Professional Documents
Culture Documents
Lymphoma Dr. Asad 13.7.2023
Lymphoma Dr. Asad 13.7.2023
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.
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
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.
❖ 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
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
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).
➢ 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
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
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
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
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:
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.
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
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
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)
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
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
→ 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
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
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:
For the purposes of coding and staging, involved areas are divided as
➢ 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
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
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
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 -
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.
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
Repeat cycle every 21 days
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
Repeat cycle every 21 days
Add Rituximab 375 mg/m2 IV on day 1 in case of RCHOP
GVD:
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 (?)
❖ 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.
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
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)
Mantle RT
Included area:
➢ Bilateral cervical,
➢ supraclavicular,
➢ infraclavicular,
➢ hilar,
➢ mediastinal
➢ axilla lymphatics
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
Inverse Y R T
Uninvolved regions:
25–30 Gy; 1.5–2.0 Gy per fraction.
ISRT for NLPHL
includes extension to clinically relevant initially uninvolved
nodes.
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
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%
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)
Active bone marrow can be delineated using various imaging modalities and is most
abundant in the pelvic bones, thoracic-lumbar spine, and sacrum.
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.
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.
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.
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.
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
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
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
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
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.
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
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
Factors
Age older than 60 y
LDH >upper limit normal
Hb level <12 g/dL
Ann Arbor stage stage III or IV
Number of extranodal disease sites greater than FOUR
** Hb level is included instead of ECOG, number of extra nodal site is four here.
✓ 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
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.
❖ 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)
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
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)
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.
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 (?)
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
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.
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.
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.
❖ 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
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
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)
R- CVP
R Rituximab 375 mg/m2 D1
C Cyclophosphamide 400mg/m2 D2-D5
800mg/m2 D1
V Vincristine 1.4mg/m2 (max2) D1
P Prednisolone 100mg/m2 D1-D5
Repeat cycle every 21 days
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
Repeat cycle every 28 days
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
Repeat cycle every 28 days
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
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)
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)
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+.
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,
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.
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.
✓ 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.
Dose:
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
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
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)
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.
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
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
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
✓ PR, stable : Score:4,5 No new lesions
✓ Progressive : 4,5, new lesions
If there is CR Rituximab maintenance (category 1)
If there is PR, Progressive disease 2nd line therapy
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.
*** Prophylaxis for tumor lysis syndrome should be considered during the induction therapy.
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.
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)
Acalabrutinib and
zanubrutinib have not
been shown to be
effective for
ibrutinibrefractory MCL
with BTK C481S
mutations.
N.B:
Smoldering verity dose not need treatment
As most of the cases are presented in stage III, IV, in case of confusion treat as
Advanced stage.
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
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).
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
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
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.
RCEOP Rituximab,
Cyclophosphamide,
Etoposide,
Vincristine,
Prednisone
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.
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
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:
Typical immunophenotype:
✓ 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
✓ 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)
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)
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
❖ 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.
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
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
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.
Others:
➢ HIV testing
➢ LDH
However, to date,
no markers are currently established as diagnostic in routine clinical practice
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.
❖ 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
➢ Patients with HIVrelated DLBCL receiving ART are suitable candidates for CAR T-
cell therapies with appropriate supportive care measures for HIV control.
Patients with HIVrelated DLBCL receiving ART are suitable candidates for CAR T-
cell therapies with appropriate supportive care measures for HIV control.
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:
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)
According to aggressiveness:
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
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.
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)
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
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.
For details please go through NCCN, there is slight change in 2nd line schedule in ALCL. To
avoid complexity, details is not discussed.
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
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.
Treatment options:
Dose of RT:
International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and
Related Disorders (dv):
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 10% or more clonal plasma cells is considered as
multiple myeloma. (dv)
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:
All 4 criteria must be met:
➢ 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.
POEMS Syndrome
All 4 criteria must be met:
❖ 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
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)
➢ 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)
➢ 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)
➢ 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.
➢ 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
➢ 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.
➢ 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.
In urine:
Serum electrophoresis/ Immunofixation/Immuno-
electrophoresis shows presence of light chain only, which
may present 20%of cases. (Free light chain assay)
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.
➢ The International Staging System (ISS) uses serum albumin and beta-2
microglobulin levels only, and discriminates 3 prognostic groups
➢ 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
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
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
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)
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
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
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.
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)
➢ Systemic therapy may be considered in patients with high risk of progression based
on the clinical context.
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.
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
Special consideration:
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.
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.
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.
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
o 30 drops/min for next 30min
o 40 drops/min for next 30min
o 50 drops/min for next 30min
o 60 drops/min for next 30min
o 70 drops/min for next 30min
o 80 drops/min for next 30min
Special consideration:
➢ 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.
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.
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
Source: https://www.ncbi.nlm.nih.gov/books/NBK576394/
https://emedicine.medscape.com/article/2219018-
overview?icd=login_success_email_match_norm
NCCN
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
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