Dr. Asad R10

In case of elderly patients, 1st line therapy considering toxicities:

Preferred regimen
• Rituximab (375 mg/m2 weekly for 4 doses)
• Chlorambucil ± Rituximab
• Cyclophosphamide ± Rituximab
First-Line Consolidation or Extended Dosing (optional):

Preferred regimens following chemoimmunotherapy
• Rituximab maintenance 375 mg/m2 one dose every 8–12 weeks for 2 years for patients
initially presenting with high tumor burden (category 1)
• Obinutuzumab maintenance (1000 mg every 8 weeks for 12 doses)
• If initially treated with single-agent rituximab, consolidation with rituximab 375 mg/m2
one dose every 8 weeks for 4 doses
❖ Rituximab maintenance dose is mainly recommended for patients with high tumor
burden following treatment with RCVP and RCHOP. There are no data for rituximab
maintenance following other regimens. (NCCN)
R-CHOP
R Rituximab 375 mg/m2 D1
Repeat cycle every 21 days for 6 cycle
Patient who have response, can receive
Rituximab maintenance 375 mg/m2 3 monthly for 2 years (chu)
Dr. Asad R10

R- CVP
C Cyclophosphamide 400mg/m2 D2-D5
800mg/m2 D1
V Vincristine 1.4mg/m2 (max2) D1
P Prednisolone 100mg/m2 D1-D5
for 6 cycle
Patient who have response, can receive
Rituximab maintenance 375 mg/m2 3 monthly for 2 years
R- Bendamustine
Rituximab 375 mg/m2 D1
Bendamustine 90 mg/m2 D1
for 4 cycle
Lenalidomide + rituximab
Lenalidomide 20 mg/m2 D1-D21
Rituximab 90 mg/m2 D1,8,15,22 of cycle 1 and D1 on cycle 2-5
After completing 6 cycle of RCHOP/ other CT regiments

check the response with PET/CT scan or CT scan
Response assessment In PET CT scan:
Complete response means
✓ Lymph nodes and extralymphatic sites:
Score 1, 2, 3 with or without a residual mass on 5-point scale (5-PS)
✓ Bone marrow: No evidence of FDG-avid disease in marrow
Partial Response:
✓ Lymph nodes and extralymphatic sites:
Score 4 or 5 with reduced uptake compared with baseline.
No new progressive lesions.
At interim these findings suggest responding disease.
At end of treatment these findings may indicate residual disease.
✓ No new lesions
✓ Bone marrow: Residual uptake higher than update in normal marrow
but reduced compared with baseline (diffuse uptake compatible with reactive changes
from chemotherapy allowed).
No response or stable disease
✓ Target nodes/nodal mass and extralymphatic sites:
Score 4 or 5 with no significant change in FDG uptake from
baseline at interim or end of treatment.
✓ No new lesions
✓ Bone marrow: No change from baseline
Dr. Asad R10

Progressive disease:
✓ Target nodes/nodal mass and extralymphatic sites:
Score 4 or 5 with no significant change in FDG uptake from
baseline
✓ New FDG-avid foci consistent with lymphoma rather than another etiology (eg,
infection, inflammation). If uncertain regarding etiology of new lesions, biopsy or
✓ interval scan may be considere
✓ Bone marrow: New or recurrent FDG-avid foci
Response assessment In CT scan (NCCN)
Dr. Asad R10

If there is Complete response:

start observation
If there is partial response/ Progression
Start 2nd line CT with or without Palliative ISRT
** options in 2nd line CT is more or less same with 1st line CT

In NCCN, they add
▪ Tazemetostat (irrespective of EZH2 mutation status)
*** Brentuximab vedotin and ibrutinib are not options for second-line therapy for FL
As EZH2 is one of the most commonly mutated genes in FL, the EZH2 inhibitor
tazametostat was studied in relapsed/refractory FL in a single arm, phase II trial in both
EZH2 mutant and EZH2 wildtype tumors. The ORRs were 69% and 35%, respectively.
After 2nd line CT, if still disease has partial response or progressing:
➢ Consider observation (specially for PR)
➢ Consider 3rd line CT (specially for progressive disease) with palliative ISRT (if RT
not given previously)
➢ Consider T cell directed therapy.
** no definite options of ASCT, even with 3rd line (?)
***after 1st line CT, if FL progresses, Re-biopsy is mandatory before 2nd line/3rd line
therapy, as it may transform into other verity (specially DLBCL)
3rd line CT options mentioned in NCCN:
B-cell kinases are logical targets for therapy in FL. Several phosphoinositide 3-kinase
(PI3K) inhibitors, idelalisib, copanlisib, and umbralisib are all FDA approved for
patients with relapsed and refractory FL. Idelalisib has an overall RR of 57% and
median duration of response of 12.5 months.131,132 Copanlisib and umbralisib have
similar responses to idelalisib. (dv)
Dr. Asad R10

T cell mediated therapy:

Tisagenlecleucel:
✓ T cell is separated from patients
peripheral blood
✓ Then, this T cell is genetically
modified to produce some specific
receptor known as chimeric
antigen receptor. (CAR)
✓ In case of Tisagenlecleucel , this
CAR is anti CD19.
✓ This anti CD 19 receptor
containing T cell will infused back
to patients body, that will destroy
the B cells containing CD 19.
$306,000 Price :D :D :D
Stem cell transplantation in FL: (dv)

✓ The use of either ASCT or alloSCT in FL is controversial and the subject of
numerous clinical trials (dv)
✓ High-dose therapy and autologous stem cell transplantation (ASCT) have been used to
consolidate the first remission for patients with FL. These studies generally preceded
the widespread use of rituximab. With ASCT in the first remission, about 50% of
patients are disease-free at 10 years and beyond following ASCT, but ASCT is
associated with an increased risk of second malignancies, including myelodysplastic
syndrome, acute myeloid leukemia, and solid tumors
✓ Although allogeneic stem cell transplantation (alloSCT) can potentially lead to a cure
for patients with FL, due to the significant treatment-related mortality, it is largely
reserved for patients with relapsed or more refractory disease.
✓ AlloSCT has been investigated in patients with relapsed FL. Both myeloablative and
reduced-intensity conditioning (RIC) approaches have been employed. Unfortunately,
myeloablative conditioning has treatment-related mortality of up to 40%; however,
the relapse rate is <20%
✓ However, for younger patients with more resistant disease, alloSCT remains a
potentially curative option for relapsed FL
Follicular Lymphoma Grade III (dv)

➢ FL grade III has been historically referred to as follicular large cell lymphoma. It is
histologically defined by the presence of >15 centroblasts per hpf.
➢ It is further subdivided into grade IIIa, where centrocytes are present, and grade IIIb,
where there are sheets of centroblasts.
➢ These are further differentiated by the presence of BCL6 rearrangements and the
absence of BCL2 rearrangements in a high fraction of grade IIIb cases.
➢ Although the follicular architecture is intact, the clinical presentation, behavior,
and outcome with treatment in many patients with FL grade IIIb more
closely approximates that of DLBCL.
Dr. Asad R10

Marginal Zone Lymphomas

MZLs are indolent NHLs that include three diseases arising from post-GC marginal zone B
cells: (dv)
❖ Splenic marginal zone B-cell lymphoma (± villous lymphocytes),
❖ extranodal marginal zone B-cell lymphoma of MALT type (MALT-type lymphoma,
or MALT lymphoma), and
❖ nodal marginal zone B-cell lymphoma.
Epidemiology and incidence: (ad)

➢ Marginal zone lymphoma (MZL) is the second most common B-cell–indolent non-
Hodgkin Lymphoma (NHL; <10% of NHL cases in adults).
➢ MZL generally presents at a median age of 60 years old,
➢ women have a slightly increased propensity toward MZL developing compared with
men.
Type Percentage of total NHL cases (ad)

Extranodal MZL of mucosa-associated represents 7% to 8% of all NHLs
lymphoid tissue (MALT lymphoma),
Nodal marginal zone B-cell lymphoma represents approximately 2% of all NHLs
Splenic B-cell marginal zone lymphoma resenting less than 1% of all NHLs.
(SMZL),
Splenic MZL can be associated with circulating lymphocytes with villous cytoplasmic
projections. The entity previously described as splenic lymphoma with villous
lymphocytes is, in most cases, SMZL. (ad)
Immunohistochemistry marker:
Type Marker (Dv)
Extranodal MZL of mucosa-associated express surface Ig and are
lymphoid tissue positive for B-cell markers
✓ CD19,
✓ CD20,
✓ CD79a,
✓ CD22
negative for
✓ CD5,
✓ CD10,
✓ CD23, and
✓ cyclin D1.
Nodal marginal zone B-cell lymphoma express monoclonal surface Ig (IgM, IgG, IgA)
positive for
✓ CD19,
✓ CD20, and
✓ CD79a and
negative for
✓ CD10 and
✓ CD23.
A minor subset of cases is CD5+.
Dr. Asad R10

Marker (Dv)
Splenic B-cell marginal zone lymphoma express monoclonal surface IgM, IgD,
(SMZL), Positive for:
✓ CD19,
✓ CD20.
generally, lack
✓ CD5 and
✓ CD10
CD5 positivity is sometimes seen.
typically, are negative for
✓ CD25,
✓ CD103, and
✓ annexin A1
**SMZL typically, are negative for CD25, CD103, and annexin A1, findings that help to
distinguish splenic MZL from hairy cell leukemia (dv)
From NCCN:
Extranodal MZL of the Stomach CD10-, CD5-, CD20+, cyclin D1-, BCL2- follicles.
Extranodal MZL of Nongastric Sites
CD10-, CD5-, CD20+, CD23-/+, CD43-/+,
cyclin D1-, BCL2- follicles
Nodal Marginal Zone Lymphoma CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and
cyclin D1-, BCL2- follicles.
Splenic marginal zone lymphoma CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and
(SMZL), cyclin D1-, BCL2- follicles, annexin A1, and
CD103- with expression of both IgM and IgD.
**In CD5+ cases, concurrent IHC positivity for cyclin D1 is more compatible with the
diagnosis of MCL. FISH for t(11;14) is helpful to exclude the diagnosis of MCL,
Extranodal Marginal Zone Lymphoma (EMZL)

➢ EMZL, also known as lymphoma of mucosa-associated lymphoid tissue (MALT),
by definition arises in extranodal tissues.
➢ most common site is the stomach,
➢ but EMZL has been described in many organs and tissues, including skin, salivary
glands, lung, small bowel, ocular adnexa, breasts, bladder, thyroid, dura,
and synovium.
Association with:
➢ It has been associated with a variety of chronic inflammatory and infectious conditions,
including
➢ autoimmune diseases such as infections with
▪ Sjögren syndrome and ➢ H. pylori,
▪ Hashimoto thyroiditis, ➢ B. burgdorferi,
➢ Chlamydophila psittaci,
➢ Campylobacter jejuni, and
➢ HCV
Dr. Asad R10

➢ EMZL behaves indolently and is principally observed until symptoms related to

organ impairment become evident; however, in many cases, early-stage disease
treatment with radiation therapy or antibiotic therapy appears to be curative.
Epidemiology of EMZL:
➢ accounts for approximately 5% to 8% of all NHLs
➢ represents 50% to 70% of all MZLs
➢ It is the third most common subtype of NHL after DLBCL and FL.
➢ Nearly half of all EMZL involves the gastric mucosa,
➢ over 60% are associated with an H. pylori infection.
➢ The median age at diagnosis is 60 years,
➢ incidence nearly equal in men and women.
➢ Two thirds of patients present with stage I/II disease.
➢ B symptoms and bone marrow involvement are rare.
➢ EMZL can transform into a more aggressive lymphoma, but this occurs rarely. The
most common transformation is into an ABC-like DLBCL.
chromosomal translocations in EMZL: (ad)

Four chromosomal translocations are well characterized in MALT lymphomas:
→ t (11;18),
→ t (14;18),
→ t (1;14), and
→ t (3;14).
The frequency of these translocations varies by anatomic site of the lymphoma, and
each translocation results in dysregulation of specific genes
This chromosomal translocation can be identified by (NCCN)

→ Karyotype or FISH: t (1;14); t (3;14); t (11;14)
→ FISH or PCR: t (14;18)
Clinical Presentation
✓ The clinical presentation of EMZL depends in large part on the site of the disease.
Gastric and intestinal EMZL may present with symptoms of dyspepsia and abdominal
pain, sometimes with signs and symptoms of bowel obstruction, or, rarely, with
bleeding
✓ Involvement of the salivary and lacrimal glands, on the other hand, can result in a
Sjögren-like syndrome of dry eyes and mouth.
Dr. Asad R10

✓ EMZL involving the ocular adnexa typically presents with painless conjunctival
injection and photophobia, resembling allergic conjunctivitis.
✓ Patients with bronchus-associated lymphoid tissue lymphomas typically are older men
and can have symptoms including cough, fever, and/or weight loss.
✓ At other sites, the disease often presents as an obstructing mass. Some patients are
diagnosed incidentally, either because of imaging studies, or an exam of the eye or GI
tract done for another reason, or as part of an evaluation for a monoclonal gammopathy,
which is present in approximately 25% to 35% of EMZL patients
✓ B symptoms are rare in this disease.
✓ Bone marrow involvement is present in a minority of patients; therefore, cytopenias are
rare, as is disease in the peripheral blood.
Overall Investigation workup in EMZL:

After routine investigation, following inv are advised
➢ LDH
➢ Upper GI endoscopy:
In cases where primary site is thought to be in head/neck or lungs, upper GI
endoscopy should be considered.
➢ Colonoscopy/skin/bronchoscopy biopsy: depending on site
➢ Image guided biopsy
➢ Immunohistochemistry
➢ in case of gastric EMZL: investigation related to H. pylori is done including:
o Assessment of H. pylori by histopathology
o If H. pylori negative by histopathology, then use noninvasive H. pylori testing
▪ stool antigen test or
▪ urea breath test
➢ t(11;18) t(11;18):
Helicobacter pylori (H. pylori) stain (gastric), if positive, then polymerase chain
reaction (PCR) or FISH for t(11;18)
➢ Viral marker:
→ Hepatitis B testing: indicated because of the risk of reactivation with
immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a
patient with no risk factors. For patients with risk factors or previous history of
hepatitis B, add e-antigen
→ Hepatitis C testing: HCV testing should be performed
→ HIV test is advised
➢ Imaging for staging:
→ Staging is done with CT scans of the chest, abdomen, and pelvis, as well
as imaging of the neck, including the parotids and salivary glands, and orbits
with CT or MRI.
→ PET-CT scan especially when ISRT anticipated
➢ Bone Marrow Biopsy: not commonly done.
should be considered for patients with multifocal disease,
Dr. Asad R10

Investigations Useful under certain circumstances:

➢ Molecular analysis to detect:
Ig gene rearrangements; MYD88 mutation status to help differentiate
Waldenström macroglobulinemia (WM) (90%) versus MZL (10%) if
plasmacytic differentiation present
➢ Karyotype or FISH: t (1;14); t (3;14); t (11;14)
➢ FISH or PCR: t (14;18)
Staging of of EMZL of the stomach: comparison of different systems

TNM
Lugano
Staging
Modification of
Lugano Staging System for System
Ann Arbor Tumor Extension
Gastrointestinal Lymphomas Adapted for
Staging
Gastric
System
Lymphoma
Confined to GI tract (Single primary or multiple, noncontiguous)
I1 = mucosa, Mucosa,
IE T1 N0 M0
submucosa submucosa
Stage I
I2 = muscularis IE T2 N0 M0 Muscularis propria
propria,
IE T3 N0 M0 Serosa
serosa
Extending into abdomen
II1 = local nodal T1-3 N1 Perigastric lymph
IIE
involvement M0 nodes
Stage II
More distant
II 2 = distant nodal T1-3 N2
IIE regional lymph
involvement M0
nodes
Penetration of serosa
Invasion of
Stage IIE to involve adjacent IIE T4 N0 M0
adjacent structures
organs or tissues
T1-4 N3 Lymph nodes on
Stage IVb Disseminated
M0 both sides of the
extranodal
diaphragm/distant
involvement
metastases (eg,
or concomitant T1-4 N0-3
IV bone marrow or
supradiaphragmatic M1
additional
nodal involvement
extranodal sites)
** there is no Lugano stage III in gastric lymphoma (?)
Dr. Asad R10

Treatment of Extra nodal MZL of the Stomach (Gastric Lymphoma)

In NCCN:
Treatment options of gastric lymphoma is described as
➢ Stage I1, or I2 or Stage II1 (local nodal involvement)
▪ H. pylori positive, t(11;18) negative or t(11;18) unknown
▪ H. pylori positive, t(11;18) positive
▪ H. pylori negative
➢ Stage II2 (distant nodal involvement) or
Stage IIE or Stage IV (distant nodal, advanced stage)
Treatment of Stage I1, or I2 or Stage II1 (local nodal involvement):

When H. pylori positive, t(11;18) negative or t(11;18) unknown:
➢ Treatment is currently accepted antibiotic therapy for H. pylori
➢ Treatment is based on a PPI taken simultaneously with two antibiotics (from
amoxicillin, clarithromycin and metronidazole) for at least 7 days. High-dose, twice-
daily PPI therapy increases efficacy of treatment, as does extending treatment to 10–
14 days. (Davidson)
After 1st line triple therapy:
➢ Restage at 3 months with endoscopy/biopsy for H. pylori/lymphoma (restage
earlier than 3 months if symptomatic) after antibiotics
Next treatment options depends of repeat endoscopy findings:
repeat endoscopy findings treatment options
H. pylori negative, Follow up endoscopy
Lymphoma negative 3-6 months for 5 years
H. pylori negative, Observe for another 3 months or
Lymphoma positive, Asymptomatic ISRT
H. pylori negative, ISRT
Lymphoma positive, Symptomatic
H. pylori positive, Second-line antibiotic treatment
Lymphoma negative
H. pylori positive, Second-line antibiotic treatment
Lymphoma positive, Stable disease
H. pylori positive, ISRT AND second line antibiotic
Lymphoma positive, treatment
Progressive/symptomatic disease
➢ Once it is H pylori negative, Lymphoma negative, follow up the patient with endoscopy
3-6 monthly for 5 year
➢ If disease reappear, consider ISRT (if previously not given)
➢ If ISRT previously given, first line chemotherapy
When H. pylori positive, t (11;18) Positive:

Preferred treatment option is:
➢ Antibiotic therapy for H. pylori and ISRT (preferred)
Another option is:
➢ Antibiotic therapy for H. pylori and Rituximab (if ISRT is contraindicated)
Next: Restage at 3 months with endoscopy/biopsy for H. pylori/lymphoma (restage
earlier than 3 months if symptomatic)
Dr. Asad R10

Repeat endoscopy findings treatment options

H. pylori negative, Follow up endoscopy
Lymphoma negative 3-6 months for 5 years
H. pylori positive, Consider Second-line antibiotic treatment
Lymphoma negative
H. pylori negative,
Lymphoma positive, 1st line Chemotherapy for marginal zone lymphomas
H. pylori positive,
Lymphoma positive,
Dose:
When H. pylori negative stage I, II1:

Treatment option is
➢ ISRT, (preferred)
or
➢ Rituximab (if ISRT is contraindicated)
Next: Restage at 3 months with endoscopy/biopsy
If lymphoma remains positive: First-line Therapy for Marginal Zone Lymphomas
❖ In patients with H. pylori–negative lymphomas, EMZL with a t(11;18) translocation,

or lymphomas that fail to respond to H. pylori therapy, RT is the preferred treatment
modality. (dv)
ISRT dose:
➢ EMZL of the stomach can be treated with 24–30 Gy in 20 fractions (1.5 Gy/
fractions) to minimize acute GI toxicity.
➢ Dose in Nancy:
▪ 30 Gy (1.5 Gy/fraction) in indolent verity
▪ 30–36 Gy depending on response in aggressive verity
Dr. Asad R10

Rituximab dose:
➢ Rituximab (375 mg/m2 weekly for 4 doses) then
➢ Consolidation with rituximab 375 mg/m2 one dose every 8–12 weeks for up to 2
years (optional, not mandatory)
Treatment of Stage II2 (distant nodal involvement) or Stage IIE or Stage IV (distant
nodal, advanced stage):
First evaluate the indications for treatment:
➢ Candidate for clinical trial
➢ Symptoms
➢ Gastrointestinal (GI) bleeding
➢ Threatened end-organ function
➢ Clinically significant bulky disease
➢ Steady or rapid progression
If no indication for treatment: Only observation in enough

If indication present:
1st line Chemotherapy for marginal zone lymphomas
Palliative ISRT can also be considered (4-30Gy)

• Bendamustine + rituximab
or rituximab
• Lenalidomide + rituximab (category 2B)
• Rituximab (375 mg/m2 weekly for 4 doses) for EMZL

Preferred regimen
First-Line Extended Therapy (optional):

• Consolidation with rituximab 375 mg/m2 one dose every 8–12 weeks for up to 2
years
N.B:
➢ Surgical resection is generally limited to specific clinical situations (ie, life-
threatening hemorrhage) (NCCN)
➢ EMZL is extremely sensitive to radiation therapy, and low-dose RT (4 Gy) can
provide effective local palliation. (dv) may be extended upto 30 Gy (NCCN)
Dr. Asad R10

Treatment of Extranodal Marginal Zone B-Cell Lymphoma Extranodal MZL of

Nongastric Sites (Noncutaneous):
Overall treatment options are:
❖ ISRT can be considered in all stage. May not be possible, when multiple site is
involved.
❖ Surgery may be considered for certain sites (lung, breast [lumpectomy], thyroid,
colon/small bowel) in early stage (stage IE, contiguous stage IIE)
❖ After surgery, if margin remains positive again consider about ISRT
❖ Observation may be considered for patients whose diagnostic biopsy was excisional,
or where RT could result in significant morbidity. It can be considered for any stage,
mainly reserved for advanced stage
❖ Chemotherapy as mentioned earlier can be considered when it is in advanced
stage, relapsed case, multiple site, ISRT/surgery is not feasible. Specially when
▪ Clinical Symptoms:
▪ Threatened end-organ function
▪ Clinically significant or progressive cytopenia secondary to lymphoma
▪ Clinically significant bulky disease
▪ Steady or rapid progression
Overall treatment options mentioned in NCCN:

Options
Stage IE or ISRT (preferred)
contiguous stage IIE or
Surgery may be considered for certain sites (lung,
breast [lumpectomy], thyroid, colon/small bowel)
or
Rituximab in selected cases
or
Observation in selected cases
Stage IV ISRT
or
Observation in selected cases
or
Manage per advanced-stage NMZL by 1st line CT, if above
mentioned indications are present,
Dr. Asad R10

Nodal Marginal Zone Lymphomas

➢ Nodal MZLs constitute <1% of all NHLs.
➢ By definition, these lymphomas are primarily nodal diseases without evidence of
extranodal involvement.
➢ Over 70% of patients present with stage III/IV disease and the majority are
asymptomatic. Bone marrow involvement is less common (45%) than in most indolent
lymphomas. The 5-year survival for patients with nodal MZL is 55% to 79%.
➢ Treatment options are like follicular lymphoma:
Stage Treatment options (any of the following)

Stage I or ➢ ISRT (preferred)
Contiguous stage II ➢ ISRT + anti-CD20 mA ± chemotherapy
➢ Only anti-CD20 mA ± chemotherapy in case of bulky
intra-abdominal or mesenteric stage I disease
Noncontiguous stage II ➢ Anti-CD20 mA ± chemotherapy
± ISRT for local palliation
➢ Observation:
when there is more chance of toxicities, elderly age
Stage III, IV ➢ Observe (category 1)
➢ 1st line systemic chemotherapy if
▪ Clinical Symptoms:
▪ Threatened end-organ function
▪ Clinically significant or progressive
cytopenia secondary to lymphoma
▪ Clinically significant bulky disease
▪ Steady or rapid progression

or rituximab
• Lenalidomide + rituximab (category 2B)
• Rituximab (375 mg/m2 weekly for 4 doses) for EMZL
Preferred regimen
First-Line Extended Therapy (optional):
• Consolidation with rituximab 375 mg/m2 one dose every 8–12 weeks for up to 2
years
Dr. Asad R10

Splenic Marginal Zone Lymphoma

➢ Splenic MZL constitutes <1% of all NHLs, (dv)
➢ median age of 65 to 70 years; it is uncommon before the age of 50 years.
➢ It is more frequent in Caucasians and has no gender predominance.
➢ Splenic MZL has been associated with viral infections, specifically
▪ hepatitis C and
▪ Kaposi sarcoma-associated herpesvirus.
➢ In one study, treatment of hepatitis C induced regression of the lymphoma
➢ Because of marrow and peripheral blood involvement, >90% of cases have stage IV
disease at diagnosis
Clinical features:
➢ Patients typically present with
✓ splenomegaly,
✓ lymphocytosis, and
✓ cytopenias,
➢ lymphadenopathy being a much less common feature.
➢ B symptoms and elevated LDH are uncommon. .
➢ IgM monoclonal gammopathies and mixed cryoglobulinemia can be seen, especially
with a hepatitis C infection.
➢ Acquired C1 esterase deficiency, seen in many B-cell lymphoproliferative disorders,
can be a feature of splenic MZL.
Treatment options (dv+NCCN):

Observation:
➢ Similar to other indolent NHLs, many patients with splenic MZL do not require
immediate therapy, irrespective of stage
➢ Asymptomatic patients without splenomegaly or cytopenias can be observed.
treatment of hepatitis C:
➢ induced regression of the lymphoma
➢ in case of asymptomatic hepatitis C positive SMZL, only hepatitis C treatment is
recommended
In case of symptomatic hepatitis C negative patients:
➢ Includes patient with
✓ splenomegaly,
✓ lymphocytosis, and
✓ cytopenias
➢ is advised for
❖ Rituximab (preferred) or
❖ Splenectomy (category 2B)
➢ If disease still progresses, start 1st line CT as mentioned earlier
➢ Follow up is 3-6 month interval with imaging
Dr. Asad R10

Dr. Asad R10

Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a distinct category of B-cell non-Hodgkin lymphoma (B-
NHL). These patients generally exhibit an
➢ aggressive, albeit heterogeneous, clinical course but
➢ smoldering or indolent forms of MCL are also recognized.
Pathology: (dv)
➢ MCLs are neoplastic counterparts of naïve “mantle zone” B cells.
➢ MCL is a B-cell malignancy that is highly associated with t(11;14), which leads to
overexpression of the cyclin D1 cell cycle regulator
➢ Morphologically, MCL can have either diffuse architecture or a vaguely nodular
appearance, occasionally growing predominantly in expanded mantle zones around
reactive GCs.
➢ Cytologically, in most cases, the neoplastic cells are small- to medium-sized and have
irregular nuclei and scant cytoplasm.
➢ Some cases of MCL have a predominance of intermediate-size cells with more
open “blastic” chromatin; such blastic variants are associated with a high mitotic rate.
➢ Other cases are composed of a spectrum of cells, including large cells (pleomorphic
variant).
Immunophenotype and Genetics: (dv)
▪ MCLs express B-cell antigens,
▪ surface IgM and IgD,
▪ CD5, and CD43 and
▪ usually lack ** CD10 and CD23.
▪ Overexpression of cyclin D1 further distinguishes these tumors from most other
entities
▪ By FISH, >90% of MCLs have the t(11;14) associated with the rearrangement of the
cyclin D1 gene (CCDN1).
▪ The remaining cases do not overexpress cyclin D1, but instead usually overexpress
cyclin D2, cyclin D3, or cyclin E due to the presence of translocations involving these
genes and the IgH locus.
▪ SOX11 overexpression can be diagnostically helpful in rare cases that lack cyclin D1
overexpression.207 Rare SOX11-negative cyclin D1–positive tumors are more likely
to involve the peripheral blood, yet also tend to pursue an indolent course.
▪ Deep sequencing has identified NOTCH1 mutations in a minority of cases, which may
be associated with a poor prognosis.
From NCCN:
➢ Typical immunophenotype:
→ CD5+, CD20+, CD43+,
→ CD23-/+, cyclin D1+, CD10-/+.
➢ Note: Some cases of MCL may be CD5- or CD23+. If the diagnosis is suspected, cyclin
D1 staining or FISH for t(11;14) should be done.
➢ Ki-67 proliferation fraction of <30% in lymph nodes is associated with a more
favorable prognosis
➢ TP53 mutation has been associated with poor prognosis in patients treated with
conventional therapy, including transplant.
➢ Most common biomarker for indolent disease: SOX11- [IGHV mutated].
Dr. Asad R10

Clinical Features:(dv)
➢ MCL constitutes about 7% of all NHLs.
➢ About 75% of patients are males, with a median age of 63 years.
➢ Approximately 70% of patients have stage IV disease,
➢ B symptoms are observed in approximately one-third of patients.
➢ Typical sites of involvement are the
▪ lymph nodes,
▪ spleen, liver,
▪ Waldeyer’s ring, and
▪ bone marrow.
▪ Peripheral blood involvement is present in 25% to 50% of patients at
presentation.
▪ MCL can involve any region of the GI tract (88% lower tract, 43%
upper tract by endoscopy) and occasionally presents as multiple
intestinal polyposis.
➢ CNS involvement is rare and is usually associated with a leukemic phase
Indolent verity of mantle cell lymphoma:

➢ Approximately 10% to 15% of patients have a disease with a more indolent disease,
with
▪ minimal lymphadenopathy,
▪ mild splenomegaly, and
▪ a proliferation index measured by Ki-67 staining of around 10%.
➢ These patients have a disease that behaves more like an indolent NHL, where a watchful
waiting approach does not compromise response to therapy or survival.
Blastic transformation
➢ occurs in 35% of patients, with a risk of 42% at 4 years;
➢ once this occurs, the median survival is 3.8 months
Prognostic factor:
➢ As per IPI
➢ High Ki-67 indicates bad prognosis
➢ Mutations and deletions of TP53 are also associated with a worse prognosis and poor
response to conventional chemoimmunotherapy
➢ SOX11 – is good, as it indicated indolent verity
➢ Overexpression of cyclin D not helpful.
Clinical features: (ad)

commonly present as
✓ symptomatic progressive generalized lymphadenopathy,
✓ cytopenia, and bone marrow infiltration.
✓ Enlarged spleen, tonsils, and parts of the gastrointestinal tract
(lymphomatous polyposis) are common.
✓ Extranodal involvement of the kidneys and central nervous system (CNS) is rare.
Dr. Asad R10

According to the presentation MCL is described as 3 types:

1. Smoldering MCL
2. Asymptomatic purely leukemic nonblastoid MCL
3. Conventional MCL (most common)
❖ The asymptomatic indolent or smoldering nodal/extranodal or leukemic nonnodal

presentation is seen in about 10% to 20% of cases and generally does not require
immediate systemic treatment, and can simply be safely observed.
❖ Conversely, most patients with MCL (~80%) present with symptomatic
lymphadenopathy or extranodal disease requiring systemic therapy
Clinical manifestations of MCL are summarized: (ad)

Clinical
Clinicopathologic Features
Presentation
Main indicators for Smoldering MCL:
▪ Asymptomatic
▪ absence of B symptoms (drenching night sweats, unintentional
weight loss of >10% of normal body weight over a period of ≤6
months or less, fever >38 °C), main indicator
Other features:
✓ Normal serum LDH, β2 microglobulin levels
✓ White blood cell count <30,000 K/µL
✓ Low MIPI (mantle cell lymphoma international prognostic index)
Smoldering MCL score
✓ Ki-67% on lymphoma cells in nonmarrow tissue biopsy of <30%
✓ Nonblastoid/pleomorphic cytomorphologic pattern in tissue
biopsy
✓ Maximum lymph node diameter <3 cm,
✓ spleen size <20 cm
✓ PET scan showing the maximum standardized uptake value <6
✓ Absence of TP53 or NOTCH1/2 mutations by DNA sequencing
✓ Absence of deletion 17p or MYC translocation/amplification by
FISH testing, absence of complex karyotype
Asymptomatic Monoclonal B lymphocytosis (with typical MCL immunophenotype
purely leukemic and nonblastoid morphology) in peripheral blood with or without
nonblastoid MCL splenomegaly
Conventional ▪ Symptomatic bulky nodal/extranodal disease
MCL ▪ Classic or blastoid/pleomorphic cytomorphology
(most common) At initial diagnosis or at clinical progression
** Localized presentation is extremely rare (NCCN)
Dr. Asad R10

Laboratory workup (ad)

➢ complete blood cell count with differential count,
➢ comprehensive metabolic panel,
➢ serum lactate dehydrogenase (LDH) levels,
➢ β2 microglobulin levels, and
➢ hepatitis panel.
➢ Core biopsy from tissue
➢ Adequate immunophenotype to confirm diagnosis
Paraffin panel:
▪ Pan B-cell marker (CD19, CD20, PAX5),
▪ CD3, CD5, CD10, and cyclin D1
▪ Ki-67 (proliferation rate)
or
Flow cytometry immunophenptyping:
kappa/lambda light chains, CD5, CD10, CD19, CD20,
CD23, FMC-7, CD200, and CD43
Use In Certain Circumstances:
Molecular genetic analysis
Somatic hyper-mutation for IGHV gene rearrangement and mutation status
o TP53 o BTK
o NSD22 o KMT2D3
o CDKN2A3 o NOTCH
o NOTCH1
➢ Immunohistochemistry for SOX-112

➢ FISH to detect t(11;14) (q13;q32)/CCND1-IgH, TP53, and MYC
Other mandatory investigations

➢ Bone marrow aspiration/ biopsy and involved tissue biopsy is routinely performed
at initial diagnosis: is routinely per-formed at initial diagnosis.
➢ For staging imaging:
PET-CT scan (preferred) or
C/A/P CT with contrast of diagnostic quality if systemic therapy is planned
Differential Diagnoses of MCL (ad)
➢ MCL can be distinguished from other masquerading lymphoid malignancies such as

❖ SLL/CLL,
❖ follicular lymphoma,
❖ marginal zone lymphoma, and
❖ B-cell–prolymphocytic leukemia.
Dr. Asad R10

➢ Translocation t(11;14) (q13;q32) can be observed in a fraction of patients with

▪ multiple myeloma (20%–25%),
▪ SLL/ CLL (2%–5%), and
▪ plasma cell leukemia and
▪ B-cell– prolymphocytic leukemia (20% with t (11;14) and cyclin D1+
cells, and these are considered as the leukemic phase of MCL).
➢ 20% cases of B-cell– prolymphocytic leukemia is presented with t (11;14) and

cyclin D1+ cells, and these are considered as the leukemic phase of MCL
➢ Cyclin D1 expression is also observed in a subset of patients with

▪ myeloma,
▪ hairy cell leukemia, and
▪ splenic lymphoma
➢ SOX-11 expression can be seen in

▪ Burkitt lymphoma (20%–25%),
▪ hairy cell leukemia, and
▪ lymphoblastic lymphoma.
Dr. Asad R10

Treatment of Mantle Cell Lymphoma:

Various factors should be considered before selecting therapy. These include (ad)
✓ performance status,
✓ age,
✓ comorbidities,
✓ disease status (smoldering nodal MCL vs leukemic non-nodal vs
conventional nodal MCL presentation),
✓ organ dysfunction,
✓ prior therapies (if relapsed),
✓ toxicities from prior therapy,
✓ eligibility for SCT,
✓ financial constraints, and
✓ availability of a clinical trial.
❖ Chemoimmunotherapy still remains a standard frontline treatment in most centers

❖ Considerable advances are made in the treatment for patients with MCL.
❖ Currently, the focus is headed toward chemotherapy-free treatments in the frontline and
relapsed settings
At MDACC, we approach patients with MCL using the following five clinical categories: (ad)
(1) smoldering MCL;
(2) previously untreated patients
(5) relapsed-refractory MCL
Smoldering MCL:(ad)
For patients with
➢ excellent performance status (0),
➢ no B symptoms or asymptomatic,
➢ nonbulky disease (<5 cm) with normal LDH levels,
➢ low Ki-67% (<30%), and
➢ nonaggressive cytomorphology,
we do not recommend systemic therapy and these patients can simply be observed
during observation at 3-6 months interval , if the disease progresses, treat as

Conventional MCL.
** Limited-stage disease, ie, stages I/II, is uncommon.

These patients can fall into the smoldering MCL category; however, there are patients
who have limited stage disease but significant symptoms and they
need treatment—either local radiation or systemic therapy alone.
(when Smoldering MCL is in stages I/II, ISRT or CT still can be considered? if there is
significant sympoms)
Dr. Asad R10

Treatment of Previously untreated Conventional MCL

In case of early stage: Including
➢ Stage I
➢ Stage II, non-bulky (bulky means >7.5cm like DLBCL?)
❖ Usual treatment option is chemo-immunotherapy(induction therapy) with no
intension to Transplant (SCT)
❖ ISRT (30-36 Gy) can also be a alternative treatment options except for Stage II non-
contiguous cases, where ISRT not feasible.
Then Assessment of progression:

In PET CT:
✓ CR : Score: 1,2, 3
✓ PR, stable : Score:4,5 No new lesions
✓ Progressive : 4,5, new lesions
** (details including CT assessment, discussed in FL part)
❖ After ISRT if there is Partial response or progression,

Start, chemo-immunotherapy with no intension to Transplant (SCT)
❖ After chemo-immunotherapy with no intension to Transplant

if there is Partial response or progression,
start 2nd line induction chemotherapy
ISRT may be considered if there is residual, after 1st line CT in stage I, II (???)
For advanced-stage disease younger patients (<65years) and elderly fit patients
This group includes:
➢ Stage II bulky, (>7.5cm?)
➢ Stage III,
➢ Stage IV
First Assess the TP 53 mutational status:
In case of,
Classical TP53 wild type (non- chemoimmunotherapy, Induction Therapy –
mutated type) intention to proceed to transplant
(CT schedules without SCT can also be considered)
Classical TP53 mutated type consider chemoimmunotherapy, Induction Therapy –
NO intention to proceed to transplant
** TP53 mutated type has poor prognosis, So CT schedule with Stem cell transplantation
options are not included (?)
❖ chemoimmunotherapy, Induction Therapy – intention to proceed to transplant is
collectively also known as Induction CT followed by consolidation therapy
Then Assessment of progression:
In PET CT:
✓ CR : Score: 1,2, 3
If there is CR Rituximab maintenance (category 1)
If there is PR, Progressive disease 2nd line therapy
Dr. Asad R10

 As most of the patients are presented in stage III, IV, Induction CT followed by
consolidation therapy is the main treatment options for MCL
 Rituximab maintenance therapy is not mentioned after complete response in early stage,
better to advise to avoid confusion. (?) mainly indicated after HDT/ASCR, only RCHOP
 Reminder, in stage III, IV, if it is smoldering type, observation is enough.
Induction therapy in MCL:(NCCN)

Intention to proceed to transplant (with consolidation therapy)
Preferred regimens
• RDHA (rituximab, dexamethasone, cytarabine) +
Platinum (carboplatin, cisplatin, or oxaliplatin)
• Alternating RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin,
vincristine, prednisone)/(rituximab, dexamethasone, cytarabine, cisplatin)
• NORDIC regimen (dose-intensified induction immunochemotherapy with rituximab
+ cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP])
alternating with rituximab + high-dose cytarabine
• Rituximab, bendamustine followed by rituximab, high-dose cytarabine
Other recommended regimen
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone
alternating with high-dose methotrexate and cytarabine) + rituximabd
(NOTE: There are conflicting data regarding the need for consolidation with
HDT/ASCR)
Consolidation Therapy: HDT/ASCR [with above mentioned schedule]
Maintenance After HDT/ASCR: Maintenance rituximab every 8 weeks x 3 y (category 1)
Intention NOT to proceed to transplant (without consolidation therapy)

Preferred regimens
• VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone)
• RCHOP
• Lenalidomide (continuous) + rituximab
• RBAC500 (rituximab, bendamustine, cytarabine)
Maintenance after less aggressive induction therapy:
• Rituximab every 8 weeks for 2–3 years following RCHOP (category 1) or BR
• Not evaluated after VR-CAP, RBAC500
*** Prophylaxis for tumor lysis syndrome should be considered during the induction therapy.
Dr. Asad R10

In MD Anderson:
At MDACC, the standard of protocol treatment for physically fit, transplant-eligible patients
is
➢ intensive chemoimmunotherapy with rituximab with HCVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone) as part A and
➢ methotrexate-ara-C as part B (R-HCVAD/ methotrexate-ara-C).
➢ We do not recommend consolidation with SCT after R-HCVAD.
At other centers,
intensive chemoimmunotherapy is followed by auto-SCT and rituximab
maintenance in high-risk MCL.
***Overall, Dosing and trails are not mentioned here, for details please read Anderson.
In elderly(>65years) fit patients,

less-aggressive treatment regimens, such as R-CHOP followed by rituximab
maintenance. R-FC (rituximab + Fludarabine, cyclophosphamide) (As mentioned in
Intention NOT to proceed to transplant without consolidation therapy regiments )
For elderly patients who are not candidates for any of the above CT:
Palliative CT / milder chemo-immunotherapy regimens (eg, chlorambucil plus
rituximab, bendamustine plus rituximab, chlorambucil single agent)
2nd line induction

Indicated after Partial response/ progression/ relapse after induction therapy
Assess BTK inhibitor-naïve/refractory:
Acalabrutinib and
zanubrutinib have not
been shown to be
effective for
ibrutinibrefractory MCL
with BTK C481S
mutations.
Dr. Asad R10

L y m p h o m a | 100
According to Zuma-2 study, FDA approved brexucabtagene autoleucel (anti–CD19-CAR-T)

in relapsed or refractory MCL. (cost $373,000 for a one-time infusion :D :D :D) (ad)
Allogenic HCT in MCL:

For , Selected cases include mobilization failures and persistent bone marrow involvement
(After ASCT?) (NCCN)
N.B:
Smoldering verity dose not need treatment
Early stage can be treated with ISRT alone/CT
As most of the cases are presented in stage III, IV, in case of confusion treat as
Advanced stage.
No role of RT in advanced stage of MCL, even in relapsed, refractory stage
intensive chemoimmunotherapy is followed by auto-SCT and rituximab maintenance

is the main treatment option in Advanced stage MCL
Treatment of Lymphoblastic Lymphoma:

➢ The lymphoblastic lymphoma (LL) category comprises two diseases, T-cell LL (LL-T;
90%) and B-cell LL (LL-B; 10%), which corresponds to T-cell acute
lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL),
respectively, with presentations in extramedullary sites.
➢ This disease is complex and curable
❖ Treated as Acute Lymphoblastic Leukemia
Dr. Asad R10

L y m p h o m a | 101
Diffuse Large B-Cell Lymphoma

➢ DLBCL constitutes 31% of all NHLs (dv)
➢ the most common histologic subtype of NHL
➢ There is a slight male predominance
➢ the median age is 64 years
➢ Caucasian Americans have a higher incidence of DLBCL than African Americans
Important risk factors: (dv)

➢ Family History: 3.5-fold increased risk in relatives of probands with DLBCL
➢ EBV infection
➢ Immunosuppression:
Patients with congenital or acquired immunodeficiency, patients on
immunosuppression, and patients with autoimmune disorders have a higher risk
of developing DLBCL, often EBV-related.
➢ Indolent lymphoma: DLBCL also can arise as an HT from any indolent B-cell NHL
or CLL.
Clinical Presentation (ad)

➢ B-type symptoms or bulky disease occurs in one-third of patients.
➢ Nodal presentation is most common,
➢ extranodal sites are involved in approximately 40% of patients
➢ more than one-third of patients have more than one extranodal site of disease.
➢ Slightly more than half of patients have stage III or IV disease.
➢ Bone marrow involvement occurs in approximately 10% to 20% of patients.
DLBCL uncommonly involves privileged sites, such as the testes and CNS, of which
the latter portends a poorer prognosis.
➢ Cure rate for stage I, II- 80% and III, IV- 50%
Microscopic Morphology/pathology :
➢ DLBCL is defined as a neoplasm with a diffuse growth pattern composed of
medium-size or large B cells whose nuclei are the same size as, or larger than,
the nuclei of normal macrophages, or more than twice the size of normal lymphocytes.
(ad)
➢ The only unifying feature is the relatively large size of the tumor cells (at least three to
four times wider in diameter than a normal resting lymphocyte), which may have
centroblastic, immunoblastic, plasmablastic, or anaplastic morphologies (dv)
➢ This large cell not only found in DLBCL-NOS, but also other types of lymphoma,
including: (ad)
❖ T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
❖ Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System
❖ Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
❖ Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation
❖ Epstein-Barr Virus–Positive Diffuse Large B-Cell Lymphoma, Not Otherwise
Specified
❖ Epstein-Barr Virus–Positive Mucocutaneous Ulcer
❖ Lymphomatoid Granulomatosis
Dr. Asad R10

L y m p h o m a | 102
❖ Large B-Cell Lymphoma with IRF4 Rearrangement

❖ Primary Mediastinal (Thymic) B-Cell Lymphoma\
❖ Intravascular Large B-Cell Lymphoma
❖ ALK-Positive Large B-Cell Lymphoma
❖ Plasmablastic Lymphoma
❖ Primary Effusion Lymphoma
❖ HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Immunophenotype and Genetics

➢ Based on gene expression, DLBCLs have been subclassified into (dv)
❖ Germinal Center B cell type (GCB types) or
❖ Anaplastic B cell type (ABC types).
➢ GC and non-GCB derivation can be determined by the expression of markers such as
✓ CD10,
✓ B-cell lymphoma 6 protein, and
✓ interferon response factor 4 (IRF4), also known as multiple myeloma
oncogene 1 (MUM1).
➢ Based on immunohistochemistry, it is estimated that
▪ approximately 40% of DLBCLs are of the GCB subtype,
▪ with the remainder falling into the non-GCB group.
DLBCL Tumor cells generally express B-cell antigens :

✓ CD19,
✓ CD20,
✓ CD45
✓ CD79a,
✓ monoclonal sIgM, and,
✓ occasionally, other heavy chain isotypes.
CD 3 negative
CD10 and BCL6 expression typify expression of
tumors of GC origin (GCB) interferon response factor 4(IRF4)
/MUM1 favors a non-GC, ABC-type
origin.
▪ CD30 positivity (14% of cases) is associated with better survival
▪ CD5+ cases are uncommon and may have a worse prognosis.
▪ 80% are reported to express BCL2, (20% with BCL2 translocation)
▪ whereas approximately 70% express BCL6. (30% with BCL6 translocation)
MYC is rearranged in 10% of DLBCLs, with the partner gene being one of the Ig
genes in 60% of cases and some other gene in 40% of cases
20% to 30% of DLBCLs are associated with the t(14;18).
Dr. Asad R10

L y m p h o m a | 103
Double-hit lymphomas:
➢ Double hit lymphoma, is a subtype of DLBCL characterized by the presence of two
specific genetic alterations in the cancer cells.
➢ It is considered an aggressive and high-risk form of DLBCL.
➢ The two genetic alterations typically observed in double-hit lymphoma are:
o MYC rearrangement: Similar to triple hit DLBCL, MYC rearrangement
involves alterations or rearrangements in the MYC gene, leading to its
overexpression. MYC plays a role in regulating cell growth and division, and
its abnormal expression can promote uncontrolled cell proliferation.
o BCL2 and/or BCL6 rearrangement: In addition to MYC rearrangement,
double-hit lymphoma may also involve alterations in the BCL2 and/or BCL6
genes. BCL2 and BCL6 are involved in regulating apoptosis (programmed cell
death) and B-cell development, respectively. Rearrangements in these genes can
disrupt normal cellular processes and contribute to the development and
progression of lymphoma.
Triple-hit lymphoma:
➢ Triple hit DLBCL, also known as triple-hit lymphoma, is a rare and aggressive form of
diffuse large B-cell lymphoma (DLBCL), which is a type of non-Hodgkin lymphoma.
➢ It is characterized by the presence of three specific genetic abnormalities or
alterations in the cancer cells. These includes:
o MYC rearrangement: MYC is a gene that plays a crucial role in regulating
cell growth and division. In triple hit DLBCL, there is a rearrangement or
alteration of the MYC gene, leading to its overexpression.
o BCL2 rearrangement: BCL2 is a gene involved in regulating programmed cell
death (apoptosis). In triple hit DLBCL, there is a rearrangement or alteration of
the BCL2 gene, resulting in its overexpression.
o BCL6 rearrangement: BCL6 is a gene that helps regulate the development of
B-cells, a type of immune cell. In triple hit DLBCL, there is a rearrangement or
alteration of the BCL6 gene, leading to its overexpression.
o
Double-hit lymphomas MYC rearrangement+ BCL2 rearrangement
MYC rearrangement+ BCL6 rearrangement
Triple-hit lymphoma MYC rearrangement+ BCL2 rearrangement+
BCL6 rearrangement
*** MYC gene overexpression/rearrangement with BCL2 ± BCL6 has bad prognosis
❖ In the 2016 WHO classification of lymphoid neoplasms, double-hit & triple hit
lymphomas are placed in a new category, high-grade B-cell lymphoma with
rearrangement of MYC and BCL2 and/or BCL6. Some double-hit/triple hit
lymphomas have morphologies identical to DLBCL, whereas others have
morphologies similar to BL or lymphoblastic lymphoma
High-Grade B-Cell Lymphoma

❖ High-grade B-cell lymphoma (HGBL) is a subset of very aggressive tumors with
features intermediate between DLBCL and BL, or with a blastoid appearance.
Mentioned as a separate entity in WHO 2016 classification. Will be discussed later.
Dr. Asad R10

L y m p h o m a | 104
Clinical features of DLBCL: (dv)

➢ Patients present with rapidly enlarging masses, which may be nodal or extranodal.
➢ DLBCL presents as s
▪ tage I or IE disease approximately 20% of the time.
▪ The disease is confined to one side of the diaphragm (stage I or II) in
approximately 30% to 40% of patients.
▪ Stage IV disease is seen in approximately 40% of patients.
➢ B symptoms occur in 30% of patients, and
➢ serum LDH is elevated in over half of the patients.
➢ Extranodal disease occurs in 40% of cases and may involve the GI tract, testis, bone,
thyroid, skin, CNS, and/or bone marrow.
➢ DLBCL is highly invasive, with local compression of blood vessels, airways,
involvement of peripheral nerves, and destruction of bone.
➢ Bone marrow involvement initially is found in only 10% to 20% of patients and has a
strong correlation with the risk of spread to the CNS.
➢ Other sites of extranodal disease, specifically testicular, paranasal sinus, epidural, and
the presence of multiple extranodal sites, also are associated with a high risk of CNS
dissemination
Investigations:
➢ (FDG-PET/CT) scan
is recommended as standard practice for staging patients with DLBCL.
Indeed, PET/CT is more sensitive, especially for extranodal disease, and
improves staging accuracy and subsequent response assessment
➢ Bone marrow
▪ Adequate bone marrow biopsy (>1.6 cm) ± aspirate; from iliac crest (NCCN)
▪ bone marrow biopsy is not necessary if PET-CT scan demonstrates bone
disease.
▪ Bone marrow biopsy with a negative PET-CT scan may reveal discordant
lymphoma
➢ CSF study may required (NCCN):
➢ Testicular lymphoma
➢ HGBL with translocations of MYC and BCL2 and/or BCL6 HGBL, NOS
➢ Primary cutaneous DLBCL, leg type
➢ Stage IE DLBCL of the breast
➢ kidney or adrenal gland involvement
Other investigations:
As usual
✓ LDH, β2-microglobulin
✓ Hepatitis panel, HIV panel
Dr. Asad R10

L y m p h o m a | 105
Treatment of DLBCL
For treatment purpose, DLBCL can be described as (NCCN)
➢ Stage I, Stage II, (excluding extensive metastatic disease)
✓ Bulky >7.5cm
✓ Non-bulky <7.5cm
➢ Stage III, Stage IV (including stage II extensive metastatic disease)
Less than 20% of patients with DLBCL have localized disease. The recommended
treatment for localized disease outside of clinical trials is abbreviated, (dv)
➢ combination chemoimmunotherapy plus involved-site radiotherapy, or
➢ combination chemoimmunotherapy alone.
Non-bulky <7.5cm Stage I, Stage II, (excluding extensive metastatic disease):

Treatment option is
RCHOP x 3 cycles
R-CHOP
Then restaging with PET-CT after 3 cycles
✓ CR : Score: negative, 1,2, 3

➢ RCHOP x 1 cycle (total of 4 cycles)
Or
➢ ISRT (30–36 Gy)
If there is partial response:
➢ RCHOP x 1–3 cycles (total of 4–6 cycles) ± ISRT
Or
➢ ISRT (if PET+ after 3 cycles of RCHOP) (36–50 Gy)
If there is progressive disease:
Repeat biopsy,
if positive, treat as relapse or refractory disease.
Dr. Asad R10

L y m p h o m a | 106
Bulky >7.5cm Stage I, Stage II, (excluding extensive metastatic disease):

Treatment option is
RCHOP x 6 cycles ± ISRT
Before starting RT, reassess the disease response by PET CT scan
The dose if ISRT depends upon the pre-RT PET CT response
DS score Dose
Complete response negative, 1,2, 3 30–36 Gy
Partial Response 4 36–50 Gy
Partial Response 5 40–55 Gy
When it ISRT is not planned initially in this stage:

Start treatment with RCHOP
Then restaging with PET-CT after 3 cycles
Complete planned course of treatment
(total of 6 cycles of RCHOP)
If there is partial response:
➢ RCHOP x 1–3 cycles (total of 4–6 cycles) ± ISRT
Or
➢ ISRT (if PET+ after 3 cycles of RCHOP) (36–50 Gy)
If there is progressive disease:
Repeat biopsy,
if positive, treat as relapse or refractory disease.
Stage III, Stage IV (including stage II extensive metastatic disease)

Treatment option is
❖ First-line therapy
Preferred regimens
RCHOP (category 1) Rituximab,

Cyclophosphamide,
Doxorubicin,
Vincristine,
Prednisone
Pola-R-CHP Polatuzumab vedotin-piiq,
category 1, when (IPI ≥2) Rituximab,
Cyclophosphamide,
Doxorubicin,
Prednisone
Dr. Asad R10

L y m p h o m a | 107

in alphabetical order by category
DA- Etoposide, RGCVP Rituximab,

EPOCH Prednisone, Gemcitabine,
Vincristine, Cyclophosphamide,
Cyclophosphamide, Vincristine,
Doxorubicin + Prednisone
Rituximab
RCDOP Rituximab, RCEPP Rituximab,

Cyclophosphamide, (category 2B) Cyclophosphamide,
Liposomal Etoposide,
doxorubicin, Prednisone,
Vincristine, Procarbazine
Prednisone
RCEOP Rituximab,
Cyclophosphamide,
Etoposide,
Vincristine,
Prednisone
Patients with Poor Left Ventricular Function (All Stages)
DA-EPOCH Etoposide, RGCVP Rituximab,

Prednisone, Gemcitabine,
Vincristine, Cyclophosphamide,
Cyclophosphamide, Vincristine,
Doxorubicin + Prednisone
Rituximab
RCDOP Rituximab, RCEPP Rituximab,
Cyclophosphamide, Cyclophosphamide,
Liposomal doxorubicin, Etoposide,
Vincristine, Prednisone,
Prednisone Procarbazine
RCEOP Rituximab,
Cyclophosphamide,
Etoposide,
Vincristine,
Prednisone
Very Frail Patients and Patients >80 Years of age with comorbidities, (All Stages)
alphabetical order:
• RCDOP
• R-mini-CHOP
• RGCVP
• RCEPP (category 2B)
First-Line Consolidation (Optional):
Lenalidomide maintenance (category 2B) for patients 60–80 y of age
Dr. Asad R10

L y m p h o m a | 108
Concurrent Presentation with CNS Disease:

Parenchymal:
➢ systemic high-dose methotrexate (≥3 g/m2 or more given with RCHOP cycle that
has been supported by growth factors).
➢ Different schedules have been used for the integration of high-dose methotrexate with
RCHOP (early- or mid-cycle or day 15 of a 21-day cycle)
Leptomeningeal:
➢ RCHOP + IT methotrexate/cytarabine:
Intra-Thecal methotrexate/cytarabine, consider Ommaya reservoir placement
➢ Systemic high-dose methotrexate (3–3.5 g/m2) can be given in combination with
RCHOP or as consolidation after RCHOP + IT methotrexate/cytarabine
** Concurrent high-dose methotrexate with dose-adjusted EPOCH can result in
unacceptable toxicities
During 1st line Chemotherapy

Restage the patient’s disease status with PET CT scan after 2–4 cycles
In PET CT:
✓ CR : Score: 1,2, 3
If there is
Complete response or partial response:
Continue first line therapy to a total of 6 cycles (category 1)
No response or progressive disease: Repeat biopsy
If positive: treat as relapse of refractory disease
At completion of treatment (ex. Total 6 cycle), repeat all positive studies (PET CT scan)
➢ In case Complete response : F/U
➢ In case of Partial response : treat as refractory disease
➢ In case of progressive disease : Repeat biopsy and if positive, do a biopsy.
Treatment of Relapse of Refractory cases:

Can be described in 2 types for treatment discussion:
➢ Relapse after 12 months or refractory disease
➢ Relapse within 12 months or Primary refractory disease
Dr. Asad R10

L y m p h o m a | 109
Relapse after 12 months or refractory disease:

Treatment depends upon whether Stem cell transplantation possible or not
If Intention to proceed to transplant:
➢ Start 2nd line chemotherapy
After 2nd line chemotherapy: if there is
Next treatment option is
Complete response HDT/ASCR (category 1) ± ISRT
Partial response HDT/ASCR (category 1) ± ISRT or
Consider Anti-CD19 CAR T-cell therapy
Disease is still progressing Alternative systemic therapy for R/R disease (not
previously used)
Palliative ISRT
Anti-CD19 CAR T-cell therapy (if not previously
given)
** HDT/ASCR (category 1) ± ISRT is recommended with 2nd Line CT. Alternative
systemic therapy for R/R disease or Anti-CD19 CAR T-cell therapy is recommended
when there is partial response or disease is still progressing
2nd line chemotherapy:

➢ DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or
oxaliplatin) ± rituximab
➢ GDP (gemcitabine, dexamethasone, cisplatin) ± rituximab or (gemcitabine,
dexamethasone, carboplatin) ± rituximab
➢ ICE (ifosfamide, carboplatin, etoposide) ± rituximab
Other recommended regimens (in alphabetical order)
➢ ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± rituximab
➢ GemOx (gemcitabine, oxaliplatin) ± rituximab
➢ MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab
If there is NO Intention to proceed to transplant:

Treatment depends upon whether Stem cell transplantation possible or not
If Intention to proceed to transplant:
➢ Start 2nd line chemotherapy
After 2nd line chemotherapy: if there is
Next treatment option is
Complete response F/U
Partial response ➢ Alternative systemic therapy for R/R
Disease is still progressing disease (not previously used)
➢ Palliative ISRT
➢ Anti-CD19 CAR T-cell therapy (if not
previously given)
**As Stem cell transplantation is not planned or not possible, after 2nd line CT, if the
disease dose not completely response, consider about Alternative systemic therapy or
Anti-CD19 CAR T-cell therapy
Dr. Asad R10

L y m p h o m a | 110
Relapse within 12 months or Primary refractory disease:

It is better to consider about Anti-CD19 CAR T-cell therapy at first, if not possible 2nd
line chemotherapy and if needed, Alternative systemic therapy for R/R disease later
Dr. Asad R10

L y m p h o m a | 111
DHAP (salvage regimen):
Cisplatin 100 mg/m2 IV continuous infusion over 24 D1

hours
Cytarabine 2,000 mg/m2 IV over 3 hours every 12 hours D2
for 2 doses on day 2 after completion of
cisplatin infusion
Dexamethasone 40 mg PO or IV D1-D4
Add Rituximab 375 mg/m2 IV on day 1
ICE (salvage regimen)
I Ifosfamide 5,000 mg/m2 IV continuous infusion for 24 hours D2

C Etoposide 100 mg/m2 IV D1-D3
E Carboplatin AUC of 5 D2
Mesna 5,000 mg/m2 IV in combination with ifosfamide
dose
Add Rituximab 375 mg/m2 IV on day 1 in case of RICE
ESHAP (salvage regimen)
Etoposide 40 mg/m2 IV D1–4

Methylprednisolone 500 mg IV D1–4
Cisplatin 25 mg/m2/day IV continuous infusion D1–4
Cytarabine 2,000 mg/m2 IV on day 5 after D5
completion of cisplatin and etoposide
MINE (salvage regimen)
M Mesna 1,330 mg/m2 IV administered at same D1-D3

time as ifosfamide on days 1–3, then
500 mg IV 4 hours after ifosfamide
I Ifosfamide 1,330 mg/m2 IV D1-D3
N Mitoxantrone 8 mg/m2 IV D1
Allogenic bone marrow transplantation in DLBCL

Can be considered Selected cases include mobilization failures and persistent bone
marrow involvement.
Dr. Asad R10

L y m p h o m a | 112
Follow-up After Completion of Treatment Up to 5 Years:

✓ It is recommended that the patient be provided with a treatment summary at the
completion of therapy, including details of RT, organs at risk (OAR), and cumulative
anthracycline dosage given.
✓ Follow-up with an oncologist is recommended and should be coordinated with the
primary care physician (PCP), especially during the first 5 y after treatment to detect
recurrence, and then annually due to the risk of late complications including second
cancers and cardiovascular disease.
✓ Late relapse or transformation to large cell lymphoma may occur in NLPHL.
Interval Duration
History and Every 3–6 months for 1–2 years, then
physical examination Every 6-12 months until year 3, then
Annually Continue
CBC, platelets, ESR as clinically indicated
(if elevated at time of initial
diagnosis), chemistry profile
neck/chest/abdomen/pelvis Consider no more often than every 6 for the first 2 years
CT scan with contrast months
as clinically indicated After 2 years
Treatment of High-grade lymphoma

➢ LBCL with translocations of MYC and BCL2 and/or BCL6 as detected by FISH or
standard cytogenetics are known as "double-hit" lymphomas. If all three are
rearranged, they are referred to as "triple-hit" lymphomas.
➢ The vast majority are germinal center B-cell–like lymphomas
HGBL, NOS:
➢ Cases that appear blastoid or cases intermediate between DLBCL and BL, but which
lack an MYC and BCL2 and/or BCL6 rearrangement.
➢ This category excludes patients with translocations of MYC and BCL2 and/or BCL6
or clear DLBCL
Clinical presentation:
➢ Often patients present with poor prognostic parameters, such as
▪ elevated LDH,
▪ bone marrow and CNS involvement, and
▪ a high IPI score.
➢ These patients are at higher risk for CNS involvement
Dr. Asad R10

L y m p h o m a | 113
Treatment of High-grade lymphoma (NCCN):

➢ DA-EPOCH-R
➢ R-Hyper CVAD:
▪ Rituximab,
▪ Cyclophosphamide,
▪ Vincristine,
▪ Doxorubicin, and
▪ Dexamethasone alternating with
▪ high-dose methotrexate and cytarabine
➢ R-CODOX-M/R-IVAC:
▪ rituximab,
▪ cyclophosphamide,
▪ vincristine,
▪ doxorubicin, and
▪ methotrexate
alternating with
▪ rituximab,
▪ ifosfamide,
▪ etoposide, and
▪ cytarabine)
➢ Last two regiments are Potentially toxic regimens; performance status and
comorbidities should be considered
➢ Clinical trial is also recommended.
❖ R-mini-CHOP may be considered for frail or elderly Patients

❖ RCHOP in HGBL may be associated with a suboptimal outcome. Could be
considered for low-risk IPI patients.
Role of radiotherapy in HGBL:

➢ Consolidative ISRT is preferred for localized disease in double hit, triple hit type.
➢ Consider consolidative ISRT for early-stage disease of HGBL, NOS
Dose of ISRT in HGBL (NCCN)

➢ Consolidation after chemoimmunotherapy
▪ CR (5-PS 1–3) - 30–36 Gy
▪ PR (5-PS 4) - 36–50 Gy
➢ For Refractory disease (5-PS 4–5) - 40–55 Gy
Dr. Asad R10

L y m p h o m a | 114
Burkitt Lymphoma
➢ BL is a rare disease in adults, comprising <1% of adult NHLs
➢ BL constitutes 30% of nonendemic pediatric lymphomas.
➢ BL has a male predominance
➢ typically seen in patients younger than 35 years of age
Pathology:
➢ BL cells resemble the small noncleaved cells within normal GCs of secondary
lymphoid follicles. The mitotic rate is high and analogous to normal GCs; frequent
tingible body macrophages are seen, producing the classic starry sky appearance.
The fraction of Ki-67 positive (proliferating cells) in BL is typically close to 100%.
Immunophenotype and Genetics(dv)
➢ BL is a tumor of B-lineage derivation identified by the expression of
▪ CD19, CD20, sIgM, CD10, and BCL6,
▪ but not BCL2.
➢ Endemic BLs are EBV-positive, whereas the majority of nonendemic BLs are EBV-
negative.
➢ BL is associated with a translocation involving MYC on chromosome 8q24 in over
95% of the cases
From NCCN:
✓ sIg+,
✓ CD10+,
✓ Cd20+,
✓ TdT-,
✓ Ki-67+ (≥95%),
✓ BCL2-,
✓ BCL6+.
Karyotype ± FISH for :
✓ t(8;14) or variants;
✓ MYC, BCL2; BCL6 rearrangement
** should also be as it may present
** double- or triple-hit tumors are treated as HGBL (NCCN)
Clinical Features:(dv)
BL is, in general, a pediatric tumor that has three major clinical presentations:
➢ Endemic (African) form
➢ Nonendemic form
➢ Immunodeficiency-related cases
Dr. Asad R10

L y m p h o m a | 115
Endemic (African) form Nonendemic form Immunodeficiency-related

cases
presents as a usually has an more often involve
jaw or facial bone ✓ abdominal lymph nodes and
tumor presentation may present with peripheral
that spreads to extranodal ✓ with massive disease, blood involvement.
sites, including the ✓ ascites, and
✓ ovary, testis, kidney, ✓ renal, testis,
breast, and especially and/or ovarian
bone marrow involvement and, like
and meninges. the endemic form,
✓ also spreads to the bone
marrow and CNS.
is associated with EBV associated with EBV Occurs in
infection in 95% to 100% of infection in 25% to 40% of ✓ HIV infection
patients. patients ✓ post-transplant,
✓ Congenital immune
deficiency.
✓ In HIV-infected patients, BL appears often when CD4+ T-cell counts are still in the
normal range or low, but not extremely low, and the risk of developing BL persists in
spite of highly active antiretroviral therapy.(ad)
✓ In general, all variants of BL show similar morphologic features. All BL types are of
mature B-cell lineage and of GCB origin, expressing surface Ig, pan–B-cell
antigens, CD10, and BCL6. (ad)
BL-IPI (prognostic factor of BL): (dv)

used four factors:
➢ age >40,
➢ PS >2,
➢ LDH >3 × ULN, and
➢ CNS disease.
This identified three groups with OS from 96% to 59%.
Additional Investigations in BL: (NCCN)

➢ PET-CT scan is recommended (initiation of therapy should not be delayed for
PET-CT scan)
➢ Lumbar puncture & Flow cytometry of cerebrospinal fluid
➢ Unilateral or bilateral bone marrow biopsy ± aspirate
➢ HIV testing
➢ Hepatitis B testing
Dr. Asad R10

L y m p h o m a | 116
Treatment of Burkitt’s lymphoma:

First assess the risk status of the patient:
Low risk High risk
✓ Normal LDH or ✓ stage I and Abdominal mass or
✓ Stage I and ✓ Extra-abdominal mass >10 cm or
Completely resected ✓ Stage II–IV
abdominal lesion or
✓ Single extra-abdominal mass <10 cm
Treatment plan is systemic chemotherapy and the schedule depends on risk status and
patients age: (NCCN)
CHOP is not an adequate therapy
Preferred regimens (alphabetical order)
→ CODOX-M (original or modified) (cyclophosphamide,
doxorubicin, vincristine with intrathecal methotrexate and
cytarabine followed by high-dose systemic methotrexate) +
rituximab (3 cycles)
RISK → Dose-adjusted EPOCH (etoposide, prednisone, vincristine,
Low cyclophosphamide, doxorubicin) + rituximab
Risk (minimum 3 cycles with one additional cycle beyond CR) (regimen
includes intrathecal methotrexate)
→ HyperCVAD (cyclophosphamide, vincristine, doxorubicin,
dexamethasone) alternating with high-dose
methotrexate and cytarabine + rituximab (regimen includes
intrathecal therapy)
Preferred regimens (alphabetical order)
High-risk patients presenting with symptomatic CNS disease should be
AGE
started with the portion of the systemic therapy that contains CNS-
<60 y
penetrating drugs.
→ CODOX-M (original or modified) (cyclophosphamide,
doxorubicin, vincristine with intrathecal methotrexate
and cytarabine followed by high-dose systemic methotrexate)
alternating with IVAC (ifosfamide, cytarabine,
High etoposide, intrathecal methotrexate) + rituximab
Risk → HyperCVAD (cyclophosphamide, vincristine, doxorubicin,
dexamethasone) alternating with high-dose
methotrexate and cytarabine + rituximab (regimen includes
intrathecal therapy)
Other recommended regimen
→ Dose-adjusted EPOCH (etoposide, prednisone, vincristine,
cyclophosphamide, doxorubicin) + rituximab
(for high-risk patients with baseline CNS disease not able to tolerate
aggressive treatments) (regimen includes intrathecal methotrexate)
Dr. Asad R10

L y m p h o m a | 117
Preferred regimen
→ Dose-adjusted EPOCH (etoposide, prednisone, vincristine,
cyclophosphamide, doxorubicin) + rituximab
Low and
(minimum 3 cycles with one additional cycle beyond CR)
≥60 y High
(regimen includes intrathecal methotrexate
Risk
In high-risk patients presenting with symptomatic CNS disease,
the management of the CNS disease should be addressed with the
initial regimen
From Dv:
➢ CHOP with intrathecal methotrexate should be considered insufficient treatment.
➢ Short, intensive therapy with CNS prophylaxis is the standard approach.
➢ The original Magrath regimen (CODOX-M/IVAC) had a 92% 2-year OS
➢ The addition of rituximab to chemoimmunotherapy is now considered the standard of
care when treating patients with BL. In a phase III randomized study, the inclusion of
rituximab led to an improved EFS at 3 years
➢ A study of DA-EPOCH-R for six to eight cycles (two cycles past CR) reported
outstanding results with freedom from progression of 95% and OS of 100% at a
median follow-up of 86 month
After systemic chemotherapy:

if there is complete response : Follow up
if no complete response : Palliative ISRT
Dose of palliative RT in (NCCN)

DLBCL/HGBL/PMBL/Mediastinal gray zone lymphoma and BL:
➢ Standard hypo fractionated palliative treatment schedules such as
▪ 20–30 Gy in 5–10 fractions. 20 Gy in 5 fractions and
▪ 30 Gy in 10 fractions are appropriate depending upon clinical scenario.
➢ higher doses/fraction typically appropriate
Second-Line Therapy for BL:

➢ Patients with disease relapse >6–18 months after appropriate first-line therapy should
be treated with alternate regimens. While no definitive second-line therapies exist, there
are limited data for the following regimens: (NCCN)
▪ Dose-adjusted EPOCH
▪ RICE
▪ RIVAC
▪ RGDP
▪ High-dose cytarabine + rituximab
❖ Autologous SCT and ISRT can be considered with 2nd line CT as usual in case of PR
or progressive disease specially when relapse occurs >6–18 months
❖ Allogenic SCT in case of persistent cases.
Dr. Asad R10

L y m p h o m a | 118
Primary Mediastinal Large B-cell Lymphoma (dv)

Within the category of DLBCL is a distinct clinical entity known as primary mediastinal B-
cell lymphoma (PMBL), representing
→ 2.4% of all NHLs and
→ 7% of all cases of DLBCL
PMBLs have a female predominance, with a median age of 40 years.
Immunophenotype and Genetics
✓ PMBLs express B-cell antigens CD19, CD20, and CD22 but lack sIg and CD5.
✓ Unlike other DLBCLs, low-level expression of CD30 is seen in most cases, and a high
fraction of tumors express TRAF1, CD200, and MAL, and have nuclear c-REL.
✓ BCL2 and BCL6 rearrangements are absent.
Clinical Features:
➢ Over 70% of these patients present with stage I/II bulky disease involving the
mediastinum.
➢ Pleural and pericardial effusions are seen in about 50% of the patients.
➢ Superior vena cava syndrome is a frequent complication.
➢ An elevated LDH (77%) and B symptoms (47%) are common.
➢ Relapses occur locally or in extranodal sites, including the liver, GI tract, kidneys,
ovaries, and CNS.
Treatment
➢ The first-line therapy for PMBL consists of anthracycline-based
chemoimmunotherapy.
➢ Options mentioned in devita on the basis of trails:
❖ DA-EPOCH-R × 6C ± RT
❖ R-CHOP × 6C + RT
➢ study from the National Cancer Institute treated 51 patients with dose-adjusted
etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) plus
rituximab (DA-EPOCH-R), and no RT, reported an outstanding PFS (93%) and OS
(100%).
➢ Retrospective analyses have compared R-CHOP plus RT versus DA-EPOCH-R,
showing similar outcome.
➢ While prospective randomized comparison is lacking, DA-EPOCH-R has become a
de facto standard of care for these patients
Chemotherapy-refractory or relapsed PMBL

→ generally, has a poor prognosis.
→ Radiation can salvage incomplete responses or localized relapses, but second-
line chemotherapy often fails to get patients to an ASCT, and relapse rates are high
even in those patients who do get to transplant.
→ These patients were included in the CAR T-cell trials of axicabtagene ciloleucel,
and the response was favorable in this cohort; as a result, this therapy is FDA
approved for relapsed/refractory PMBL.
Dr. Asad R10

L y m p h o m a | 119
Dr. Asad R10

L y m p h o m a | 120
Primary Central Nervous System Lymphoma (dv)

➢ Primary central nervous system lymphoma (PCNSL) is a rare and aggressive
extranodal non-Hodgkin lymphoma confined to the
✓ brain,
✓ leptomeninges,
✓ eyes, or
✓ spinal cord,
o without involvement of other organs at initial diagnosis and with anecdotal
cases of systemic dissemination at relapse
➢ It accounts for approximately 1% of all non-Hodgkin lymphomas
➢ approximately 2% of all primary central nervous system (CNS) tumors.
➢ Its annual incidence rate is 0.43 cases per 100,000 population
➢ More common in males and Whites
➢ The overall incidence of PCNSL has been rising, especially in the elderly.
➢ Median age of 65 years at diagnosis
➢ Among the immunocompetent population, the risk of PCNSL increases with
advancing age, with the highest rates occurring in the group >70 years
Prognosis of primary CNS lymphoma: (dv)
➢ The 5-year survival rate in the United States is <40%.
➢ Untreated median overall survival (OS) is approximately 1.5 months
➢ In one study, there was a 7-year OS of 70% in patients ≤70 years treated with high
dose MTX or WBRT.
Molecular profile: (dv)

➢ The tumor cells express pan-B-cell antigens including
▪ CD19, CD20, CD22, and CD79a.
▪ Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor
4 (IRF4) is nearly always present,
➢ B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL6) is expressed in
approximately 50% of cases,
➢ BCL2 is variably expressed, and
➢ CD10 is expressed in approximately 10% of cases
Pathogenesis and hypothesis:

➢ This immunophenotype (MUM1/ IRF4+, BCL6+, CD10−), present in most PCNSLs,
most closely resembles that of a post germinal center or an activated B-cell (ABC)
lymphoma, which has been confirmed as the genetic signature of PCNSL.
➢ As the CNS does not contain germinal centers, PCNSL is hypothesized to derive from
malignant B cells that undergo transformation outside the CNS with subsequent
migration to the brain. The mechanism of this CNS tropism is unknown
➢ The hypothesis is that, PCNSL is secondary to antigen-dependent activation of
circulating B cells, which subsequently localize to the CNS by expression of various
adhesion and extracellular matrix– related genes.
Dr. Asad R10

L y m p h o m a | 121
Diagnosis and Investigations:

Clinical features:
➢ Presenting symptoms vary with the CNS site involved: lasting from weeks to months,
vary with the CNS site involved
➢ Common symptoms include
▪ Cognitive and/or behavioral changes lasting from weeks to months,
▪ Focal neurologic deficits, and
▪ Symptoms of increased intracranial pressure.
➢ Because PCNSL tends to involve deep brain structures, neurocognitive symptoms are
the most common presenting clinical features of PCNSL.
➢ Other common symptoms include focal neurologic deficits depending on the site of the
CNS involved and symptoms of increased intracranial pressure,
➢ seizures are relatively uncommon.
➢ Approximately 10% to 20% of patients have concurrent intraocular involvement and
may report ocular symptoms
➢ B symptoms such as weight loss, fevers, and night sweats are infrequent in PCNSL.
➢ PCNSL confined to the eye, CSF, or spinal cord at presentation is rare.
Physical examination should consist of a

✓ lymph node examination,
✓ testicular examination in men, and a
✓ comprehensive neurologic examination.
Investigations: (dv)
MRI brain:
➢ A gadolinium-enhanced brain magnetic resonance imaging (MRI) scan is the most
sensitive radiographic study for the detection of PCNSL. Presented as
❖ single brain mass, typically located in the supratentorial region with a
predilection for the frontal lobe and periventricular areas
❖ PCNSL is characterized on T1-weighted, postcontrast images by homogeneous
enhancement with well-defined borders.
❖ It is typically isointense to hypointense on T2-weighted MRI
❖ restricted diffusion on diffusion-weighted imaging
❖ Perilesional vasogenic edema is common.
Spine MRI: Mentioned in NCCN
Magnetic resonance spectroscopy:

PCNSL shares with other tumoral processes (glioblastoma and metastases) a
comparable pattern on magnetic resonance spectroscopy such as
✓ High choline peak,
✓ Reversed choline/creatinine ratio,
✓ Markedly decreased n-acetylaspartate, and
✓ Lactate peak
Dr. Asad R10

L y m p h o m a | 122
Stereotactic brain biopsy:(dv)

➢ Diagnosis of PCNSL is typically made by stereotactic brain biopsy.
➢ When PCNSL is suspected, corticosteroids should be avoided prior to biopsy, if
possible, as these drugs may interfere with histopathologic diagnosis, resulting in
diagnostic delay with possible negative impact on outcome.
CSF study:
PCNSL is diagnosed by CSF cytology and flow cytometry or by
vitrectomy/ chorioretinal biopsy. (NCCN)
A lumbar puncture should be performed if not contraindicated, and CSF analysis should
include (dv)
✓ cytology,
✓ flow cytometry, and
✓ immunoglobulin heavy chain gene rearrangement.
Testicular Ultrasound (NCCN)

Consider testicular ultrasound for men >60 y (category 2B)
Bone marrow biopsy

is considered as category 2B in NCCN
For assessment of complete involvement:

➢ Contrast-enhanced chest/ abdominal/pelvic CT or
➢ Whole body PET/CT scan
In one study, 18FDG-PET was superior to contrast-enhanced CT and identifed occult
systemic disease in 4% to 12% of patients with a prior presumptive diagnosis of PCNSL
(dv)
Others:
➢ HIV testing
➢ LDH
However, to date,
no markers are currently established as diagnostic in routine clinical practice
Prognostic status: (dv)

PCNSL patients were divided into three groups based on age and Karnofsky PS Scale (KPS):
(1) <50 years old,
(2) 50 years and older with a KPS ≥70, and
(3) 50 years and older with a KPS <70.
Based on these three divisions, the median OS was
8.5 years,
3.2 years, and
1.1 years, respectively.
The median failure-free survival was 2 years, 1.8 years, and 0.6 years,
respectively
Dr. Asad R10

L y m p h o m a | 123
Treatment of Primary CNS lymphoma

from Dv:
➢ Historically, PCNSL was treated only with WBRT at doses ranging from 36 to 45 Gy,
which resulted in a high proportion of radiographic responses but also in an
unacceptably high rate of early relapses.
➢ Given the lack of durable responses and the risk of neurotoxicity associated with this
treatment modality, WBRT is no longer recommended as exclusive treatment for
patients with newly diagnosed PCNSL.
➢ Newly diagnosed PCNSL is now typically treated with induction chemotherapy to
achieve a radiographic response followed by consolidation therapy, with the goal to
eradicate any residual disease.
➢ Resection is not part of the standard treatment approach for PCNSL.
Treatment option is (NCCN): (As induction therapy:)

➢ High-dose methotrexate-based regiment
other systemic therapy regimen if patient is unsuitable for or intolerant to high-dose
methotrexate
OR
➢ Whole brain RT (WBRT) if patient is NOT a candidate for systemic therapy
Dose: 24–36 Gy to whole brain followed by a
boost to gross disease for a total dose of 45 Gy
After CT, if complete response (CR) or complete response unconfirmed (CRU)

consider: (as consolidation therapy)
➢ Continue monthly high-dose methotrexate-based regimen for up to 1 year
➢ High-dose systemic therapy with stem cell rescue
➢ High-dose cytarabine ± etoposide
➢ Low-dose WBRT:
→ low-dose WBRT should be limited to 23.4 Gy in 1.8 Gy fractions
following a complete response (CR) to systemic therapy
→ For less than CR, consider WBRT to 30–36 Gy followed by a limited field
to gross disease to 45 Gy or focal radiation to residual disease only
If residual disease present after CT: (as consolidation therapy)

➢ WBRT 24–36 Gy to whole brain, boost to gross disease 45 Gy
➢ Consider high-dose cytarabine ± etoposide
➢ Best supportive care
If there is CSF positive or spinal MRI positive, (NCCN)

consider intra-CSF systemic therapy + focal spinal RT (45–54 Gy/1.8Gy #)
Intra-CSF therapy with
◊ Methotrexate
◊ Cytarabine
◊ Rituximab
Dr. Asad R10

L y m p h o m a | 124
If there is Eye involvement: (NCCN)

if eye exam shows vitreoretinal involvement and disease is not responding to systemic
therapy, consider orbital RT
Induction chemotherapy options: (dv)

➢ Although there is general agreement that induction should include HD-MTX, there is
NO consensus on the optimal dose and schedule of HD-MTX, or the optimal
chemotherapy combination.
➢ Studies of HD-MTX monotherapy at doses of 3.5 to 8 g/m2 are associated with
overall response rates of 35% to 74%, median PFS of 10 to 12.8 months, and median
OS of 25 to 55 months.
➢ In general, a methotrexate (MTX) dose ≥3 g/m2 delivered as an initial bolus
followed by an infusion over 3 hours, administered every 10 to 21 days, is
recommended for optimal outcomes and adequate CSF concentrations.
➢ Role of rituximab in induction CT is controversial. The results of a recent meta-
analysis of randomized trials showing that rituximab in combination with MTX-based
chemotherapy may improve PFS and the report that rituximab does not
negatively affect cognitive functions are observations in favor of its
ongoing incorporation into induction regimens.
Consolidative Treatment:
➢ Nonmyeloablative chemotherapy and WBRT alone or in combination, and
HDT/ASCT, have all been proposed as consolidation strategies,
➢ It is now widely recognized that there is a higher incidence of neurotoxicity with
combined modality treatment that includes WBRT. This observation prompted
studies focusing on either reducing the WBRT dose or deferring WBRT until the time
of relapse.
Dr. Asad R10

L y m p h o m a | 125
Treatment of the Elderly (dv)

➢ Elderly patients account for more than half of all subjects diagnosed with PCNSL in
population-based studies. A standard of care for elderly patients with PCNSL is not
yet established.
➢ However, it is generally agreed that, due to the higher risk of neurotoxicity in the elderly
population, WBRT should be deferred until the time of disease relapse and initial
treatment should include HD-MTX–based combination chemotherapy. Whether
incorporation of a reduced dose of WBRT can be safely used in this population remains
to be determined.
➢ Several studies have indicated that HD-MTX at doses of 3.5 to 8 g/m2 can be well
tolerated in elderly patients with manageable grade 3 or 4 renal and hematologic
toxicity
➢ Historically, HDT/ASCT was not considered a feasible option for elderly patients,
but experience from randomized phase II trials has demonstrated that “fit” patients up
to the age of 70 years can be treated with this approach without excessive treatment-
related mortality.
Management of Refractory/ Relapsed Primary CNS Lymphoma:(dv)

➢ Approximately 20% to 50% of newly diagnosed PCNSL patients do not achieve a CR
with currently available treatment regimens, highlighting the need for better induction
strategies. Moreover, even after a CR, patients with PCNSL may experience
relapse, especially in elderly subjects.
➢ In this study, a better prognosis was observed in patients who received HDT/ASCT at
relapse; however, these patients tended to be younger with better PS and
more chemosensitive disease
➢ Whenever available, clinical trials should be the preferred option in the R/R setting,
as no standard of care exists. When a clinical trial is not available, therapeutic choice
should be based on available data from published nonrandomized trials
➢ Rechallenge with HD-MTX can be effective in patients previously responsive to this
agent.
➢ HDT/ASCT is also an option at the time of relapse, especially for fit patients with a
good PS who did not receive prior myeloablative therapy.
➢ Age >60 years and shorter time (<6 months) between initial HD-MTX–based therapy
and salvage WBRT were associated with a higher risk of neurotoxicity
Grey Zone Lymphoma

➢ B-cell Lymphoma In 2008, the WHO created provisional diagnoses to capture B-
cell lymphomas with features between two established diagnoses:
▪ BL and DLBCL, and
▪ classical Hodgkin lymphoma (cHL) and DLBCL.
o These lymphomas constituted the grey zone lymphomas.
➢ Grey zone B-cell lymphoma with features intermediate between DLBCL and cHL is
retained in the 2016 WHO classification, but grey zone lymphoma with features
intermediate between BL and DLBCL has been eliminated (mainly covers high
grade lymphoma , with MYCN gene, BCL 2, BCL 6 mutation)
Dr. Asad R10

L y m p h o m a | 126
Testicular Diffuse Large B-cell Lymphoma

➢ DLBCL presenting in the testis is the most common malignant testicular tumor in men
older than 60 years of age and constitutes 1% of all lymphomas.
➢ Other less common histologies include BL in children and, rarely, FL.
➢ Despite therapy, patients are at risk for relapse systemically in the
• CNS and
• the contralateral testis.
➢ Therefore, following orchiectomy, patients require systemic therapy, and strong
consideration should be given to CNS prophylaxis with either systemic or intrathecal
methotrexate, as well as prophylactic radiation to the contralateral testis.
treatment options are (as from trail basis) :(dv)
Treatment description
1st step Orchiectomy of affected testis
2nd step systemic therapy eight cycles of RCHOP-21
rd
3 step CNS prophylaxis four weekly doses of intrathecal
methotrexate:
12 mg
th
4 step RT to the contralateral testis 30 Gy
RT to regional node 30 to 36 Gy to regional nodes for
patients with stage II disease
❖ With a median follow-up of 65 months, the OS and PFS at 5 years were 85% and 74%,
respectively.This study defines the current standard of care with chemoimmunotherapy,
CNS prophylaxis, and radiation to the contralateral testis.
❖ Primary testicular lymphoma has been found to have recurrent genetic alterations
involving the programmed cell death protein ligands 1 and 2 (PD-L1 and PD-L2) locus
on chromosome and in components of the Toll-like receptor signaling pathway.
❖ Immune checkpoint blockade has demonstrated early preliminary efficacy in this
disease in the relapsed/refractory setting, and nivolumab is currently being tested
in a larger, multicenter clinical trial
AIDS related B cell lymphoma (NCCN):

These are:
❖ Burkitt’s lymphoma
❖ Primary CNS lymphoma
❖ DLBCL
❖ HHV8-positive DLBCL
❖ Primary effusion lymphoma
❖ Plasmablastic lymphoma
➢ Antiretroviral therapy (ART) can be administered safely with chemotherapy, but
consultation with an HIV specialist or pharmacist is important to optimize
compatibility.
➢ With continued development of new ARTs, effective alternatives are often available to
patients when the existing ARTs are expected to affect metabolism of or share toxicities
with chemotherapy.
➢ In general, avoidance of zidovudine, cobicistat, and ritonavir is strongly
recommended. Concurrent ART is associated with higher CR rates
Dr. Asad R10

L y m p h o m a | 127
➢ Patients with HIVrelated DLBCL receiving ART are suitable candidates for CAR T-
cell therapies with appropriate supportive care measures for HIV control.
Suggested regimens Special consideration

Burkitt’s ➢ CODOX-M/IVAC Granulocyte colony-stimulating
lymphoma with (modified) factor (G-CSF) for all patients
HIV ➢ DA-EPOCH-R
➢ R-Hyper CVAD
❖ DLBCL ➢ R-EPOCH ✓ G-CSF for all patients
❖ HHV8- (preferred) ✓ Intrathecal (IT) therapy
positive ➢ RCHOP ✓ If CD20-, rituximab is not
DLBCL, NOS indicated
❖ Primary
effusion
lymphoma
Plasmablastic ➢ EPOCH (preferred) ✓ Standard CHOP is not adequate
lymphoma Others: therapy
➢ CODOX-M/IVAC ✓ Intrathecal (IT) therapy
(modified) ✓ Consider HDT/ASCR in first
➢ HyperCVAD complete remission in
select high-risk patients
In above all cases:
If CD4 <50, maximize supportive care and monitor closely for cytopenia and
infections while administering lymphoma therapy
Patients with HIVrelated DLBCL receiving ART are suitable candidates for CAR T-
cell therapies with appropriate supportive care measures for HIV control.
In case of primary CNS lymphoma with HIV: (NCCN)

➢ Initiate ART, if not already receiving
➢ Even with poorly controlled HIV and/or marginal performance status, consider high-
dose methotrexate
➢ For select patients with good performance status on ART, see the NCCN Guidelines
for CNS Primary CNS Lymphoma
➢ Consider RT alone as initial treatment for patients who are not candidates for systemic
therapy
➢ at presentation, then reassess eligibility for systemic therapy after RT
Treatment recommendation (ad):
➢ HAART is the first step in the treatment of these patients. There is a clear
correlation between the immune status of the patient and prognosis.
➢ The use of steroids and anticonvulsants is debated among some investigators
concerned with the potential of steroids to confound the histologic diagnosis.
However, a few days of steroids (4–5 days) can be of clinical benefit, particularly
when there is an obvious mass effect.
➢ Anticonvulsive therapy administered for a few days
➢ Even solitary lesions of PCNSL tend to infiltrate surrounding tissues. Thus, there is
no role of surgical resection in the treatment of this disease
Dr. Asad R10

L y m p h o m a | 128
RT vs systemic therapy in Primary CNS lymphoma+HIV: (ad)

➢ Before HAART, whole-brain radiotherapy was the standard of care for PCNSL,
until it was replaced by best comfort measures, because the brains of severely
immunocompromised patients tolerated the administration of radiotherapy poorly.
➢ Similar to immunocompetent patients with PCNSL, high dose methotrexate and
rituximab have replaced the administration of radiotherapy in patients with
HIV and PCNSL.
➢ Investigators have suggested a modification of a standard regimen used for the
treatment of patients without HIV, which includes
▪ Rituximab 500 mg/m2 on day 1 and
▪ Methotrexate 3.5 g/m2 and
▪ Vincristine 1.4 mg/m2 given only on day 2.
▪ Leucovorin rescue is given in standard fashion, and
▪ HAART treatment is initiated or continued.
➢ This modified regimen is administered for five to six cycles depending on the
tolerance of the patient, followed by four courses of monthly maintenance with
radiotherapy administered in a stereotactic manner at the discretion of the treating
physician.
➢ For patients not eligible to receive high-dose methotrexate, options include the use of
▪ temozolomide-rituximab and,
▪ in selected cases, focal radiotherapy followed by maintenance with
an immunomodulatory agent such as lenalidomide or pomalidomide.
Plasmablastic lymphoma: (net)

➢ Plasmablastic lymphoma (PBL) is an uncommon but aggressive subtype of diffuse,
large, B-cell lymphoma. The diagnosis of PBL is difficult because its features overlap
with myeloma and lymphoma.
➢ The primary organs involved are usually the gastrointestinal system, lymph nodes, oral
mucosa, and sometimes the skin. It has a very aggressive disease course comprising
relapses and refractoriness to chemotherapy. PBL is a very rare diagnosis, and hence
there is no established standard to treat PBL
➢ It is more prevalent in patients with human immunodeficiency virus (HIV) and Ebstein-
Barr virus (EBV) infections and patients with a suppressed immune system (such as
patients on immunosuppressive medications).
Primary effusion lymphoma (PEL) (net)

➢ rare B-cell lymphoma with a particularly aggressive course.
➢ This disease usually affects the variably immunocompromised and maintains a
predilection for body cavities, leading to the development of malignant effusions.
➢ Pathogenesis suggests an association with HHV8 and EBV, although this is unclear.
➢ There are no definitive guidelines for the treatment of PEL, but commonly used initial
regimens include those similar to DA-EPOCH and CHOP.
➢ The prognosis remains poor, even with advanced treatment.
➢ Newer therapies incorporate the use of axicabtagene ciloleucel, CAR-T cell therapies,
and augmented EPOCH regimens.
Dr. Asad R10

L y m p h o m a | 129
Primary Intraocular Lymphoma (pz)

➢ Primary intraocular lymphoma (PIOL), formally known as ocular reticulum
cell sarcoma, is an uncommon clinical manifestation of non-Hodgkin
lymphoma, which arises in the retina or the vitreous humor.
➢ Primary adnexal lymphoma (involving the conjunctiva, lacrimal gland, or orbital soft
tissues) is primarily MALT (mucosa-associated lymphoid tissue) lymphoma whereas
diffuse large B-cell lymphoma (DLBCL) is more commonly seen in ocular
involvement in primary CNS lymphoma (which occurs in up to ¼ of this subset of
patients). (cPZ)
Relation with primary CNS lymphoma:
➢ Intraocular lymphoma may occur
▪ independently,
▪ prior or subsequent to a primary central nervous system lymphoma
(PCNSL).
➢ PIOL progresses to intracranial involvement in 60% to 85% of cases.
➢ Historically, PIOL has been difficult to diagnose, often taking several years from the
onset of symptoms to establishing a diagnosis, which likely contributed to suboptimal
outcome in many cases.
Clinical features
➢ Patients often complain of
▪ blurred vision, a painless loss of vision, and floaters.
➢ It usually develops in patients in the fifth and sixth decade of life as a chronic,
relapsing and steroid-resistant uveitis and vitritis.
Treatment options:
➢ Given the tumor’s rarity, the optimal treatment of PIOL is unclear.
➢ The staging workup is the same as that used for non-Hodgkin’s lymphoma at other
sites.
For indolent lymphomas of the orbit:
➢ For indolent lymphomas of the orbit, primary radiotherapy is the standard of care,
➢ doses of 24 to 25 Gy in smaller daily fractions (1.5 to 1.8 Gy)
➢ CTV including the entire orbit; partial orbital irradiation is associated with a
higher likelihood of local failure. An exception may be those tumors confined to
the conjunctiva.
➢ A whole orbital radiation technique that avoids the contralateral orbit is a superior-
inferior wedge pair, though IMRT is also effective
For DLBCL:
➢ Start chemotherapy RCHOP, After chemotherapy:
• In case of complete response: dose can be limited to 30 Gy,
• In case of partial response: doses over 36 Gy confined to sites of gross disease
Dr. Asad R10

L y m p h o m a | 130
Cutaneous Lymphomas
➢ The cutaneous lymphomas comprise a heterogeneous group of malignancies of both T and
B lymphocytes that localize to the skin
➢ According to Surveillance, Epidemiology, and End Results (SEER) data, the skin is the
second most common site of extranodal non-Hodgkin lymphoma
➢ The Dutch and Austrian Cutaneous Lymphoma registries report that
▪ >70% of all cutaneous lymphomas are of T-cell origin, and
▪ 22% are of B-cell origin.
World Health Organization European Organization for Research and Treatment of
Cancer 2018 Classification of Cutaneous Lymphomas:
Type Frequency (%) 5-Year DSS (%)

Cutaneous T-cell and NK-cell lymphomas
Mycosis fungoides (MF) 39% 88
MF variants and subtypes
Folliculotropic MF 5 75
Pagetoid reticulosis <1 100
Granulomatous slack skin <1 100
Sézary syndrome 2 36
Adult T-cell leukemia/lymphoma <1
Primary cutaneous CD30+ lymphoproliferative 8 95
disorders
Primary cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
Subcutaneous panniculitis–like T-cell lymphoma 1 87
Extranodal NK/T-cell lymphoma, nasal type <1 16
Primary cutaneous peripheral T-cell lymphoma, <1 <30
unspecified
Primary cutaneous aggressive epidermotropic
CD8+ T-cell lymphoma (provisional)
Cutaneous γ/δ T-cell lymphoma (provisional)
Primary cutaneous CD4+ small/medium-sized
pleomorphic T-cell lymphoma (provisional)
Precursor hematologic neoplasm
CD4+/CD56+ hematodermic neoplasm (blastic
NK-cell lymphoma)
Cutaneous B-cell lymphomas

Primary cutaneous marginal zone B-cell lymphoma 9 95-100,
Primary cutaneous follicle center lymphoma 12
Primary cutaneous diffuse large B-cell lymphoma, 4
leg type
Primary cutaneous diffuse large B-cell lymphoma, <1 72
other
Intravascular large B-cell lymphoma <1
Dr. Asad R10

L y m p h o m a | 131
According to aggressiveness:
Common clinical features of cutaneous lymphoma: (ad)

➢ Patients with cutaneous lymphoma typically present with patches, plaques, and
tumors on the skin.
➢ Patches are characterized by fat, nonpalpable erythematous involvement in the skin.
If lesions become thickened and palpable, they are considered plaques.
➢ More advanced stages are associated with tumors in the skin that are more indurated or
ulcerated.
➢ Other less common cutaneous findings associated with CTCL include
▪ leonine facies,
▪ palmar plantar hyperkeratosis,
▪ poikiloderma
▪ hypopigmentation
➢ to rule out pseudolymphoma, It is important to take previous H/O:
▪ medication history
▪ history of recent exposures to viral or infectious organisms
➢ All patients with B-cell cutaneous lymphoma should undergo screening for systemic
disease
Physical examination:
➢ It is important assess the BSA area:
➢ The modified SWAT is the most recognized method of measuring cutaneous
involvement with CTCL and is often used clinically and in clinical trials for
skin assessment.
➢ The patient’s hand size is used to estimate about 1% BSA.
➢ Patches are weighted with factor of 1, plaques are weighted with factor of 2, and tumors
are weighted with factor of 4 to determine the modified SWAT
Dr. Asad R10

L y m p h o m a | 132
Overall Investigation of cutaneous lymphoma should include: (ad+NCCN)

➢ Multiple biopsies may be necessary to capture the pathologic variability of disease at
diagnosis
➢ IHC panel of skin biopsy may include:
o CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD56, ALK
➢ Molecular analysis to detect clonal T-cell receptor (TCR) gene rearrangements
➢ Baseline investigation, including LDH
➢ Imaging:
▪ Chest/abdomen/pelvic (C/A/P) CT with contrast or
▪ integrated whole body PET-CTl for T3 or T4 (arms/legs included when
disease assessment of entire body is needed)
For screening, it may require to do
▪ syphilis,
▪ human immunodeficiency virus(HIV),
▪ hepatitis B and C, and
▪ in select patients, human T-cell leukemia/lymphoma virus-1 (HTLV-1) if
applicable
In this section, our main discussion is on cutaneous T cell lymphoma

The term cutaneous T-cell lymphoma (CTCL) was formally adopted in 1979 at
a conference sponsored by the National Cancer Institute (NCI) to describe a
heterogeneous group of malignant T-cell lymphomas with primary manifestations in
the skin
Dr. Asad R10

L y m p h o m a | 133
Mycosis Fungoides/Sézary Syndrome (Mf/Ss)

➢ The most common subtype of CTCL is MF, which accounts for approximately 50% to
60% of cases of cutaneous lymphoma
➢ typically carries an indolent course
➢ median age at diagnosis, ~55–60 years
Clinical features: (ad)
➢ typically present with erythematous patches on the skin, which in some patients
progress over years to plaques and tumors.
➢ The lesions favor a “double-hidden” distribution in non–sun-exposed areas
➢ The distribution of the lesions favors non– sun-exposed areas such as the “bathing
trunk” distribution (i.e., involving the buttocks, upper thighs, breasts, and intertriginous
areas) (dv)
➢ Patients present with patches and plaques, which are often mistaken for other
dermatoses such as atopic dermatitis or psoriasis for years before the correct diagnosis
is made. The median delay in diagnosis of 36 months was recently reported in a large
series of patients.
➢ The plaques are typically dark red in appearance and can have variable amounts of
scale. Tumors are often ulcerated and have a variable growth rate.
Description of skin involvement:
➢ A patch is defined as a lesion that is not elevated or indurated and may be hyper- or
hypopigmented and associated with fine wrinkling.
➢ A plaque is raised or indurated and may be associated with scaling, crusting, or erosive
changes.
➢ A tumor is a lesion >1 cm with evidence of depth or vertical growth.
➢ Erythroderma is defined as diffuse erythema involving >80% of the skin surface, with
or without scaling
Pathogenesis:
➢ No definite cause or association leading to the development of MF has been identified.
However, it is believed that it is triggered by chronic antigenic stimulation, leading to
expansion of clonal skin homing T lymphocytes to the skin, such as chronic exposure
of (may have role of)
▪ Staphylococcus aureus enterotoxins
▪ Epstein-Barr virus (EBV) and
▪ cytomegalovirus (CMV)
Immunohistochemistry of MF: (NCCN):
➢ CD2+, CD3+, CD5+, CD7-, CD4+, CD8- (rarely CD8+), CD30-/+ cytotoxic
granule proteins negative.
➢ Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can
also be seen in patients with non-malignant conditions.
Dr. Asad R10

L y m p h o m a | 134
Variants of Mycosis Fungoides:

Folliculotropic MF
➢ entity in which the malignant lymphocytes have affinity for the pilosebaceous units.
Typically, mucin deposits are also seen, and there is associated follicular mucinosis.
➢ Clinically, these patients present with acneiform lesions along with scalp involvement
and alopecia.
➢ Patients with folliculotropic MF were also found to have increased risk of disease
progression and lower overall survival.
➢ This is likely attributed to decreased response to skin-directed therapy because of
disease sanctuary in the follicles
Granulomatous slack skin
➢ rare indolent variant of MF in which there are granulomatous T-cell infiltrates in the
skin and destruction of elastic fibers, resulting in loose skin folds.
➢ Given that the infiltration of malignant cells is typically deep into the dermis
and subcutis, localized radiation can be used for local control of the disease.
➢ Systemic treatment is needed for advanced-stage disease
Hypopigmented MF
➢ unique variant of MF seen in younger patients.
➢ The median age of onset is 28 to 35 years with an overall favorable prognosis.
➢ This is predominantly a CD8+ phenotype; however, CD4+ variants have been reported.
Phototherapy is an effective treatment modality in this variant
Diagnosis of Early Mycosis Fungoides proposed by the International Society for

Cutaneous Lymphoma
A total of 4 points is required
for the diagnosis of mycosis
fungoides based on any
combination of points from the
clinical, histopathologic,
molecular, and
immunopathologic criteria (ad)
Dr. Asad R10

L y m p h o m a | 135
Sézary Syndrome
➢ SS is characterized by the presence of atypical T cells (Sézary cells) in skin causing
▪ diffuse erythema (erythroderma) and
▪ significant blood involvement with abnormal T cells (>1000
abnormal cells/uL) defined as Sézary cells by cytopathologic
assessment or flow cytometry (abnormal subsets including but not
limited to CD4+CD7- or CD4+CD26- cells; TRBC1 may contribute in
detecting clonality and is especially useful in cases where CD7 or CD26
are not lost).
➢ SS represents the leukemic variant of CTCL and is closely related to MF but has unique
characteristics. SS is rare, accounting for less than 5% of cutaneous lymphomas and
predominantly affects older individuals
➢ SS is thought to arise from thymic memory T cells, while skin resident effector
memory T cells are the cells of origin of MF.
Clinical features:
➢ Clinical features of the SS include extensive skin involvement with erythroderma,
which may progress to lichenification, palmoplantar hyperkeratosis, and diffuse
exfoliation.
➢ Skin edema, hypoalbuminemia due to insensible fluid loss related to impaired skin
integument, and intense pruritus are frequently observed in patients with advanced
disease.
➢ Lymphadenopathy, histopathologic effacement of nodes, and bone marrow
involvement are common.
Staging of MS and SS:
Dr. Asad R10

L y m p h o m a | 136
Treatment of MF and SS
➢ The goals of treatment for MF are similar to those of other indolent lymphomas in
maintaining remission and treating symptoms, but cure of disease is rare
➢ In patients with early stage disease (stage IA to IIA) with skin-limited disease, skin-
directed treatment is used frontline. (ad)
➢ Early aggressive intervention with chemotherapy and radiation for MF has not been
shown to improve prognosis compared with topical therapy.
➢ In patients with advanced stages of disease (stage IIB–IVB), the disease is often
treatment refractory, and the prognosis is poor. The duration of response for systemic
treatment options such as immunotherapy and targeted therapy is relatively
short, and in select younger patients, allogeneic stem cell transplantation should be
considered when remission is achieved (ad)
Overall treatment options are:

➢ Skin-Directed Therapies
▪ Topical Corticosteroids
▪ Nitrogen Mustard
▪ Imiquimod
▪ Topical Bexarotene: 1% gel bexaroten
▪ Phototherapy: 311 nm UVB light and 320 to 400 nm UVA light
➢ Radiation:
▪ single or two fractions of low-dose radiation (8 Gy) as local therapy
early stage
▪ Total-skin electron-beam therapy (TSEBT):
✓ 30–36 Gy delivered over 8–10 weeks
✓ reserved for patients with skin-limited disease with more
significant disease burden involving plaques and tumors.
➢ Systemic Therapies
▪ Retinoids
▪ INF-α and INF-Y
➢ Immunotherapy:
▪ Brentuximab Vedotin
▪ Mogamulizumab
▪ Histone Deacetylase Inhibitors: romidepsin and vorinostat
▪ Alemtuzumab
➢ Antimetabolites: Methotrexate and pralatrexate
➢ Gemcitabine
➢ Combination chemotherapy with CHOP, EPOCH
➢ Stem Cell Transplantation
Dr. Asad R10

L y m p h o m a | 137
Dr. Asad R10

L y m p h o m a | 138
Total-skin Electron Beam Therapy (dv)

➢ Total-skin electron beam therapy (TSEBT) involves the use of electrons ranging in
energy between 4 and 7 MeV applied homogeneously to the skin surface. Structures
below the deep dermis are relatively spared because most of the dose (80%) is
typically administered within the first 10 mm of depth, and <5% beyond 20 mm depth.
➢ Generally, doses to the skin target are in the range of 30 to 36 Gy. Blood and
superficial lymph nodes may receive 20% to 40% of the skin surface dose, and this may
be clinically important.
➢ TSEBT may be administered as just one in a sequence of treatments for CTCL in a
particular patient. For example, TSEBT is excellent treatment for patients with
diffuse involvement with thick plaques or cutaneous tumors and is also suitable for
patients with symptomatic erythroderma–T4 disease.
➢ TSEBT is also an excellent alternative for patients with extensive patches or
thin plaques refractory to PUVA or other skin-directed therapies.
Dr. Asad R10

L y m p h o m a | 139
From Ad:
Gemcitabine:
In a phase II prospective study of gemcitabine in 30 previous treated patients with MF
and 14 patients with peripheral T-cell lymphoma, an ORR of 70% was observed with
11% achieving complete response
Pegylated Liposomal Doxorubicin:
In a phase II trial in patients with advanced-stage MF, a 41% ORR was observed.
Combination Chemotherapy
Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone) or CHOP-based treatments for CTCL was found to have ORR of 40% with
25% complete response, but the median duration of response is only 5.7 months
and with more toxicity
Mogamulizumab
Mogamulizumab is a humanized monoclonal antibody against chemokine receptor type
4 (CCR4) approved in the United States for patients with relapsed or refractory MF or
SS after at least one prior systemic therapy.
N.B:
✓ Skin directed therapy and immunotherapy/systemic chemotherapy options can be given
all together specially in advanced cases. (except for IA, where local skin therapy is
mainly recommended.
✓ In stage III, IV, systemic chemotherapy option is more focused then local treatment.
✓ After CR, better to consider about ASCT, Allogenic SCT is for advanced relapse
refractory cases.
Treatment of patients with SS:
➢ similar to the management of patients with advanced-stage MF with blood
compartment involvement.
➢ Frontline treatment incorporating the use of ECP in the setting of multimodality
therapy in combination with retinoid or INF produces high overall responses of 75%
with a 30% complete response.
➢ Mogamulizumab can also be considered in this group of patients given its high blood
compartment response of 68%
Extracorporeal Photopheresis Procedure (ECP):
indicated in cutaneous T cell lymphoma, Graft versus
host reaction etc
T cell is irradiated with UVA light added with 8-
methoxypsoralane, and retuned back inside body to
produce immune reaction. (net)
Steps are:
1. Whole blood is separated via centrifugation and
the leukocyte rich buffy coat layer is retained (2a).
2. Red blood cells and plasma are returned to the
patient (2b).
3. Methoxsalen at 20 μg/ml is added to the buffy coat
4. Buffy coat is treated with ultraviolet A (UVA) light at 1–2 J/cm² for 30–90 min [4] and
then returned to the patient
5. This process occurs continuously in the newer CELLEX machines
Dr. Asad R10

L y m p h o m a | 140
Primary CD30+ Lymphoproliferative Disorders

➢ Lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell
lymphoma (pcALCL) are two entities on the spectrum of CD30
lymphoproliferative disorders that are associated with good prognoses.
LyP,
➢ clinically small (<1 cm), red, grouped papules or nodules that spontaneously resolve
within 1 to 2 months.
➢ This condition is considered to be benign, but in 10% to 20% of patients, it can
appear along with another type of lymphoma, most commonly in MF.
➢ It is also reported in patients with other hematologic malignancies such as
Hodgkin lymphoma or pcALCL.
Primary cutaneous ALCL
➢ often histologically indistinguishable from LyP.
➢ Unlike systemic ALCL, pcALCL does not express anaplastic lymphoma kinase and if
positive suggests a secondary ALCL in the skin.
➢ This condition typically presents as single ulcerated tumor or cluster of tumors. In
contrast to LyP, there is rarely spontaneous resolution, but the prognosis is good with
the estimated 5-year survival rate at more than 90%
Treatment options:
PC-ALCL Solitary lesion:

ISRT Or Surgical excision ± ISRT
Multifocal:
Preferred regimen Brentuximab vedotin
Other recommendation:
Methotrexate (≤50 mg weekly)
Systemic retinoids
Pralatrexate
Observation, if asymptomatic
Interferon
Consider about additional skin directed therapy
Cutaneous ALCL with Preferred regimens
regional node (N1) ➢ Brentuximab vedotin ± ISRT
➢ ISRT in selected cases
➢ Brentuximab vedotin + CHP
➢ Methotrexate ± ISRT
➢ Pralatrexate ± ISRT
➢ CHOP or CHOEP ± ISRT in selected cases
LyP Limited lesions, asymptomatic:
Observation (preferred)/Topical steroids
Limited lesions, symptomatic:
Topical steroids/ Phototherapy/ Observation
Extensive lesions:
Methotrexate (10–35 mg weekly
Phototherapy
Systemic retinoids
Topical steroids
Topical mechlorethamine (nitrogen mustard)
Dr. Asad R10

L y m p h o m a | 141
Some other non-cutaneous variety of T cell lymphoma:

T-Cell Large Granular Lymphocytic Leukemia (LGLL) (NCCN)
➢ LGLL is an indolent T-cell lymphoproliferative disorder (LPD) of the mature
cytotoxic lymphocytes of effector memory cell phenotype.
➢ Most cases have an indolent and non-progressive clinical course, and moderate to
severe autoimmune neutropenia is a frequent laboratory abnormality.
➢ Thrombocytopenia and anemia are less common and may accompany neutropenia
leading to bilineage or trilineage cytopenias.
➢ There is significant clinical and pathophysiologic overlap with autoimmune
syndromes, in the majority of patients, LGLL is diagnosed concurrently with
rheumatologic disease (ie, rheumatoid arthritis [RA] and systemic lupus erythematosus
[SLE]
➢ The diagnosis is generally established based on the persistence (>6 months) of LGL
with typical morphologic features (moderate to copious cytoplasm with prominent
azurophilic granules) in the peripheral blood and the bone marrow of the patients
(>2000/uL), and exclusion of other potential conditions or illnesses where LGL is part
of the pathologic process (ie, viral infections, other malignancies, rheumatologic
disease).
➢ Typical immunophenotype for T-LGLL:
CD3+, CD8+, CD16+, CD57+, CD56+/-, CD28, CD5 dim, and/or CD7 dim,
CD45RA+, CD62L-, TCRαβ+, TIA1+, granzyme B+, or granzyme M+.
Overlap with reactive LGL is frequent.
Treatment is needed in following conditions:
✓ ANC <0.5 x 109/L
✓ Hemoglobin <10 g/dL or need for red blood cell (RBC) transfusion
✓ Platelets <50 x 109/L
✓ Autoimmune diseases with T-LGLLs requiring therapy
✓ Symptomatic splenomegaly
✓ Severe B symptoms
✓ Pulmonary artery hypertension secondary to LGLL
If these features are not present: observation
If these features are present:
➢ Low-dose methotrexate ± corticosteroids
➢ Oral cyclophosphamide ± corticosteroids
➢ Cyclosporine ± corticosteroids
➢ CR is defined as: recovery of blood counts to Hgb >12 g/dL, ANC >1.5 x 109/L,
platelet >150 x 109/L, resolution of lymphocytosis (<4 x 109/L), and circulating LGLL
counts within normal range (<0.5 x 109/L).
➢ PR is defined as: recovery of hematologic parameters to Hgb >8 g/dL, ANC >0.5 x
109/L, platelet >50 x 109/L, and absence of transfusion
In case of CR / PR: Continue treatment or intermittent therapy
If no response: Alternate first line therapy or Alemtuzumab
➢ Methotrexate with or without steroids may be beneficial in patients with autoimmune
disease; cyclophosphamide or cyclosporine may be used as a first- or second-line
option in patients with anemia
Dr. Asad R10

L y m p h o m a | 142
Peripheral T-Cell Lymphomas:(NCCN)

➢ Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group
of lymphoproliferative disorders arising from mature T cells,
➢ accounting for about 10% of non-Hodgkin lymphomas (NHLs)
Verities are:
❖ PTCL-not otherwise specified (PTCL-NOS; 26%) is the most common subtype,
❖ Angioimmunoblastic T-cell lymphoma (AITL; 19%),
❖ Anaplastic large cell lymphoma (ALCL),
❖ Anaplastic lymphoma kinase (ALK)-positive (7%),
❖ ALCL, ALK-negative (6%),
❖ enteropathy-associated T-cell lymphoma (EATL; <5%).
❖ Nodal PTCL with T-follicular helper (TFH) phenotype (PTCL,TFH) and
follicular T-cell lymphoma (FTCL) [newly added in WHO classification]
PTCL-NOS
➢ most often involves nodal sites;
➢ however, many patients present with extranodal involvement, including the liver, bone
marrow, gastrointestinal (GI) tract, and skin.
➢ PTCL-NOS is associated with poorer overall survival (OS) and event-free survival
(EFS) rates compared to aggressive B-cell lymphomas.
Angioimmunoblastic T-cell lymphoma:
AITL is the classic form of the TFH phenotype, usually presents with generalized
lymphadenopathy, and is often with associated hypergammaglobulinemia,
hepatomegaly or splenomegaly, eosinophilia, skin rash, and fever
Association with EBV is common.
Anaplastic Large Cell Lymphoma (ALCL)
➢ ALCL is a CD30-expressing subtype that accounts for less than 5% of all cases of NHL.
➢ There are now four distinctly recognized subtypes of ALCL:
1. systemic ALCL, ALK-positive;
2. systemic ALCL, ALK-negative;
3. breast implant-associated ALCL (BIA-ALCL), and
4. primary cutaneous ALCL.
The majority of patients with systemic ALCL present with advanced stage III or IV
disease (65% for ALK-positive and 58% for ALK-negative) frequently associated with
systemic symptoms and extranodal involvement.
Overall treatment options:

Type Stage Treatment options
Anaplastic Large Cell Stage I, II Multiagent chemotherapy x 6 cycles ± (ISRT) or
Lymphoma (ALCL) ALK Multiagent chemotherapy x 3–4 cycles + ISRT
positive Stage III, IV Multiagent chemotherapy x 6 cycles
Any other histology: Stage I–IV Multiagent chemotherapy 6 cycles ± ISRT
PTCL-NOS ALCL ALK (-)
AITL, EATL, MEITLg
Nodal PTCL, TFH FTCL
Dr. Asad R10

L y m p h o m a | 143
For details please go through NCCN, there is slight change in 2nd line schedule in ALCL. To
avoid complexity, details is not discussed.
T-Cell Prolymphocytic Leukemia

➢ T-cell prolymphocytic leukemia (T-PLL) is a rare malignancy, comprising approximately
2% of all mature lymphoid malignancies.
➢ Clinically, patients frequently present with B symptoms, lymphadenopathy,
hepatomegaly, splenomegaly, and elevated white blood cell (WBC) counts.
➢ Rarely, patients can present with an asymptomatic leukocytosis.
➢ Skin lesions can also be present in approximately 30% of patients, although the
cutaneous presentation is not well characterized.
➢ Central nervous system (CNS) involvement is rare and is seen in less than 10% of patients.
Dr. Asad R10

L y m p h o m a | 144
Treatment:
➢ In Asymptomatic disease: Observe until progression
➢ In symptomatic disease:
▪ Alemtuzumab (IV) alone
▪ FMC (fludarabine, mitoxantrone, cyclophosphamide) followed
by alemtuzumab (IV) in selected patients
▪ Alemtuzumab (IV) and pentostatin in selected patients
After CR/PR: consider allogeneic HCT
Adult T-Cell Leukemia/Lymphoma

➢ Adult T-cell leukemia/lymphoma (ATLL) is malignancy of peripheral
T lymphocytes caused by the human T-cell lymphotropic virus type I (HTLV-1),
➢ associated with a long period of latency (often manifesting several decades after
exposure).
➢ ATLL is endemic to several regions, including southwest regions in Japan, the
Caribbean, and parts of central Africa, owing to the distribution of HTLV-1.
➢ In the International Peripheral T-Cell Lymphoma (PTCL) Project, ATLL comprised
approximately 10% of the diagnosis for confirmed cases of PTCL or natural killer
(NK)-cell/T-cell lymphomas
The Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG) has
classified ATLL into four subtypes
Type Description
Smoldering subtype (10%) • Indolent type
• characterized by greater than or equal to 5%
abnormal T-lymphocytes in the peripheral blood, and
may have skin or pulmonary lesions (but no ascites or
pleural effusion)
• normal lymphocyte count,
• normal serum calcium level,
• LDH levels within 1.5 times upper limit of normal
(ULN), and
• no involvement of the liver, spleen, central nervous
system (CNS), bone, or gastrointestinal (GI) tract
Chronic subtype (10%) • Indolent type
• characterized by greater than or equal to 5%
abnormal T-lymphocytes in the peripheral blood, and
may have skin or pulmonary lesions (but no ascites or
pleural effusion)
• absolute lymphocytosis (≥4 x 109/L) with T
lymphocytes greater than or equal to 3.5 x 109/L,
• normal calcium level,
• LDH levels within two times the ULN, and
• no involvement of CNS, bone, or GI tract;
lymphadenopathy and
• involvement of liver and spleen may be present.
Dr. Asad R10

L y m p h o m a | 145
lymphoma subtype (20%) • absence of lymphocytosis,

• less than or equal to 1% abnormal T-lymphocytes,
• histologically proven lymphadenopathy with or
without extranodal lesions.
acute subtype (60%) • elevated LDH levels,
• hypercalcemia (with or without lytic bone lesions),
• B symptoms,
• generalized lymphadenopathy,
• splenomegaly, hepatomegaly,
• skin involvement, and organ infiltration.
➢ The acute subtype is associated with a rapidly progressive disease (PD) course and usually
presents with leukemic manifestation and tumor lesions, and represents cases that are not
classified as any of the other three subtypes above.
Immunophenotype:
➢ In the NCCN Guidelines, the following is included as representative of a typical
immunophenotype for ATLL: CD2+, CD3+, CD4+, CD7-, CD8-, CD25+, CD30-/+, TCR
αβ+
Treatment options are:
Chronic/Smoldering Observation (asymptomatic smoldering)

subtype Skin-directed therapies as clinically Indicated or
Zidovudine and interferon
Lymphoma subtype Systemic therapy
If there is response Consider allogeneic HCT
Acute subtype Systemic therapy or
Zidovudine and interferon
If there is response Consider allogeneic HCT
1st line therapy include:

• Dose-adjusted EPOCH
• Brentuximab vedotin + CHP
for CD30+ cases
• Zidovudine and interferonc
(acute and
chronic/smoldering subtypes)
Other recommended regimens:
• CHOEP
• HyperCVAD
• CHOP
Dr. Asad R10

L y m p h o m a | 146
Extranodal Natural Killer/T-Cell Lymphomas

➢ Natural killer (NK)/T-cell lymphomas are a rare and distinct subtype of non-
Hodgkin lymphomas (NHL) that are predominantly extranodal.
➢ The majority of extranodal NK/T-cell lymphomas (ENKL) are of nasal type, often
localized to the upper aerodigestive tract including the nasal cavity, nasopharynx,
paranasal sinuses, tonsils, hypopharynx, and larynx.
➢ However, ENKL can also have an extranasal presentation (ENKL of non-upper
aerodigestive tract), with skin, testis, and gastrointestinal tract being the most common
sites of extranasal involvement or metastatic disease
➢ Extranasal presentation is associated with more unfavorable prognostic factors, more
advanced stage, and poorer prognosis
➢ The most common clinical features of ENKL, nasal type include nasal obstruction or
nasal bleeding
➢ Necrosis is very common in diagnostic biopsies and may delay diagnosis.
Immunophenotype:
→ The typical immunophenotype for NK-cell ENKL is CD20-, CD2+, cCD3ε+ (surface
CD3-), CD4-, CD5-, CD7-/+, CD8-/+, CD43+, CD45RO+, CD56+, TCRαβ-, TCRδγ-,
Epstein-Barr virus (EBV)-Epstein-Barr encoding region (EBER)+, and cytotoxic
granule proteins positive (eg, TIA-1+, granzyme B+). For NK-cell lineage, TCR and
immunoglobulin gene represent germline sequences.
→ The typical immunophenotype for T-cell lineage is CD2+, cCD3ε+, surface CD3+,
variable CD4/CD5/CD7/CD8, TCRαβ+ or TCRδγ+, EBV-EBER+, and cytotoxic
granule proteins positive
The initial workup should include
➢ history and physical (H&P) examination with attention to node-bearing areas
(including Waldeyer’s ring), testicles and skin, complete ear, nose, and throat (ENT)
evaluation of nasopharynx, as well as evaluation of B symptoms and
performance status
➢ Bone marrow involvement is uncommon at diagnosis and occurs in less than 20% of
patients within the disease course.
Treatment options:
Nasal type Stage I, II Systemic Chemotherapy + RT

Only RT if not for chemotherapy
Stage IV Systemic Chemotherapy + RT
Extra-nasal Type Combined modality therapy or
Combination chemotherapy
(asparaginase-based) ± RT
Dose of RT:
Dr. Asad R10

L y m p h o m a | 147
Dr. Asad R10

L y m p h o m a | 148
Plasma cell neoplasms

➢ Plasma cell neoplasms are defined by monoclonal proliferation of plasma cells and
the secretion of Monoclonal proteins. (dv)
➢ Plasma cell dyscrasias are heterogeneous disorders arising from the proliferation of a
monoclonal population of plasma cells.
➢ Some of these disorders can present serendipitously as benign processes that can be
observed; others are highly aggressive and require immediate intervention (ad)
The most common plasma cell dyscrasia and Related disorders include (ad)
❖ Monoclonal gammopathy of undetermined significance (MGUS):
benign condition that can be observed.
❖ Smoldering multiple myeloma (SMM),
❖ Multiple myeloma (MM),
❖ Solitary plasmacytoma of the bone,
❖ Extramedullary plasmacytoma,
❖ Waldenström macroglobulinemia,
❖ Primary amyloid light-chain amyloidosis,
❖ Heavy-chain disease,
❖ POEMS syndrome:
✓ polyneuropathy,
✓ organomegaly,
✓ endocrinopathy,
✓ monoclonal gammopathy, and
✓ skin changes
❖ TEMPI syndrome:
✓ telangiectasias,
✓ elevated erythropoietin and erythrocytosis,
✓ monoclonal gammopathy,
✓ perinephric fuid collection, and
✓ intrapulmonary shunting
➢ MGUS represents one end of the spectrum, an asymptomatic premalignancy, while MM
and WM are serious malignancies representing the other end of the spectrum.
➢ SMM is an intermediate entity comprising a mixture of patients who share a
similar clinical phenotype but are biologically heterogeneous with some having
premalignancy (MGUS), and some having occult malignancy (MM)
Monoclonal Proteins:
➢ Plasma cell neoplasms arises from a single clone that, secreted antibodies which are
electrophoretically and immunologically homogeneous known as monoclonal
proteins.
➢ Monoclonal proteins are commonly referred to as M proteins, myeloma proteins, or
paraproteins
➢ They share the same heavy and light chain immunoglobulin types and can be readily
identified on protein electrophoresis or immunofixation
➢ In the majority of clonal plasma cell disorders, intact immunoglobulin molecules
are secreted as M proteins.
Dr. Asad R10

L y m p h o m a | 149
➢ However, in most patients with MM and approximately one-third of patients with

MGUS, there is additional secretion of excess monoclonal free light chains
(FLC) that circulate unbound to immunoglobulin heavy chains.
Polyclonal gammopathy:
➢ Results from polyclonal proliferation of plasma cells and result in the secretion of
excess polyclonal immunoglobulins
➢ It is a result of reactive processes (infections, autoimmune disorders)
➢ Monoclonal and polyclonal proteins can be distinguished readily on serum protein
electrophoresis and immunofixation.
On bone marrow examination,

➢ as in other B cell neoplasms, monoclonal plasma cell disorders exhibit “light chain
restriction” wherein almost all plasma cells homogeneously stain for either kappa
or lambda light chains, indicating that they arose from a neoplastic clonal proliferative
process.
➢ In contrast, in reactive polyclonal plasma cell proliferation, cells would be a mix of
kappa and lambda light chain– expressing cells.
International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and
Related Disorders (dv):
Smoldering multiple myeloma:

Both criteria must be met:
❖ Serum monoclonal protein (IgG or IgA) ≥3 g/dL, or
urinary monoclonal protein ≥500 mg per 24 h and/or
clonal bone marrow plasma cells 10%–60%
❖ Absence of myeloma-defining events or amyloidosis
Dr. Asad R10

L y m p h o m a | 150
Multiple myeloma:
BOTH criteria must be met:
❖ Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
plasmacytoma
❖ Any one or more of the following myeloma-defining events: (CRAB)
➢ Evidence of end-organ damage that can be attributed to the underlying plasma
cell proliferative disorder, specifically:
• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the
upper limit of normal or >2.75 mmol/L (>11 mg/dL)
• Renal insufficiency: creatinine clearance <40 mL per minute or serum
creatinine >177 μmol/L (>2 mg/dL)
• Anemia: hemoglobin value of >2 g/dL below the lower limit of normal or a
hemoglobin value <10 g/dL
• Bone lesions: one or more osteolytic lesions on skeletal radiography,
computed tomography (CT), or positron emission tomography–CT (PET-CT)
➢ Clonal bone marrow plasma cell percentage ≥60%
➢ Involved: uninvolved serum FLC ratio ≥100 (involved FLC level must be ≥100
mg/L)
➢ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5 mm
in size)
Solitary Plasmacytoma:
All 4 criteria must be met:
➢ Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma
cells
➢ Normal bone marrow with no evidence of clonal plasma cells
➢ Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the
primary solitary lesion)
➢ Absence of end-organ damage such as CRAB that can be attributed to a lympho-
plasma cell proliferative disorder
Solitary plasmacytoma with minimal marrow involvement:

➢ Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma
cells
➢ Clonal bone marrow plasma cells <10%
➢ Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary
solitary lesion)
➢ Absence of end-organ damage such as CRAB that can be attributed to a lympho-
plasma cell proliferative disorder
*** Solitary plasmacytoma with 10% or more clonal plasma cells is considered as
multiple myeloma. (dv)
Dr. Asad R10

L y m p h o m a | 151
Smoldering Waldenström macroglobulinemia:

Both criteria must be met:
➢ Serum IgM monoclonal protein ≥3 g/dL and/or
bone marrow lymphoplasmacytic infiltration ≥10%
➢ No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy,
or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative
disorder
Waldenström macroglobulinemia:
All criteria must be met:
➢ IgM monoclonal gammopathy (regardless of the size of the M protein)
➢ ≥10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small
lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical
immunophenotype (e.g., surface IgM+, CD5±, CD10–, CD19+, CD20+, CD23–)
that satisfactorily excludes other lymphoproliferative disorders,
including chronic lymphocytic leukemia and mantle cell lymphoma
➢ Evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or
hepatosplenomegaly that can be attributed to the underlying lymphoproliferative
disorder
Systemic AL amyloidosis:
➢ Presence of an amyloid-related systemic syndrome (such as renal, liver, heart,
gastrointestinal tract, or peripheral nerve involvement)
➢ Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow,
or organ biopsy)
➢ Evidence that amyloid is light-chain related established by direct examination of the
amyloid using mass spectrometry (MS)–based proteomic analysis or immuno-electron
microscopy
➢ Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein,
abnormal free light chain ratio, or clonal plasma cells in the bone marrow)
Approximately 2%–3% of patients with AL amyloidosis will not meet the requirement for
evidence of a monoclonal plasma cell disorder listed above; the diagnosis of AL
amyloidosis must be made with caution in these patients. Patients with AL amyloidosis
who also meet criteria for multiple myeloma are considered to have both diseases.
Dr. Asad R10

L y m p h o m a | 152
POEMS Syndrome
❖ Polyneuropathy
❖ Monoclonal plasma cell proliferative disorder (almost always lambda)
❖ Any one of the following 3 other major criteria:
1. Sclerotic bone lesions
2. Castleman disease
3. Elevated levels of vascular endothelial growth factor (VEGF)
❖ Any one of the following 6 minor criteria
1. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
2. Extravascular volume overload (edema, pleural effusion, or ascites)
3. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
4. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata,
plethora, acrocyanosis, flushing, white nails)
5. Papilledema
6. Thrombocytosis/polycythemia
**In order to consider endocrinopathy as a minor criterion, an endocrine disorder other

than diabetes or hypothyroidism is required since these two disorders are common in
the general population.
Multiple Myeloma
➢ MM is a malignant proliferation of plasma cells.
➢ In virtually all cases, myeloma cells (as well as their precursors MGUS and SMM)
secrete immunoglobulins (Igs). (ad)
➢ in 2014, the International Myeloma Working Group (IMWG) revised the diagnostic
criteria for multiple myeloma, allowing the use of specific biomarkers in addition to
traditional end-organ damage to define the disease, which represents a major paradigm
shift.
The diagnosis of multiple myeloma currently requires (dv)
➢ 10% or more clonal bone marrow plasma cells (BMPCs) in the bone marrow
➢ and/or a biopsy-proven plasmacytoma
➢ plus one or more of the following multiple myeloma defining events (MDE):
▪ evidence of end-organ damage (hypercalcemia, renal insufficiency,
anemia, or bone lesions) attributable to the underlying plasma cell
disorder,
▪ 60% or more clonal plasma cells in the bone marrow,
▪ serum involved/uninvolved FLC ratio ≥100 (provided involved FLC
level is ≥100 mg/L),
▪ or >1 focal lesion (5 mm or more in size) on magnetic resonance
imaging (MRI)
Dr. Asad R10

L y m p h o m a | 153
Incidence and Prevalence:

➢ Multiple myeloma accounts for approximately 10% of hematologic malignancies.
▪ 4.3 per 100,000 cases in USA
➢ Worldwide:
▪ 170000 new cases and
▪ 11700 people died in multiple myeloma (GLOBOCAN 2020)
➢ no statistically significant differences in incidence rates over 6 decades
➢ The median age at diagnosis is 66 years
➢ only 2% of patients are less than 40 years of age.
➢ Multiple myeloma is twice as common in African Americans compared with whites
and slightly more common in males than females.
Risk factors that predispose to MGUS and MM (ad)

• Age : increased age is a risk factor
• Family history : Increased risk of MGUS has also been reported in first-degree
family members of patients with MGUS and MM (risk ratio
between 2 and 3).
• Race : more common in black race
• Obesity : increase the chance
• History of autoimmune or inflammatory disorders
• Radiation exposure, pesticides:
are also associated with an increased risk of MGUS and MM.
Pathophysiology and Genetics/Molecular Classification:
➢ MM arises from terminally differentiated B cells or even early committed B cells
(germinal-center B cells) that manifest clinically as more differentiated plasma cells.
(ad)
➢ The major role of normal differentiated plasma cells is to produce Igs (antibodies) to
fight infections
➢ Genetic abnormality in MM can be described as
➢ The sequence of events by which normal plasma cells transform to a premalignant clone
is unclear but likely starts when plasma cells are dividing in response to antigenic
stimulation (dv)
Dr. Asad R10

L y m p h o m a | 154
➢ Almost all patients with MM evolve from the asymptomatic premalignant stage
termed MGUS. MGUS is present in over 3% of the population above the age of 50
years, and progresses to MM or related malignancy at a rate of 1% per year. (dv)
Cytogenetic Classification of MM: (dv)

➢ Myeloma can be classified into subtypes based on the primary cytogenetic
abnormalities in clonal plasma cells that occur with the onset of MGUS.
➢ Although each cytogenetic type probably represents a unique disease, due to
similarities in clinical phenotype and the relative rarity of the disease, each is still
considered a subtype of MM.
➢ Accordingly, the 6 main cytogenetic subtypes of MM are
▪ hyperdiploid (characterized by trisomies),
▪ t(11;14),
▪ t(4;14),
▪ t(6;14),
▪ t(14;16), and
▪ t(14;20)
➢ 10% of patients have both trisomies and one of the IgH translocations, and they are
classified based on the translocation type.
➢ Can be identified in clinical fluorescent in situ hybridization (FISH) studies
➢ No abnormalities can be detected on clinical fluorescent in situ hybridization (FISH)
studies in some patients, but this is most likely due to insufficient plasma cells or
inadequate probes to identify the underlying cytogenetic type. Most, if not all, of these
patients will have an identifiable primary cytogenetic abnormality on sequencing
studies. (NGS)
Pathogenesis of Multiple Myeloma Bone Disease: (dv)

➢ Multiple myeloma is characterized by the development of osteolytic bone lesions in
most patients
Steps of osteolytic activation:
➢ The principal step

✓ appears to be an increase in receptor activator of nuclear factor κB ligand
(RANKL) expression by osteoblasts and possibly plasma cells accompanied
by decreased stromal cell secretion of the RANKL decoy receptor,
osteoprotegerin (OPG).
✓ This causes a marked increase in the RANKL/OPG ratio, which promotes
osteoclast activation through the nuclear factor κB (NF-κB) pathway.
✓ The imbalance is made worse by syndecan-1 (CD138), which is secreted and/or
shed by myeloma cells that then inhibit the binding of OPG to RANKL.
➢ A second factor
✓ promoting osteoclast activation is the release of macrophage inflammatory
protein–1α (MIP-1α) and MIP-1β by myeloma cells. Both of these cytokines
act by increasing RANKL expression in stromal cells.
Dr. Asad R10

L y m p h o m a | 155
➢ A third mechanism:
✓ osteoclast activation is increased expression of stromal-derived factor 1α (SDF-
1α) by stromal cells and myeloma cells. SDF-1α causes osteoclast activation by
binding to CXCR4 on osteoclast precursors.
➢ In addition to these 3 factors, several other cytokines, such as IL-1β and IL-6, are also
thought to play a role in osteoclast activation and bone resorption
Osteoblast inhibition
✓ is mediated by increased Dickkopf 1 (DKK-1) expression by myeloma cells.44
DKK-1 inhibits the Wnt signaling pathway
✓ Further, cytokines such as IL-3 and IL-7 may also contribute to
osteoblast inhibition
➢ The combination of osteoclast activation and inhibition of osteoblast
differentiation is felt to be the mechanism behind the development of osteolytic
lesions in MM
Diagnostic workup in multiple myeloma:

Clinical features and physical examination:
Common clinical features are
clinical features Descriptions
Bone pain from osteolytic lesions ✓ Bone pain may be persistent or migratory, often in
the lower back and pelvis.
Additional features with bone pain:
pathologic fracture ✓ Presented as sudden onset of bone pain
nerve root or spinal cord ✓ Results from Extramedullary expansion of
compression. vertebral bone lesions
Fatigue and weakness ✓ Results from anemia
✓ Anemia occurs in 70% of patients at diagnosis
that occurs from extent of bone marrow
involvement
Acute renal failure ✓ Occurs in about 15% of patients
✓ In most patients, renal failure is related to high
amounts of serum FLC levels causing light chain
cast nephropathy.
✓ Other causes include
→ prerenal failure,
→ drug-induced nephrotoxicity,
→ hyperuricemia, and
→ hypercalcemia
Hypercalcemia ✓ found in one-fourth of patients and is usually
found in the context of myeloma bone disease
Increased risk of infections ✓ Because, most myeloma patients have suppression
of uninvolved normal immunoglobulins and are
immunosuppressed.
Dr. Asad R10

L y m p h o m a | 156
Visible and/or palpable swelling in MM: (dv)

➢ In some patients, bony plasmacytomas can protrude out through the cortical bone and
become visible and/or palpable.
➢ Soft tissue and extramedullary plasmacytomas can also occur, usually in patients with
aggressive disease at diagnosis or in patients with advanced relapsed disease.
➢ In occasional patients, MM can present with multiple plasmacytomas with no
significant bone marrow involvement. These patients are also considered to
have MM and are managed as such
Investigation of MM: (ad+dv)

Standard laboratory tests should include
• Complete blood count
• Serum creatinine,
• Serum calcium,
• Serum albumin,
• lactate dehydrogenase (LDH),
• β2-microglobulin,
• Serum-free light-chain assay to evaluate the ratio of serum κ to λ light chains
• Serum protein electrophoresis with immunofixation to quantify monoclonal protein
(M-protein) and determine immunoglobulin isotype
• Urinalysis with 24-hour urine collection with protein electrophoresis and
immunofixation
Bone Marrow Aspiration and Biopsy:
➢ It is done to confirm MM in suspected in patients who present with unexplained lytic
bone lesions, anemia, hypercalcemia, or acute renal failure.
➢ Almost all patients with MM will have 10% or more clonal bone marrow plasma cells
Flow cytometry for immunophenotyping of plasma cells: (ad)
➢ Plasma cells are positive for CD38 and CD138.
➢ Normal plasma cells have higher expression of CD19 and CD45; malignant plasma
cells typically lack these surface antigens.
➢ Malignant plasma cells have increased expression of CD56 and CD117; normal plasma
cells have weak expression of these markers.
Imaging Studies
➢ Options are
• Plain film radiographs
• whole-body low-dose computed tomography (CT),
• positron emission tomography–computed tomography (PET-CT), or
• Magnetic resonance imaging (MRI)
➢ Imaging is recommended for
✓ detection of bone lesions
✓ possible are of extramedullary involvement for biopsy.
✓ to assess baseline disease burden as an adjunct to serum and urine
markers before initiation of treatment in MM
Dr. Asad R10

L y m p h o m a | 157
➢ The International Myeloma Working Group (IMWG) now recommends that advanced
imaging with either whole-body low-dose computed tomography (CT), positron
emission tomography–computed tomography (PET-CT), or magnetic resonance
imaging (MRI) be used because they can detect up to 80% more lesions compared with
plain film radiographs.
❖ With above studies confirm the MM according to diagnostic criteria as mentioned

earlier,
Regarding Imaging in MM: (ad)
➢ A CT scan can be helpful in the characterization of soft tissue masses in the case of
extramedullary plasmacytomas and can direct to an area to be biopsied
➢ An MRI scan is useful for evaluating the axial skeleton in the presence of
symptoms and assessing for spinal cord compression. It can also identify abnormal
marrow uptake because T1-weighted images will show a diffuse decrease in
marrow signal intensity but will enhance with the administration of contrast.
➢ PET-CT can be prone to false-positive findings but has more specificity because of
its increased metabolic uptake at the site of lytic lesions, and is the preferred initial
baseline advanced imaging modality at the MDACC, in combination with skeletal
surveys
➢ There is no role for nuclear bone imaging because bone scan isotopes are not taken
up by lytic lesions.
Other studies: (dv)

➢ Conventional cytogenetic karyotyping and FISH studies, or other molecular
methods must be performed to detect
▪ trisomies;
▪ the 5 most common IgH translocations;
▪ MYC translocations; and
▪ abnormalities of chromosomes 1, 13, and 17.
From ad: FISH is for:
✓ Deletion 13q14, deletion 17p13 (TP53), and deletion of 1p32.
✓ Amplification of 1q21.
✓ Translocations involving the immunoglobulin heavy-chain locus on
chromosome 14q32 and its common partners, including 11q13 (CCND1), 4p16
(FGFR3 and MMSET), 16q23 (c-MAF), 6p21 (CCND3), and 20q12 (MAFB)
➢ Gene expression profiling (GEP) of the CD138+ bone marrow aspirate plasma cells
to identify high-risk MM and to facilitate inclusion in clinical trials.(ad)
➢ Abdominal wall fat pad biopsy (warranted if there are signs and symptoms suggestive
of amyloidosis; see separate chapter), which should be stained with Congo red.(ad)
➢ Serum viscosity: should be a clinical diagnosis, and therapeutic plasma exchange
should not be delayed while waiting for the results of serum viscosity level (ad)
Based on the above workup, a diagnosis of a plasma cell dyscrasia may be made, as
summarized earlier.
Dr. Asad R10

L y m p h o m a | 158
Testing for Monoclonal Proteins:

Multiple myeloma is characterized by the presence of M proteins in the serum and/or urine in
almost 98% of patients. Thus, testing for M proteins is usually the first step in the diagnostic
evaluation of a patient with suspected MM.
M protein can be identified in
• Serum/Urine electrophoresis
• Serum/Urine Immunofixation/Immuno-electrophoresis
• Serum/Urine Free light chain assay
Electrophoresis:
As plasma proteins are negatively charged, they will move in electrical field to anode.
Amount, speed of plasma protein detects its presence
Immunofixation/Immuno-electrophoresis:
In addition to Electrophoresis, antibody directed against specific protein is used to
detect the type. Kappa/lamda/heavy chain IgM etc
Electrophoresis Immunofixation/Immuno-electrophoresis
Only detects the Quantitative presence Detects and identifies the type, either heavy
of specific plasma protein chain, light chain . Qualitative assessment
Quantitative assessment Qualitative assessment
82% of patients with MM can be 93% of patients with MM can be detected
detected
In urine:
Serum electrophoresis/ Immunofixation/Immuno-
electrophoresis shows presence of light chain only, which
may present 20%of cases. (Free light chain assay)
Serum free light chain assay for FLC ratio: (dv)

➢ serum FLC assay is currently used in initial screening for plasma cell
neoplasms, diagnosis, and monitoring response to therapy in MM.
➢ The serum FLC assay provides an important tool to quantify monoclonal light
chains secreted by myeloma cells, especially in patients who secrete small amounts of
intact monoclonal immunoglobulin.
➢ This automated nephelometric assay allows quantitation of free kappa (κ) and lambda
(λ) chains (i.e., light chains that are not bound to intact immunoglobulin) secreted by
plasma cells.
Dr. Asad R10

L y m p h o m a | 159
➢ It is more sensitive that electrophoresis or IFE in detecting monoclonal FLCs.

➢ Patients with a kappa/lambda FLC ratio below the normal range are defined as having
monoclonal lambda FLC and those with ratios above the normal range are defined as
having a monoclonal kappa FLC.
➢ If the FLC ratio is elevated, kappa is considered to be the “involved” FLC and
lambda the “uninvolved” FLC and vice versa if the ratio is less than the normal
range.
➢ The assay is of particular value in monitoring patients with oligo-secretory or
nonsecretory MM, AL amyloidosis, and patients with the lightchain-only form of MM
➢ In order to use the FLC assay to monitor disease progression, the baseline FLC
ratio must be abnormal and the involved FLC level ≥100 mg/L.
Beta-2-Microglobulin:
➢ Beta-2-microglobulin is a LMW (17 kDa) ubiquitously expressed protein and a
component of the major histocompatibility class (MHC) I molecule family. It is
produced at a constant rate and freely filtered by the kidney.
Normal findings:
▪ Blood: 0.70-1.80 mcg/mL
▪ Urine: ≤300 mcg/L
▪ Cerebrospinal fluid (CSF): 0-2.4 mg/L
Clinically used as marker for 1st choice in
➢ B cell lymphoma
➢ B cell leukemias
➢ Multiple Myeloma
Moderate elevation occurs:
➢ Solid tumor
➢ Inflammatory conditions
➢ Benign infectious disease
➢ Primary Biliary cirrhosis
➢ AIDS
➢ ALL
➢ Lymphoma
➢ Lymphoproliferative and Myeloproliferative disorder
➢ B2M in blood is a important prognostic marker for monoclonal gammopathy.
Used routinely for evaluation
▪ Tumor cell load
▪ Disease activity
▪ Prognosis
▪ Therapeutic course
➢ Urine B2M measurement is useful in identifying renal disorder.
Dr. Asad R10

L y m p h o m a | 160
Staging and Risk Stratification

➢ There are multiple staging systems that have been used to estimate tumor burden,
provide prognostic information, and to aid comparison of results across clinical trials
in MM
➢ The Durie-Salmon staging system (DSS) provides the best estimate of true tumor
burden but is cumbersome to use and has subjective elements that make it less
reproducible.
➢ The International Staging System (ISS) uses serum albumin and beta-2
microglobulin levels only, and discriminates 3 prognostic groups
Dr. Asad R10

L y m p h o m a | 161
➢ The ISS has been recently replaced by the \

Revised International Staging System (RISS);
➢ At the Mayo Clinic, newly diagnosed MM is stratified into standard and high-risk
disease using the Mayo stratification for myeloma and risk-adapted therapy
classification
→ Patients with standard

risk MM have a median
overall survival (OS) in excess
of 7 to 10 years
→ whereas those with high-
risk disease have a median OS
of approximately 3 years,
which is currently
improving following the use of
bortezomib plus lenalidomide
as maintenance therapy.
** this staging is not that much important for Treatment, risk stratification is
Risk stratification of SMM:
(defined by the ‘20-20-20’ rule)
Dr. Asad R10

L y m p h o m a | 162
Treatment of Smoldering Multiple Myeloma: (esmo)

First assess the risk status of the SMM:
Patients with standard- or intermediate-risk smoldering MM

do not need immediate therapy.
High-risk SMM patients:
➢ should be encouraged to participate in randomised phase III trials to reveal the best
treatment that offers OS advantage.
➢ To date, no treatment has been approved for SMM.
➢ Some treatment options in SMM that shows promising results in various study
(esmo):
▪ observation.
▪ combination of lenalidomide plus dexamethasone (Rd) for 9 cycles
followed by lenalidomide maintenance
▪ lenalidomide monotherapy
▪ daratumumab (Dara) monotherapy
▪ isatuximab (Isa) monotherapy
Treatment of Multiple Myeloma

➢ The treatment of MM depends on
▪ risk stratification and
▪ eligibility for stem cell transplantation.
➢ Eligibility for stem cell transplantation is determined by
▪ age, performance status, and
▪ coexisting comorbidities.
For treatment patients of multiple myeloma can be described as

➢ Newly diagnosed patients who are eligible for high-dose therapy and autologous
transplantation
➢ Elderly patients or patients with NDMM who are ‘not’ eligible to receive HDT
and autologous transplantation
➢ Relapsed/Refractory Patients
Newly diagnosed patients who are eligible for high-dose therapy and autologous
transplantation:
➢ For fit NDMM patients, aged <70 years, without comorbidities, the recommended
treatment is (esmo)
➢ Induction followed by high-dose therapy (HDT) with
➢ Autologous stem cell transplantation (ASCT) and
➢ Lenalidomide maintenance
Dr. Asad R10

L y m p h o m a | 163
Induction regiments:
➢ Bortezomib, Lenalidomide and Dexamethasone (VRd) [8 cycle in Chu]
➢ Bortezomib, Cyclophosphamide and Dexamethasone (VCD) [3 cy then consolidation]
➢ Bortezomib, Thalidomide, Dexamethasone (VTD)
➢ Bortezomib, Doxorubicin and Dexamethasone (PAd)
➢ Daratumumab, Bortezomib, Thalidomide, Dexamethasone (Dara VTD)
Dr. Asad R10

L y m p h o m a | 164
From esmo:
➢ A three-drug combination, including at least bortezomib and dexamethasone, has
been the standard of care.
➢ VRd is likely to offer the best risk-benefit profile to date among triplet
combinations
➢ Bortezomib, thalidomide, dexamethasone (VTD) induction showed better
response rates over VCD at the expense of a higher rate of peripheral neuropathy.
➢ VCD and bortezomib, doxorubicin and dexamethasone (PAd) were equally effective in
terms of response but VCD was less toxic.
➢ The substitution of bortezomib with the second generation proteasome inhibitor (PI)
carfilzomib (K) resulted in high sustained MRD negativity rate in
carfilzomib, lenalidomide and dexamethasone (KRd) compared with VRd, especially
in patients with advanced R-ISS
Conditioning regimen before ASCT: (esmo)

➢ HDM (200 mg/m2) remains the standard conditioning regimen before ASCT for
NDMM patients.
➢ The addition of busulfan to melphalan has not shown OS benefit over HDM.
➢ The addition of bortezomib to HDM did not improve the efficacy of the conditioning
regimen and had higher toxicity
Consolidation therapy: (esmo)

➢ Consolidation therapy post-ASCT has not been established to date as standard
therapy; 2 cycles of VRd consolidation has to be considered in patients who receive
VCD induction tandem ASCT is recommended for patients with genetically
defined high-risk disease or in all patients who received VCD induction
➢ N.B: consolidation therapy is not advised except for VCD induction
Dr. Asad R10

L y m p h o m a | 165
Maintenance therapy:
➢ Maintenance with lenalidomide is considered the standard of care for all MM
patients post-ASCT for 2 years
➢ bortezomib may be considered for patients with high-risk disease
➢ Ixazomib maintenance offers PFS benefit over placebo but has not been approved by
the EMA or the US FDA
Elderly patients or patients with NDMM who are ‘not’ eligible to receive HDT and
autologous transplantation:
➢ For patients who are not eligible for ASCT, there are three new standards of care:
▪ VRd,
▪ DaraVMP and
▪ DaraRd.
➢ When DaraRd and DaraVMP are not available, VRd is the preferred option in fit
patients;
➢ Rd and VMP may be considered for patients who cannot receive the previous
regimens
Then Maintenance therapy with
Relapse/Remission cases:
➢ MM is a disease of remissions and relapses.
➢ Very few patients achieve a permanent disease-free state in the absence of ongoing
therapy (true cure).
➢ With modern therapy, myeloma patients achieve an initial remission that lasts
approximately 3 to 4 years. Subsequent remissions are of shorter duration.
➢ Given the multitude of available treatment options, patients with MM are
not uncommonly treated with five or more lines of therapy in a sequential manner
over many years.
Dr. Asad R10

L y m p h o m a | 166
Dara, daratumumab; Rd, lenalidomide/dexamethasone;

Elo, elotuzumab; S, selinexor;
Isa, isatuximab; Vd, bortezomib/dexamethasone;
Ixa, ixazomib; VMP, bortezomib/melphalan/prednislone;
K, carfilzomib; VRd, bortezomib/lenalidomide/dexamethasone;
Kd, carfilzomib/dexamethasone; Ven, venetoclax;
MM, multiple myeloma; VTD, bortezomib/thalidomide/dexamethasone.
PomVd, Patients with t(11;14) is considered for VenVd
pomalidomide/bortezomib/dexamethasone;
Dr. Asad R10

L y m p h o m a | 167
Second-line ASCT is an option for patients who received primary therapy that included an ASCT followed
by lenalidomide maintenance and had an initial remission duration of> 36 months (esmo)
Associated other symptom management ibn multiple myeloma:

Supportive treatment options are
Hypercalcemia IV hydration
bisphosphonate therapy
Hyperviscosity plasmapheresis (patient’s plasma is replaced by an appropriate
colloid solution (usually albumin) to reduce the level of
paraprotein)
Renal failure dialysis, nephrotoxic agents should be avoided.
pain According to WHO pain scoring
infection Use IV antibiotics if needed
Role of Radiotherapy in Multiple Myeloma: (NCCN)

➢ RT is primarily used for palliation in patients with MM.
N.B: not as a main treatment option at any stage, only recommended for
palliation.
➢ RT should be used judiciously in patients with MM who are undergoing or being
considered for systemic therapy.
➢ Systemic therapy should not be delayed for RT.
➢ When systemic therapy and palliative RT are used concurrently, patients must be
carefully monitored for toxicities.
RT Dosing for MM:
➢ Low-dose RT (8 Gy x 1 fraction or 10–30 Gy in 2.0–3.0 Gy fractions [5–10 total
fractions]) can be used as palliative treatment (NCCN)
✓ For uncontrolled pain,
✓ for impending pathologic fracture, or
✓ for impending cord compression.
For chemotherapy dosing please see devita page 1520
Dr. Asad R10

L y m p h o m a | 168
Treatment of Solitary Plasmacytomas (pz)

➢ The median age at diagnosis of SP is 55 to 65 years, on average about 10 years younger
than patients with multiple myeloma.
➢ Males are affected predominately (male-to-female ratio 2:1).
A diagnosis of SP is made if all the following criteria are satisfied at presentation:
▪ a histologically confirmed single lesion with negative skeletal imaging
outside the primary site,
▪ normal bone marrow biopsy (<10% monoclonal plasma cells), and
▪ no myeloma-related organ dysfunction. (No CRAB features)
➢ A monoclonal protein is Solitary Plasmacytomas present in 30% to 75% of
cases (particularly for an osseous presentation), and the level is usually
minimally elevated (IgG < 3.5 g/dL, IgA < 2.0 g/dL, and urine monoclonal κ or λ < 1.0
g per 24 hours).
Solitary bone plasmacytoma:

✓ The disease more commonly presents in bone (70%).
✓ Such cases are considered stage I multiple myeloma according to the original Durie
Salmon staging system.21 The most common location is the vertebra.
✓ Patients with bone involvement often present with
▪ pain, neurologic compromise, and
▪ occasionally pathologic fracture.
✓ A lytic lesion is typical, with or without adjacent soft tissue mass.
Extramedullary plasmacytoma (EMP)

➢ Less commonly, SP presents in an extramedullary site (20% to 30%), usually as a
mass in the upper aerorespiratory passages, and produces local compressive
symptoms.
➢ The histologic diagnosis of extramedullary plasmacytoma (EMP) can be difficult, with
the main differential diagnosis being extranodal marginal zone lymphoma (mucosa-
associated lymphoid tissue type), where there can be extensive infiltration by
plasmacytoid cells.
Management of Solitary Plasmacytoma: (pz)

➢ RT is the standard treatment for SP.
➢ Surgery should be considered for
✓ structural instability of bone or
✓ rapidly progressive neurologic compromise such as spinal cord compression
➢ For patients treated with gross tumor excision,
✓ RT is still indicated because of a high likelihood of microscopic residual
disease.
➢ Surgery alone without RT leads to an unacceptably high local recurrence rate
Treatment options mentioned in NCCN:
❖ RT ± surgery
➢ Consider surgery if structurally unstable or if there is neurologic compromise due
to mass effect
Dr. Asad R10

L y m p h o m a | 169
➢ Systemic therapy may be considered in patients with high risk of progression based
on the clinical context.
Radiation Treatment Information/Dosing:

RT (40–50 Gy in 1.8–2.0 Gy fractions [20–25 total fractions]) to involved site
the usual practice is to administer a dose of 40 to 45 Gy or even higher for bulky tumors
In contrast, plasmacytomas >5 cm have worse local control,15,17,39 and doses of 45
to 50 Gy are recommended in these bulkier tumors,
Target volume: (pz)
✓ In determining the CTV, using the GTV plus a margin of 1 to 3 cm is reasonable
(depending on the site) respecting anatomic boundaries.
✓ A GTV to CTV expansion of 0.5 to 1 cm in the axial plane may be appropriate for
covering potential microscopic extension in soft tissues, for example, in the head and
neck area.
✓ However, for a long bone site, for example the femur, the proximal and distant
expansion should be increased to 2 to 3 cm.
✓ Planning target volumes (PTV) should account for day-to-day setup variation and will
typically add 5 to 10 mm around CTV volumes depending on the immobilization
technique employed
Follow up: (NCCN)

Reassess after at least 3 months following radiation as the assessment of response with
imaging may not be accurate if the scans are performed sooner.
Patients with soft tissue and head/neck plasmacytoma could be followed less frequently
after initial 3-month follow-up.
Bortezomib
Available dose formulation: 1mg/vial, 2mg/vial
Mechanism of Action:
Reversible inhibitor of the 26S proteasome.
➢ The 26S proteasome is a large protein complex that degrades ubiquitinated proteins.
This pathway plays an essential role in regulating the intracellular concentrations of
various cellular proteins.
➢ Inhibition of the 26S proteasome prevents the targeted proteolysis of ubiquitinated
proteins, and disruption of this normal pathway can affect multiple signaling pathways
within the cell, leading to cell death.
downregulation of the NF-κB pathway:
NF-κB is a transcription factor that stimulates the production of various growth factors,
including IL-6, cell adhesion molecules, and antiapoptotic proteins, all of
which contribute to cell growth and chemoresistance. Inhibition of the NF-κB pathway
by bortezomib leads to inhibition of cell growth and restores chemosensitivity.
Half-life:
Bortezomib has a mean elimination half-life of 76 to 108 hours upon multiple dosing
with the 1.3-mg/m2 dose.
Dr. Asad R10

L y m p h o m a | 170
Indications:
❖ Multiple myeloma
❖ Mantle cell lymphoma after at least one prior therapy.
Dosage Range:
Recommended dose for relapsed multiple myeloma and mantle cell lymphoma is
1.3 mg/m2 administered by IV or SC twice weekly for 2 weeks (on days 1, 4,
8, and 11) followed by a 10-day rest period
Toxicity:
Dose limiting.
✓ Peripheral neuropathy (predominantly sensory),
✓ hematosuppression (especially dose-related thrombocytopenia with nadir at
day 11)
Common:
✓ Fatigue,
✓ fever (up to 40%),
✓ headache,
✓ GI disturbance (anorexia, nausea, vomiting, diarrhea, constipation),
✓ arthralgia, neuralgia,
✓ vomiting,
✓ lymphopenia, neutropenia
Occasional:
✓ Hypotension (10%);
✓ motor neuropathy,
✓ blurred vision,
✓ myalgia;
✓ congestive heart failure;
✓ toxic epidermal necrolysis
Rare:
✓ Interstitial pneumonia and acute respiratory distress syndrome,
✓ reversible posterior leukoencephalopathy syndrome,
✓ acute hepatic failure
In hepatic dysfunction:
✓ Patients with mild hepatic impairment do not require dose modification.
✓ However, patients with moderate or severe hepatic impairment should be
started at a reduced dose of 0.7 mg/m2 in the first cycle.
✓ Depending on patient tolerability, the dose can be either increased to 1 mg/m2
or further reduced to 0.5 mg/m2 in subsequent cycles
In renal dysfunction:
✓ dosing adjustments of bortezomib are not necessary for patients with renal
dysfunction.
✓ Since hemodialysis may reduce bortezomib concentrations, the drug should be
administered after the dialysis procedure.
Dr. Asad R10

L y m p h o m a | 171
In case of neuropathy:
✓ the dose of bortezomib should be reduced to 1 mg/m2 with grade 1 peripheral
neuropathy with pain or grade 2 peripheral neuropathy.
✓ In the presence of grade 2 neurotoxicity, therapy should be withheld until
symptoms have resolved and restarted at a dose of 0.7 mg/m2 along with
changing the treatment schedule to once per week.
✓ In the presence of grade 4 neurotoxicity, therapy should be discontinued.
Other considerations:
✓ Use with caution in patients with a history of syncope, patients who are
on antihypertensive medications, and patients who are dehydrated
because bortezomib can cause orthostatic hypotension.
✓ Patients should avoid taking green tea products and supplements, as they
have been shown to inhibit the clinical efficacy of bortezomib.
Rituximab
Available dose formulation: 1mg/vial, 2mg/vial
Mechanism of Action:
➢ Chimeric anti-CD20 antibody consisting of human IgG1-κ constant regions and
variable regions from the murine monoclonal anti-CD20 antibody.
➢ Binding of antibodies to CD20 results in inhibition of CD20-mediated signaling that
leads to inhibition of cell activation and cell cycle progression
➢ Chimeric antibody mediates complement-dependent cell lysis (CDC) in the
presence of human complement and antibody-dependent cellular cytotoxicity
(ADCC) with human effector cells.
CD20:
✓ 35-kDa cell-surface, non-glycosylated phosphoprotein
✓ expressed during early pre–B-cell development until the plasma cell stage.
✓ CD20 is expressed on more than 90% of all B-cell non-Hodgkin’s lymphomas and
leukemias.
✓ CD20 is not expressed on
▪ early pre–B cells,
▪ plasma cells,
▪ normal bone marrow stem cells,
▪ antigen-presenting dendritic reticulum cells, or
▪ other normal tissues.
Metabolism and distribution:

➢ Peak and trough levels of rituximab correlate inversely with the number of circulating
CD20-positive B cells.
➢ Antibody can be detected in peripheral blood up to 3–6 months after completion
of therapy.
➢ Elimination pathway has not been well characterized, although antibody coated cells
are reported to undergo elimination via Fc-receptor binding and phagocytosis by the
reticuloendothelial system.
Dr. Asad R10

L y m p h o m a | 172
Indication:
➢ CD20-positive,
➢ B-cell NHL,
➢ CLL,
➢ Rheumatoid arthritis,
➢ Microscopic polyangiitis,
➢ Granulomatosis with polyangiitis (Wegener granulomatosis)
Toxicity
Dose limiting:
✓ Hypersensitivity reactions,
✓ severe mucocutaneous reactions,
✓ serious cardiac arrhythmias
Common:
❖ Infusion reaction occurs in 25%, particularly during the first infusion
(decreasing in occurrence substantially on subsequent infusions).
Occasional:
✓ Severe granulocytopenia or ✓ paresthesia, hypesthesia,
✓ thrombocytopenia; ✓ agitation, insomnia;
✓ arthralgia/myalgia, ✓ hyperglycemia,
✓ malaise, headache, ✓ hypocalcemia,
✓ diarrhea, ✓ pain in chest,
✓ dyspepsia, dyspnea, back, abdomen or tumor
✓ taste perversion, site,
✓ hypertension, hypotension, ✓ rash, night sweats,
✓ tachycardia, ✓ angioedema,
✓ bradycardia, ✓ tumor lysis syndrome,
✓ lacrimation, ✓ bowel obstruction
Rare:
✓ Arrhythmias, angina;
✓ aplastic anemia,
✓ hemolytic anemia;
✓ mucocutaneous reactions (e.g., Stevens-Johnson syndrome);
✓ pneumonia;
✓ progressive multifocal leukoencephalopathy related to Jakob-Creutzfeldt virus
infections up to 1 year after treatment, reactivation of hepatitis B virus infection
Dose: 375 mg/m2 IV
Rituximab should NOT be given by IV push.
➢ Infusion should be started at an initial rate of 50 mg/hour.
➢ If no toxicity is observed during the first hour,
▪ the infusion rate can be escalated by increments of 50 mg/hour every 30
minutes to a maximum of 400 mg/ hour.
➢ If the first treatment is well tolerated, the starting infusion rate for the second and
subsequent infusions can be administered at
▪ 100 mg/ hour with 100-mg/hour increments at 30-minute intervals
▪ up to 400 mg/ hour.
Dr. Asad R10

L y m p h o m a | 173
For example:
Inj Rituximab 600mg+500ml N/S
10 drops/min for 60 min
Then if reaction not occur
o 20 drops/min for next 30min
➢ Patients should be premedicated with acetaminophen and diphenhydramine to
reduce the incidence of infusion-related reactions.
➢ Monitor for infusion-related events, which usually occur 30–120 minutes after the
start of the first infusion.
If IRCRS occurs:
➢ Infusion should be immediately stopped if signs or symptoms of an allergic reaction
are observed.
➢ Immediate institution of
▪ diphenhydramine,
▪ acetaminophen,
▪ corticosteroids,
▪ IV fluids, and/or
▪ vasopressors may be necessary.
➢ In most instances, the infusion can be restarted at a reduced rate (50%) once symptoms
have completely resolved. Resuscitation equipment should be readily available at
bedside.
Pre-existing heart disease:
➢ Use with caution in patients with pre-existing heart disease, including arrhythmias and
angina, as there is an increased risk of cardiotoxicity.
➢ The development of cardiac arrhythmias requires cardiac monitoring with subsequent
infusion of drug.
➢ Patients should be monitored during the infusion and in the immediate post-transfusion
period.
Tumor lysis syndrome:
Monitor for tumor lysis syndrome, especially in patients with high numbers of
circulating cells (>25,000/mm3) or high tumor burden. In this case, the first dose of
rituximab can be split into two doses, with 50% of the total dose to be given on days 1
and 2
Skin reaction:
Monitor for the development of skin reactions. Patients experiencing severe skin
reactions should not receive further therapy, and skin biopsies may be required to guide
future treatment.
Dr. Asad R10

L y m p h o m a | 174
Castleman Disease
➢ Castleman disease (CD) is a rare, nonclonal lymphoproliferative disorder having
distinct subtypes depending on its etiology, pathology, and clinical presentation.
➢ It can affect lymph nodes anywhere in body, imitating both benign and malignant
malformations, including the neck, chest, abdomen, and pelvis.
➢ More common in male elderly patients.
Classification:
➢ Clinically it manifests as the
more common unicentric
(localized or unifocal)
Castleman disease (UCD)
and
less common multicentric
(generalized or
multifocal) Castleman
disease (MCD).
➢ Pathologically it can be
classified as
→ hyaline vascular type
(HV-CD),
→ plasma cell type,
→ mixed type, and
→ human herpesvirus (HHV)-8 associated Castleman disease.
The hyaline-vascular variant is more common than the plasma-cell type, comprising
91% of the total cases.
Features
hyaline vascular type has an increased number of lymphoid follicles with a broad
mantle zone and hypoplastic germinal center.
Centrally placed germinal center is surrounded with small
lymphocytes arranged in concentric circles, forming an "onion
skin-like" structure.
The center of these follicles is penetrated by hyalinized capillaries
resembling a "lollipop" (also known as the lollipop sign).
plasma cell type A high number of plasmacytoid dendritic cells can be found
around these lesions.
Mature lymphocyte infiltration can be observed in plasma cell CD
with maintained mantle zone and germinal zone proportions.
The interfollicular zones are filled with mature plasma cells and are
less vascular than HV-CD.
mixed type The mixed type has the characteristics of both HV-CD and the
plasma cell type.
HHV-8 associated CD HHV-8 associated CD manifests as significant proliferation of
angiogenesis between the lymphoid follicles with unclear
boundaries and immature plasmablasts that might have restricted
lambda light chains in specific immunoglobulins.
Dr. Asad R10

L y m p h o m a | 175
History and Physical examination:

Unicentric Castleman disease
presents as a slow-growing, non-malignant painless solitary mass manifesting at a
single anatomic site that is generally asymptomatic at first but starts producing
symptoms when the surrounding structures are compressed due to its growing size
Multicentric CD
▪ occurs at multiple sites and is characterized by a proinflammatory response giving rise
to the so-called B symptoms, including fever, night sweats, malaise, and weight loss.
▪ Exaggerated effects of elevated serum IL-6 levels cause various symptoms, including
lymph node enlargement, hepatosplenomegaly, polyclonal
hypergammaglobulinemia- owing to its growth and differentiation factors for both
plasma and lymphocytes.
▪ Elevated fibrinogen levels cause deep vein thrombosis and thromboembolic disorders,
high hepcidin levels cause anemia, increased VEGF levels result in angiogenesis and
vascular permeability, which along with hypoalbuminemia induces edema, ascites,
pleural and pericardial effusions, or even generalized anasarca.
In extreme cases of iMCD, multiple organ failure with renal insufficiency can ensue, often
resulting in death.
Diagnostic criteria of Castleman disease:
Dr. Asad R10

L y m p h o m a | 176
POEMS syndrome is characterized by

polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes
It is a rare plasma cell disease with multisystem involvement.
✓ syndrome that co-occurs with HHV-8–negative MCD often results in unique clinical
features and requires treatment targeted at controlling the POEMS.
✓ Around 30% of patients with POEMS disease also have multicentric CD, more precisely the
HHV-8 positive variant.
✓ In addition, many findings of systemic CD-like ascites, lymphadenopathy,
hepatosplenomegaly, and polyneuropathy overlap POEMS syndrome.
Treatment / Management:
Unicentric Castleman disease :
❖ As a unicentric Castleman disease lesion is localized, complete surgical
resection of the tumor is the best treatment available.
If not surgically resectable:
Treatment options are (NCCN)
➢ Radiotherapy or
➢ Rituximab
± prednisone
± cyclophosphamide
Then if it became surgically resectable: go for surgery.
If incomplete resection and asymptomatic: observation
Multi centric Castleman disease

Many treatment options are available for treating multicentric CD, including
▪ surgery,
▪ cytotoxic chemotherapy with or without corticosteroids, and
▪ autologous stem cell transplantation (ASCT) with varying outcomes.
Better results have been observed by targetting CD20 and IL-6 pathways and HHV-8
replication
Dr. Asad R10

L y m p h o m a | 177
MCD with no organ failure:

HIV-1(-) HHV8(-) (Idiopathic MCD):
Treatment option is:
➢ Siltuximab
Other options are
➢ Rituximab ± prednisone
➢ Thalidomide, cyclophosphamide, prednisone
HIV-1(±) HHV8(-) (Idiopathic MCD):
Preferred treatment option is
➢ Rituximab ± liposomal doxorubicin ± prednisone or
➢ Zidovudine + ganciclovir/ valganciclovir
MCD with organ failure:

Treatment option is:
➢ Combination therapy ± rituximab
▪ CHOP
▪ CVAD
▪ CVP
▪ Liposomal doxorubicin
➢ Rituximab (if not candidate for combination therapy)
Refractory or progressive disease

➢ it should be kept in mind that not all CD cases respond to therapy and get cured.
➢ Chemotherapy and immunomodulatory drugs are best reserved for the relapse
scenarios.
Treatment options for Refractory or progressive disease (NCCN)
▪ Single-agent therapy (preferred)
▪ Etoposide (oral or IV)
▪ Vinblastine
± ganciclovir/valganciclovir if HHV8(+)
or
▪ Combination therapy ± rituximab (if not previously given)
▪ CHOP
▪ CVAD
▪ CVP
Source: https://www.ncbi.nlm.nih.gov/books/NBK576394/
https://emedicine.medscape.com/article/2219018-
overview?icd=login_success_email_match_norm
NCCN
Dr. Asad R10

L y m p h o m a | 178
Tumor Lysis Syndrome (TLS) (NCCN)

Laboratory hallmarks of TLS:
❖ High potassium
❖ High uric acid
❖ High phosphorous
❖ Low calcium
Symptoms of TLS:
✓ Nausea and vomiting, ✓ clouding of urine,
✓ shortness of breath, ✓ lethargy,
✓ irregular heartbeat, ✓ and/or joint
✓ discomfort.
Consider TLS prophylaxis for patients with the following risk factors:
➢ Histologies of BL and LL; occasionally DLBCL
➢ Spontaneous TLS
➢ Elevated white blood cell (WBC) count
➢ Bone marrow involvement
➢ Pre-existing elevated uric acid
➢ Ineffectiveness/intolerance of allopurinol
➢ Renal disease or renal involvement by tumor
Treatment of TLS:
TLS is best managed if anticipated and treatment is started prior to chemotherapy.
Centerpiece of treatment includes:
❖ Vigorous hydration
❖ Management of hyperuricemia
❖ Frequent monitoring of electrolytes and aggressive correction
Low-Risk Disease:
Allopurinol or febuxostat beginning 2–3 days prior to chemoimmunotherapy
and continued for 10–14 days
Intermediate-Risk Disease: (Stage I/II and LDH <2X ULN):
Allopurinol or febuxostat
OR
Rasburicase if renal dysfunction and uric acid, potassium,
and/or phosphate >ULN
High-Risk Disease: (Stage III/IV and/or LDH ≥2X ULN):
Rasburicase
Rasburicase (doses of 3 to 6 mg are usually effective).

➢ One dose of rasburicase is frequently adequate.
➢ Re-dosing should be individualized and is indicated for
▪ Urgent need to initiate therapy in a high-bulk patient
▪ Situations where adequate hydration may be difficult or impossible
▪ Acute renal failure
➢ Glucose-6-phosphate dehydrogenase (G6PD) testing is required prior to use of
rasburicase. Rasburicase is contraindicated in patients with G6PD
If TLS is untreated: its progression may cause acute kidney failure, cardiac arrhythmias,
seizures, loss of muscle control, and death
Dr. Asad R10

L y m p h o m a | 179
Immunohistochemistry marker in lymphoma:
Classical Hodgkin Lymphoma CD15+, CD30+, PAX-5+ (weak);

CD3-, CD20- (majority), CD45-, CD79a-
Nodular Lymphocyte CD20+, CD45+, CD79a+, BCL6+, PAX-5+;
Predominant Hodgkin Lymphoma CD3-, CD15-, CD30-
Follicular lymphoma CD10+, BCL2+, BCL6+
CD19+, CD20+,
CD23+/-
CD43-, CD5-
Rare cases of FL may be CD10- or BCL2-
Extranodal MZL of of the surface Ig
Stomach CD19+, CD20+, CD79a+, CD22+
CD5- CD10- CD23- cyclin D1- BCL2- follicles
Extranodal MZL of Nongastric surface Ig
Sites CD20+, CD23-/+, CD43-/+,
CD10-, CD5-,
cyclin D1-, BCL2- follicles
Nodal Marginal Zone Lymphoma monoclonal surface Ig (IgM, IgG, IgA)
CD19+, CD20+, CD79a+
CD10-, CD5±, CD23-/+,
Splenic B-cell marginal zone CD20+, CD23-/+, CD43-/+,
lymphoma CD10-, CD5-
cyclin D1-, BCL2- follicles, annexin A1, and CD103-
with expression of both IgM and IgD.
Mantle cell lymphoma CD5+, CD20+, CD43+,
CD23-/+, cyclin D1+, CD10-/+.
FISH for t(11;14), Ki-67 proliferation, TP53
Diffuse Large B-Cell Lymphoma CD19 +, CD20+, CD45+ CD79a+
CD 3-
CD10+, BCL6+ (GCB)
IRF4-, MUM1- (non-GCB)
CD30 ±, CD5±, BCL2± BCL6±
MYC, t(14;18) ±
Burkitt Lymphoma sIg+, CD10+, Cd20+,
TdT-,
Ki-67+ (≥95%),
BCL2-, BCL6+
t(8;14), MYC rearrangement
Primary CNS lymphoma CD19+, CD20+, CD22+ CD79a+
MUM1+, IRF4+
BCL6+,
BCL2- (variable positive) CD10- (+in 10%case)
Mycosis Fungoides/ CD2+, CD3+, CD5+, CD7-, CD4+, CD8- (rarely
Sézary Syndrome CD8+), CD30-/+ cytotoxic granule proteins negative.
Dr. Asad R10

L y m p h o m a | 180
ATLL CD2+, CD3+, CD4+, CD7-, CD8-, CD25+, CD30-/+,

TCR αβ+
Extranodal NK/T-Cell For NK-cell lineage:
Lymphomas CD20-, CD2+, cCD3ε+ (surface CD3-), CD4-, CD5-,
CD7-/+, CD8-/+, CD43+, CD45RO+, CD56+, TCRαβ-
, TCRδγ-, Epstein-Barr encoding region (EBER)+, and
cytotoxic granule proteins positive (eg, TIA-1+,
granzyme B+).
Typical T-cell immunophenotype:
CD2+, sCD3+, cCD3e+, CD4, CD5, CD7, CD8
variable, CD56+/-, EBER+, TCRαß+ or TCRγδ+,
cytotoxic granule proteins +
For detailes, please see use of immunophenotyping/genetic testing in differential
diagnosis of mature b-cell and nk/t-cell neoplasms in NCCN (NHODG-A)
Important investigations:
Bone marrow study in HL Bone marrow study is not mandatory for HL . If PET CT is
available
Bone marrow study in NHL Bone marrow study is advised in NHL if PET CT supports
bone involvement.
CSF cytology in NHL if indicated (CNS, epidural or testicular lymphoma)
serum protein electrophoresis to assess the presence of monoclonal paraproteins in NHL
serum β2-microglobulin level As independent prognostic factors in NHL
serum lactate dehydrogenase As independent prognostic factors done in both NHL and HL
Dr. Asad R10

L y m p h o m a | 181
Special consideration of Bilateral bone marrow biopsies with unilateral aspiration are
Follicular lymphoma recommended and do Flow and molecular study
For prognosis check:
✓ serum lactate dehydrogenase
✓ serum β2-microglobulin level
Marginal zone lymphoma For gastric EMZL:
Assessment of H. pylori:
By HPR, if not possible: stool antigen test, urea breath test
PCR or FISH for t(11;18)
For splenic MZL: hepatitis C
Bone Marrow Biopsy: not commonly done
Mantle cell lymphoma Ki-67. TP 53
FISH to detect t(11;14)
Bone marrow aspiration/ biopsy is routinely per-formed at
initial diagnosis
PET-CT scan commonly done
DLBCL bone marrow biopsy is not necessary if PET-CT scan
demonstrates bone disease.
Bone marrow biopsy with a negative PET-CT scan may
reveal discordant lymphoma
PET CT recommended
CSF study may required in
Testicular lymphoma
HGBL
Primary cutaneous DLBCL
Stage IE DLBCL of the breast
kidney or adrenal gland involvement
Burkitt Lymphoma PET-CT scan is recommended (initiation of therapy should
not be delayed for PET-CT scan)
Lumbar puncture & Flow cytometry of cerebrospinal fluid
Unilateral or bilateral bone marrow biopsy ± aspirate
HIV testing
Hepatitis B testing
Primary CNS lymphoma MRI brain and Spine MRI
Magnetic resonance spectroscopy
Stereotactic brain biopsy
CSF study
Testicular Ultrasound
Bone marrow biopsy (as category 2B)
Whole body PET/CT scan
HIV testing
LDH
Dr. Asad R10

Lymphoma Dr. Asad 13.7.2023

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Lymphoma Dr. Asad 13.7.2023

Uploaded by

Copyright:

Available Formats

Lymphoma |1

Extra lymphatic organ:

Dr. Asad R10

How lymph percolates:

Once a primary follicle is challenged by an antigen, it becomes enlarged and

Dr. Asad R10

This germinal center and Marginal zone of

Antigen presenting cell ✓ Presents Antigen with MHC II molecule to T and

Dr. Asad R10

Dr. Asad R10

NK Cell Surface Markers (come from lymphocyte precursors, not T cell)

Receptors present in Antigen Presenting Cells (APCs) including B cells:

Stem cell markers are CD34, tDT and HLA-DR.

Dr. Asad R10

Dr. Asad R10

WHO classification divides hematopoietic and lymphoid neoplasms into 3 major

Dr, Asad R10

Dr, Asad R10

Grossly, lymphoma can be classified as

Non-Hodgkin Lymphoma includes

Dr, Asad R10

Distribution of various types of lymphoma:

❖ Non-Hodgkin lymphoma (NHL) : approximately 90% of all lymphomas

❖ Diffuse large B cell lymphoma (DLBCL) : approximately 22% of NHL cases

According to GLOBOCAN 2020

Dr, Asad R10

Difference between Hodgkin lymphoma and non-Hodgkin lymphoma

➢ NHL- extranodal at presentation – 25%.

Dr, Asad R10

Overall important clinical examination findings in lymphoma:

Dr, Asad R10

Classification of HL: (dv)

CHL is characterized by the presence of Reed-Sternberg cells in an inflammatory

Dr. Asad R10

Reed-Sternberg cells and their variants:

Dr. Asad R10

Common Immuno-phenotyping of RS cell: (cas)

Dr. Asad R10

Dr. Asad R10

Dr. Asad R10

always associated with infiltration of the

Important Clinical features in HL:

Dr. Asad R10

Chest Xray/ CECT chest: (pz)

Bone marrow biopsy:

Dr. Asad R10

Dr. Asad R10

Overall LN Regions are:

Dr. Asad R10

Nodal site ✓ lymph nodes,

Dr. Asad R10

Cotswolds Staging Classification: (cas)

Lugano Classification for Hodgkin and NonHodgkin Lymphoma

Dr. Asad R10

Difference between ann arbor and Lugano: (AJCC)

Dr. Asad R10

The International Prognostic Score (IPS) of HL: (Hasenclever- Diehl)

Dr. Asad R10

Stage III and IV is considered as advanced disease.

Dr. Asad R10

Treatment steps of CHL depends on various study result, including

Treatment steps Stage IA/IIA Favorable (Non-bulky) CHL

After 2 cycle of ABVD next treatment options depends on Deauville score

Dr. Asad R10