EXCELLENT PPT ON NHL

1. NON-HODGKINS LYMPHOMA
Dr. Y. Raghunandhini

2. outline
• Definition and introduction
• Classification
• Risk factors and epidemiology
• Pathogenesis
• Clinical features
• Investigations
• Treatment and complications

3. Non-Hodgkin’s lymphomas-definition
and epidemiology
1. Definition: malignant disease of the
lymphoid system, highly heterogeneous,
both histologically and clinically.
2. Epidemiology:
- annual incidence: 5-10 new cases per 100 000 persons,
- age distribution: middle-age patients and the elderly,
- males are affected more often than females (1.5:1.0).

4. chronic myeloid
leukaemia
(CML)
Haematopoietic Malignancies
Polycythemia
vera
(PV)
Idiopathic
myelofibrosis
(MF)
Essential
thrombocythemia
(ET)
Acute myeloid
leukaemia
(AML)
Chronic myeloid
leukaemia
(CML)
Acute lymphatic
leukaemia
(ALL)
Chronic lymphatic
leukaemia
(CLL)
hairy cell
leukaemia
(HCL)
Hodgkin’s
lymphoma
Burkitt's lymphoma
cutaneous T-cell
lymphoma (CTCL)
Non-hodgkin’s
lymphoma
(NHL)
Myeloproliferative
diseases Leukaemias
Malignant
lymphomas

5. B cell malignancies
Pre-B acute lympho-
blastic leukemia
B cell lymphoma Chronic lympho-
cytic leukemia
Multiple myeloma
Progressive B lymphocyte maturation
Bone marrow
Lymph node,
lymph, blood,
bone marrow
Lymph node,
lymph, blood,
bone marrow
Bone marrow
Lymphoid stem cell Maturing B cell
many stages
Mature B cell Plasma cell

6. Histologic classification of non-
Hodgkin’s lymphomas
1. Rappaport - 1966
2. Lukes and Collins - 1974
3. Dorfman - 1974
4. Bennet et al., - 1974
5. Lennert - 1974
6. WHO - 1976
7. Working Formulation - 1982
8. REAL - 1994
9. WHO - 1999

7. Non-Hodgkin’s Lymphoma
Rappaport Classification
Nodular (follicular) Diffuse
Small cell Large cell
Indolent Aggressive

8. Non-Hodgkin’s Lymphoma
Working Classification
• Low Grade
– Small Lymphocytic
– Follicular small-cleaved cell
– Follicular mixed small-cleaved and large cell
• Intermediate Grade
– Follicular large cell
– Diffuse small cleaved cell
– Diffuse mixed small and large cell
– Diffuse large cell
• High Grade
– Large cell immunoblastic
– Lymphoblastic
– Small non-cleaved cell (Burkitt's and non-Burkitt's type)

10. REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF B
– CELL LYMPHOMAS
10

11. REAL/ WHO 2001/ WHO 2008 CLASSIFICATION OF
THE T/NK CELL LYMPHOMAS .
11

12. 12

13. High risk aggressive non-Hodgkin’s
lymphomas
1. Age abowe 60 years.
2. Disease stage III and IV.
3. Extranodal involvement of more than 1
site.
4. Serum LDH concentration >1 x normal.
5. Performance status < 80%.

16. RISK FACTORS
• IMMUNOLOGICAL-AUTOIMMUNE DISEASES,
• VIRAL-HIV, EBV,HCV
• ENVIRORNMENTAL-
PESTICIDES,HERBICIDES,SMOKING
• GENITIC-KLINFILTERS,SCID

17. EPIDIOMOLOGY
• Incidence is increasing with age
• NHL>HD
• Median age of presentation is 65-70 yrs
• M>F
• More often clinically disseminated at
diagnosis
• B-cell-70% ; T-cell-30%

18. classification Indolent”good” Aggressive”bad
”
Highly
aggressive
“ugly”
Type Follicular
B CLL/SLL
Lymphoplasma
cytic
Mantle
DLBCL
PTCL
Burkitt
LBL

19. INDOLENT”GOOD” AGGRESSIVE”BAD” HIGHLY
AGGRESSIVE”UGLY”
AGE Older adults Any age Children/young
adults
RATE OF GROWTH Slow waxing and
waning
fast Very fast
STAGE AT
PRESENTATION
High stage 1-1V High stage
PERIPHERAL
BLOOD AND
BONEMARROW
INVOLVEMENT
common UNCOMMON common

20. INDOLENT”GOOD” AGGRESSIVE”BAD” HIGHLY
AGGRESSIVE
CNS INVOLVEMENT rare rare common
NATURAL HISTORY
IF UNTREATED
Indolent
In a proportion
transform to high
grade lymphoma
Survival 1-2 years Survival only weeks
to months
RESPONSE TO
TREATMENT
Not curable by
RT/chemo
Potentially curable Highly responsive;
”escape” b/n
chemotherapy
cycles
CLINICAL OUTCOME Repeated relapse
Asymptomatic
patients may be
observed
70-80%per
complete remission
with treatment.
2/3rd cured of
disease
Cure with early
stage.CNS
prophylaxis
required

22. 22

23. pathogenesis

24. Malignant transformation of either the
T or B cells
Differentiation in the peripheral lymphoid
tissues
Predisposing
•Gender
•Race
•Family History
•Infections
•Immune System Deficiency
Disorders
•Autoimmune Disorders
•Chemical Exposure
•Radiation Exposure
•Lifestyle Factors
Precipitating
•Unknown
(idiopathic)

25. T lumphocytes proliferate on antigenic stimulation
and migrate into follicles, where they intact in B
lymphocytes
These activated follicles becme germinal
centers, containing macrophages, follicular
dendrite cells and maturing T and B cells
Develops in any lymphoid
tissues (lymph nodes

26. Spreads to various lymphoid tissues
throughout the body, especially the liver,
spleen and bone marrow
Non-hodgkin’s lymphoma
Group of tumors will
develop

27. Most common:
•painless enlargement
of one or more lymph
node, usually in the
neck, armpits, or groin.
(painless, superficial
lymphadenopathy)
•Usually asymptomatic
Systemic B Sx:
•Drenching night sweats
•Unexplained weight loss
•Fever
•Severe itching

30. Clinical features
• Widely disseminated at presentation
• Nodal involvement:
Painless lymphadenopathy, often cervical region is
the most common presentation
• Hepatospleenomegaly
• Extranodal Intestinal lymphoma ( abdominal pain,
anemia, dysphagia);
CNS ( headache, cranial nerve palsies, spinal cord
compression) ;
Skin, Testis; Thyroid; Lung
Bone marrow (low grade): Pancytopenia

31. Clinical features contd
 Systemic symptoms
– Sweating, weight loss, itching
– Metabolic complications: hyperuricemia,
hypercalcemia, renal failure
• Compression syndrome:
– Gut obstruction
– Ascites
– SVC obstruction
– S/C Compression

32. Oncologic emergencies
• — Potentially emergent complications of NHL
may be present at the time of diagnosis and need
to be considered during the initial workup and
evaluation of a patient with suspected pediatric
NHL..
These can include:
●Superior or inferior vena cava obstruction
●Acute airway obstruction
●Intestinal obstruction, intussusception
●Spinal cord compression

33. ●Pericardial tamponade
●Lymphomatous meningitis and/or CNS mass
lesions
●Hyperuricemia and tumor lysis syndrome
●Ureteral obstruction, unilateral or bilateral
hydronephrosis
●Venous thromboembolic disease

35. Specific subtypes of NHL have
unique clinical and pathologic
features

36. Diffuse Large B-Cell Lymphoma
(DLBLC). DLBCL is the most common type of non-
Hodgkins lymphoma, accounting for about 30% of
all NHL cases. It is an aggressive, fast-growing
lymphoma that usually affects adults but can also
occur in children. DLBCL can occur in lymph nodes
or in organs outside of the lymphatic system.
DLBCL includes several subtypes such as
mediastinal large B-cell lymphoma, intravascular
large B-cell lymphoma, and primary effusion
lymphoma.

37. Gross appearance of lymphnodes involved by non-Hodgkin lymphoma of the diffuse
large cell type. The nodes are large and show a homogenous tan cut surface. 37

38. Spleen in DLBCL

39. Follicular Lymphoma (FLs).
Follicular lymphoma is the
second most common type
lymphoma, accounting for
about 20% of all NHL cases. It is
usually indolent (slow growing)
but about half of follicular
lymphomas transform over
time into the aggressive diffuse
large B-cell lymphoma.

40. Mantle Cell Lymphoma.
Mantle cell lymphoma is an aggressive type of
lymphoma that represent about 7% of NHL
cases. It is a difficult type of lymphoma to treat
and often does not respond to chemotherapy. It
is found in lymph nodes, the spleen, bone
marrow, and gastrointestinal system. Mantle cell
lymphoma usually develops in men over age 60.

41. Small Lymphocytic
Lymphoma (SLL). SLL is
an indolent type of
lymphoma that is
closely related to B-cell
chronic lymphocytic
leukemia (CLL). It
accounts for about 5%
of NHL cases.

42. Marginal Zone
Lymphomas (MZL). MZLs
are categorized
depending on where the
lymphoma is located.
Mucosa-associated
lymphoid tissue
lymphomas (MALT)
usually involve the
gastrointestinal tract,
thyroid, lungs, saliva
glands, or skin. MALT is
often associated with a
history of an
autoimmune disorder
(such as Sjogren
syndrome in the salivary
glands or Hashimoto's
thyroiditis in the thyroid
gland).

43. Primary Central Nervous System Lymphoma.
This lymphoma involves the brain and
spinal cord. Although it is generally rare, it is
common in people who have AIDS.

44. Burkitt's Lymphoma.
This is one of the most
common types of
childhood NHL,
accounting for about
40% of NHL pediatric
cases in the United
States. It usually starts
in the abdomen and
spreads to other
organs, including the
brain. In African
children, it often
involves facial bones
and is associated with
Epstein-Barr infection.

45. BURKITT LYMPHOMA
TYPES:
1. African (endemic) BL,
2. Sporadic (nonendemic) BL,
3. Subset of aggressive lymphomas in
HIV+ individuals;
(histologically identical but with
clinical, genotypic and virologic
differences)

46. Burkitt’s lymphoma

47. BURKITTS LYMPHOMA
• IT IS ASSOCIATED WITH RECIPROCAL
TRANSLOCATIONS INVOLVING Cmyc gene on
chromosome 8
• Most comman translocation 70% cases-t[8;14]
• Cmyc gene on chromosome 8 and IgH heavy
chain on chromosome 14
• Less comman-t[8;22],t[2;8]

48. Burkitt’s lymphoma - ovaries

49. Burkitt lymphoma

50. Reciprocal translocation between 8 and 14

51. • Most burkitts lymphoma presents at
extranodal sites most commanly mandible and
abdominal viscera
• CNS involvement is frequent
• Most rapidly progrssive human tumour

52. Lymphoblastic Lymphoma.
This lymphoma is also
common in children,
accounting for about 25%
of NHL pediatric cases,
most often boys. It is
associated with a large
mediastinal mass
(occurring in chest cavity
between the lungs) and
carries a high risk for
spreading to bone
marrow, the brain, and
other lymph nodes.

53. • Tumour of CD4+ cells,
• Predilection to involve skin,
• Infiltration of epidermis and upper dermis
by T-cells with cerebriform nucleus,
• Spreads to lymphnodes and bone marrow,
• Indolent tumours – median 8 – 9 yrs;
• May transform to large T-cell lymphoma;
MYCOSIS FUNGOIDES/SEZARY SYNDROME

54. Mycosis fungoides/Sézary syndrome

55. Mycosis fungoides/Sézary syndrome

56. Anaplastic Large Cell Lymphoma
• Rearrangements of ALK gene on 2p23,
• In some - ALK fusion proteins (anaplastic
lymphoma kinase)
– tyrosine kinases,
• Large anaplastic cells (horseshoe-shaped
nuclei & voluminous cytoplasm – Hallmark
cells),
• Children or young adults,
• Involve soft tissues,
• Good prognosis – ALK+

57. T cell lymphoblastic lymphoma
• The most common presentation is
- peripheral lymphadenopathy,
- respiratory distress, wheezing,
-and superior vena cava syndrome from mediastinal
involvement .
• more common in males.
• The incidence is stable across all pediatric age groups with
a median age of diagnosis of 12 years.
• Children diagnosed with lymphoblastic lymphoma whose
bone marrow is more than 25 percent replaced by
lymphoblasts are classified and treated as acute
lymphoblastic leukemia.

58. Immune markers
T-cells
CD1, CD3, CD4, CD5,
CD8
B-cells
CD10, CD19, CD20,
CD21, CD23, CD79a,
All Leukocytes =
CD45
NK-cells =
CD16, CD56

59. IMMUNE MARKERS
• B-ALL/LBL: CD34 ±, TdT+, CD20 ±, CD79a+,
CD10 ± , CD43+
• T-ALL/LBL: CD34 ±, TdT+, CD3+, CD5+, CD43+,
CD10 ±, CD79a ±, CD99 ±
• Burkitt’s Lymphoma: CD20+, CD10+, BCL-6+,
Ki-67 ~100%, CD34 Neg, TdT Neg,

60. Laboratory features
• Laboratory tests -
• It is important to remember that the complete
blood count (CBC) may be normal.
● -Unexplained anemia,
- thrombocytopenia, or leukopenia
• These changes in peripheral blood counts can be
due to extensive bone marrow infiltration,
hypersplenism from splenic involvement, or
blood loss from gastrointestinal tract

61. • Hyperuricemia
• Elevated level of serum lactate dehydrogenase
(LDH)

62. Imaging studies
• — Initial imaging studies
-ultrasound,
-radiographs,
-computed tomography are often performed as
part of the evaluation of presenting symptoms
(eg, abdominal pain).
- These may demonstrate
masses and/or lymphadenopathy in the neck,
chest, or abdomen.

63. Imaging studies
• Integrated positron emissions
tomography (PET)/CT scanning is more sensitive
and specific than CT in certain histologic subtypes
of NHL, including the most common subtypes
seen in children
• Imaging of the bones with plain films,
CT, and/or magnetic resonance imaging (MRI) is
not routinely performed in NHL, but is indicated
in the presence of bone pain and/or suspicion of
a pathologic fracture.

64. Imaging studies
• Bone lesions in NHL are mostly osteolytic on
plain films, in contrast to those in patients with
Hodgkin lymphoma, which are predominantly
osteoblastic
• If there is suspicion of spinal cord compression,
urgent MRI of the entire spinal column is
indicated, since multiple sites may be involved.
MRI (with and without gadolinium) of the head is
also indicated for patients with neurologic
symptoms or signs.

65. DIAGNOSIS
• The diagnosis of NHL is based upon the
pathologic evaluation of involved tissue,
usually an abdominal mass, extranodal site, or
lymph node, interpreted within the clinical
context .
• Subtypes of NHL are identified using
- histology,
- immunophenotype, and genetic studies.

66. STAGING
•

67. NHL is staged according to the
Murphy stage
●Stage I – Stage I disease involves a single tumor
(extranodal) or single anatomic area (nodal), excluding
the abdomen and mediastinum.
●Stage II – Stage II disease is designated by any of the
following:
•Single extranodal area plus regional lymph nodes
•Two single extranodal tumors on the same side of the
diaphragm with or without regional lymph nodes
•Primary gastrointestinal tumor (completely resected)
with or without mesenteric lymph nodes

68. ●Stage III – Stage III disease is designated by any one of the
following:
- Primary intrathoracic (mediastinal, thymic, pleural)
disease
- Two extranodal sites on opposite sides of the diaphragm
- Extensive primary intra-abdominal disease
- Two or more nodal areas on opposite sides of the
diaphragm
- Any paraspinal or epidural tumors
●Stage IV – Any of the above with involvement of the bone
marrow, central nervous system, or both

70. T
R
E
A
T
M
E
N
T

71. •Radiation therapy
-uses high doses of X-
rays, gamma rays, or
other types of ionizing
(damaging) radiation to
kill cancer cells. It may
be applied to the whole
body or to a specific
zone.

72. •Chemotherapy is the
use of cytotoxic (cell
damaging) medicines to
target and kill tumors.
The drugs work by
interrupting the DNA of
fast-growing cells,
preventing them from
growing or reproducing.

73. •Immunotherapy uses
the body’s own immune
system to attack and
remove cancer cells.

74. •Bone marrow
transplantation
•For patients with very
advanced disease, extremely
high does of chemotherapy
may be needed. This type of
chemotherapy wipes out the
body’s entire immune system,
including the bone marrow
that produces blood cells. So,
patients need a bone marrow
transplant in order to recover.

75. Approach Considerations
The treatment of non-Hodgkin lymphoma (NHL)
varies greatly, depending on the following factors:
• Tumor stage
• Phenotype (B-cell, T-cell or natural killer [NK]
cell/null-cell)
• Histology (ie, low-, intermediate-, or high-grade)
• Symptoms
• Performance status
• Patient age
• Comorbidities

76. Management of Indolent NHL
• Follicular lymphoma (grade I-IIIa) comprises
70% of this group. Other entities in this group
include small lymphocytic lymphoma (SLL),
lymphoplasmacytoid lymphoma, and marginal
zone lymphomas (MZL, nodal or extranodal).

77. Management of Indolent NHL
• Indolent stage I and contiguous stage II NHL
• Standard management consists of radiotherapy
alone.
• Indolent noncontiguous stage II, III, and IV NHL
• Frequently used combination regimens are
-(R- CHOP) (Rituximab,cyclophosphamide,
hydroxydaunomycin [Adriamycin], vincristine
[Oncovin], and prednisone),
-CVP (cyclophosphamide, vincristine, and
prednisone), and fludarabine alone or in
combination (eg, with cyclophosphamide or
mitoxantrone).

78. Management of Indolent NHL
• Bendamustine plus rituximab has demonstrated
efficacy for the first-line treatment of advanced
follicular, indolent, and mantle cell lymphomas.
• Current National Comprehensive Cancer Network
guidelines give bendamustine plus rituximab,
RCHOP, and RCVP (rituximab,
cyclophosphamide, vincristine, prednisone)
category 1 recommendations for first-line therapy
of follicular lymphoma.

79. Management of Indolent NHL
• combination of lenalidomide plus rituximab
for both rituximab-refractory and non–
rituximab-refractory indolent NHL are used.
• In patients with indolent NHL that is
refractory to rituximab, obinutuzumab plus
bendamustine followed by obinutuzumab
maintenance has improved efficacy over
bendamustine monotherapy,

81. Aggressive NHL
• Diffuse large B-cell lymphoma is the most
common type of NHL. Other distinct entities in
this group include immunoblastic, anaplastic,
lymphoblastic, large-cell, Burkitt, and Burkitt-
like lymphomas (high-grade lymphomas).
• Mantle cell lymphomasalso behave
aggressively

82. Management of Aggressive NHL
• Aggressive stage I and contiguous stage II
(nonbulky or < 10 cm) NHL
• combination chemotherapy (3 cycles of CHOP)
plus involved-field radiation therapy.

83. Aggressive noncontiguous stage II, III,
and IV NHL
• any of the following regimens[35] :
• CHOP
• (ProMACE-CytaBOM) Prednisone,
methotrexate, leucovorin, doxorubicin,
cyclophosphamide, and etoposide—
cyclophosphamide, etoposide, Adriamycin,
cytarabine, bleomycin, Oncovin,
methotrexate, leucovorin, and prednisone

84. Aggressive noncontiguous stage II, III,
and IV NHL
• (m-BACOD) –Methotrexate, bleomycin,
doxorubicin (Adriamycin), cyclophosphamide,
Oncovin, and dexamethasone
• (MACOP-B) –
-Methotrexate-leucovorin, Adriamycin,
cyclophosphamide, Oncovin, prednisone, and
bleomycin

85. Aggressive noncontiguous stage II, III,
and IV NHL
• Hyper-CVAD (cyclophosphamide, vincristine,
doxorubicin, dexamethasone, alternating with
methotrexate and cytarabine) plus rituximab has
been shown high rate of remission in patients
with mantle cell lymphoma.
• Bendamustine and rituximab combination has
been successfully used in patients with mantle
cell lymphoma in the first and second-line
setting.

86. Management of Indolent Recurrent
NHL
• The following are possible treatment options:
• Single alkylating agents (chlorambucil or
bendamustine)
• Novel biological agents and small molecule
inhibitors include ofatumumab,
lenalidomide, and temsirolimus
• Combination chemotherapy - CVP, CHOP, and
others
• Purine analogues - Fludarabine,
• Rituximab
• Radioimmunotherapy

87. Management of Aggressive Recurrent
Adult NHL
• High-dose chemotherapy plus stem-cell
transplantation is the treatment of choice
• Second-line chemotherapy regimens such as
-ICE (ifosfamide, carboplatin, etoposide),
-DHAP (dexamethasone, high-dose cytarabine,
cisplatin), or
-EPOCH (etoposide, vincristine, doxorubicin,
cyclophosphamide, prednisone) are usually used
with rituximab if the tumor is CD20 positive.

88. Management of T-cell Lymphomas
• Treatment options for T-cell lymphoma can
be categorized as follows:
• Combination chemotherapy regimens
- CHOP,
-CHOP plus etoposide, gemcitabine based-
regimens
• Single chemotherapy agents - Pralatrexate

89. Management of T-cell Lymphomas
• Monoclonal antibodies - Alemtuzumab
(effective in prolymphocytic T-cell leukemia
and hepatosplenic gamma-delta T-cell
lymphoma)
• Immunotoxin - Denileukin diftitox
• Novel biological agents and small molecule
inhibitors - Histone deacetylase inhibitors
(vorinostat, panobinostat, romidepsin,
belinostat), lenalidomide, and bortezomib

90. Surgical Care
• The role of surgery in the treatment of
patients with NHL is limited.
• Surgery is useful in selected situations (eg, GI
lymphoma), particularly if the disease is
localized or if risk of perforation, obstruction,
and massive bleeding is present.
• Orchiectomy is part of the initial
management of testicular lymphoma.

91. Complications of Therapy
• Potential chemotherapy and other treatment-
related complications include the following:
• Cytopenias (ie, neutropenia, anemia,
thrombocytopenia)
• Nausea or vomiting
• Infection
• Fatigue
• Neuropathy

92. Complications of Therapy
• Dehydration after diarrhea or vomiting
• Cardiac toxicity from doxorubicin
• Catheter-related sepsis
• Catheter-related thrombosis
• Secondary malignancies
• Tumor lysis syndrome
• Atherosclerosis

93. Prognosis
• Low grade : Median survival –10 yrs
• High Grade:
– Increasing age, advanced stage, concomitant
disease, raised LDH,T- cell phenotype : Poor
prognosis

94. LYMPHOMA
94