1. NON HODGKIN’S LYMPHOMA
Sec C Group D
Mamba - Medenilla

2. Non-Hodgkin’s Lymphoma
Heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment
Originates in the lymphoid tissues and can spread to other organs
Reed-Sternberg cells
Separated from Hodgkin’s disease
Less predictable
Greater predilection to disseminate to extranodal sites

3. Non-Hodgkin’s Lymphoma
Can be divided into:
Aggressive (fast-growing) types
Indolent (slow-growing) types
Classification
B-cell
T-cell
Prognosis
Histologic type
Stage
Treatment

4. Indolent Lymphomas Aggressive Lymphomas Relatively good prognosis
Median survival time:10 yrs
Not usually curable in advanced stages
Early-stage (I and II) indolent NHL
treated effectively with radiation therapy alone
Most of the indolent types are nodular (or follicular) in morphology
It has a shorter natural history
Significant number of patients
cured with combination chemotherapy regimens

5. B-cell Non-Hodgkin’s Lymphomas
Precursor B cell Neoplasm
Precursor B-lymphoblastic lymphoma
Mature(Peripheral) B cell neoplasm
B cell Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
B cell prolymphocytic leukemia
Lymphoplasmacytic Lymphoma
Splenic Marginal Zone B cell Lymphoma
Plasma cell myeloma/ Plasmacytoma
Extranodal Marginal Zone B cell Lymphoma of MALT Type
Mantle Cell Lymphoma
Follicular Lymphoma
Nodal Marginal Zone B cell Lymphoma
Diffuse Large B-cell Lymphoma
Burkitt’s Lymphoma

6. T-cell Non-Hodgkin’s Lymphomas
Precursor T cell Neoplasm
Precursor T-lymphoblastic lymphoma
Mature(Peripheral) T cell neoplasm
T cell prolymphocytic leukemia
T cell granular lymphotic leukemia
Aggressive NK cell Leukemia
Adult T cell Lymphoma
Extranodal NK/T cell Lymphoma
Enteropathy-Type T cell Lymphoma
Hepatosplenic ɣδ T cell Lymphoma
Subcutaneous Panniculitis-like T cell Lymphoma
Mycosis Fungoides/Sezary Syndrome
Anaplastic large cell lymphoma, primary cutaneous type
Peripheral T cell Lymphoma, not otherwise specified
Angioimmunoblastic T cell Lymphoma
Anaplastic Large Cell Lymphoma, primary systemic type

7. General Aspects of Lymphoid Malignancies
Chronic Lymphoid Leukemia
Acute Lymphoid Leukemia
Epidemiology
Older adults; men>women; Whites>blacks
Children and young adults; among higher socioeconomic groups
Etiology/ Predisposition
Unknown
EBV (L3/Burkitt’s)
Trisomy 21, high energy radiation; industrial/agricultural chemicals exposure; smoking
Fauci, et al., Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 687

8. General Aspects of Lymphoid Malignancies
Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma
Epidemiology
Bimodal age distribution (20’s & 80s); males>females; whites>blacks
Elderly; men>women
Etiology/ Predisposition
HIV
EBV
Primary & secondary immunodeficiency states; HIV; Organ transplant patients; inherited immune deficiency; Sicca syndrome; Rheumatoid arthritis
Fauci, et al., Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 687

9. Non-Hodgkin’s Lymphoma
Incidence and patterns of expression of subtypes differ geographically
Asia
T cell Lymphoma
Western countries
B cell (follicular) Lymphoma
Southern Asia & Latin America
Angiocentric Nasal T/NK Lymhoma
Southern Japan & Carribean
Adult T cell Lymphoma
Fauci, et al., Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688

10. Non-Hodgkin’s Lymphoma
Environmental Factors:
Infectious agents
Chemical exposures
Medical treatments
Fauci, et al., Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688

11. Non-Hodgkin’s Lymphoma
Infectious agent
Lymphoid malignancy
Epstein-Barr virus
Burkitt’s lymphoma
Primary CNS diffuse large B cell lymphoma
Extranodal T cell/NK lymphoma
HTLV-1
Adult T cell leukemia/lymphoma
HIV
Diffuse large B cell lymphoma
Hepatitis C virus
Lymphoplasmacytic lymphoma
Helicobacter pylori
Gastric MALT lymphoma
Human herpesvirus 8
Primary effusion lymphoma
Multicentric Castleman’s disease
Fauci, et al., Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688

12. Non-Hodgkin’s Lymphoma
Inherited immunodeficiency states
Klinefelter’s syndrome
Chediak-Higashi syndrome
Ataxia telangiectasia syndrome
Wiscott-Aldrich syndrome
Common variable immunodeficiency states
Acquired immunodeficiency states
Iatrogenic immunosuppression
HIV-1 infection
Acquired hypogammaglobulinemia
Autoimmune disease
Sjogren’s syndrome
Celiac sprue Rheumatoid arthritis and SLE
Chemical and drug exposures
Phenytoin
Dioxin, phenoxyherbicides
Radiation
Prior chemotherapy and radiation therapy
Fauci, et al., Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688

13. Immunology
All lymphoid cells are derived from a common hematopoietic progenitor
Sequential activation of a series of TF’s, cells becomes committed to the lymphoid lineage  T and B cells

14. B cells development
A cell becomes committed to the B cell development  arrangement of immunoglobulin genes

16. T cell development A cell becomes committed to T cell differentiation
upon migration to the thymus
Reaarangement of T cell antigen genes

18. Malignancies Associated with recurring genetic abnormalities
At a variety of chromosomal changes 
Gross (translocations, additions or deletions)
Rearrangement of specific genes
Underexpression
Mutation of specific oncogenes
Altered expression or mutation of specific proteins is paritcularly important.

19. Chromosomal translocations
Antigen receptor genes
Immunoglobulin genes on Chr. 2, 14, and 22 on B cells
T cell antigen genes on chr. 7 and 14 in T cells.
Rearrangement to generate mature antigen receptors  create a site vulnerability to abnormal recombination

20. T(14;18) in follicular lymphoma, t(2;5) in anaplastic large T/null cell lymphoma, t(8;14) in Burkitt’s lymphoma t(11;14) in mantle cell lymphoma, great majority of tumors in patients with these diagnoses display this abnormality.

21. Clinical Features Lymphadenopathy
the most common manifestation of lymphoma
Waldeyer ring & mesenteric Lymph nodes are commonly involved
Spreads in noncontiguous fashion
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 686

22. Lymphadenopathy
2/3 of NHL (and virtually all cases of HL) present with NON TENDER nodal enlargement often >2cm size that can be localized or generalized
The remaining 1/3 of NHL’s arise at extranodal sites ( e.g. skin, stomach and brain)
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 668

23. Other Signs And Symptoms
fevers, night sweats, weight loss, and fatigue
pruritus
shortness of breath, chest pain, cough, abdominal pain and distension, or bone pain
pallor (suggesting anemia)
purpura, petechiae, or ecchymoses (suggesting thrombocytopenia)
Harrison’s Principle of Internal Medicine 17th edition

24. SALIENT CLINICAL FEATURES Precursor B-cell acute lymphoblastic/
TYPE
SALIENT CLINICAL FEATURES
Precursor B-cell acute lymphoblastic/
leukemia/lymphoma
Predominantly children with Sx relating to pancytopenia secondary to marrow involvement; aggressive
Precursor T-cell acute lymphoblastic/
Predominantly adolescent males w/ thymic masses, variable splenic, hepatic and bone marrow involvement; aggressive
Burkitt lymphoma
Adolescents/young adults w/ jaw or extranodal abdominal masses, uncommonly presents as “leukemia”; aggressive
Diffuse large B-cell lymphoma
All ages but most common in adults; often appear as a single rapidly growing mass; 30% extranodal; aggressive
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 671

25. SALIENT CLINICAL FEATURES Extranodal marginal zone lymphoma
TYPE
SALIENT CLINICAL FEATURES
Extranodal marginal zone lymphoma
In adults w/ chronic inflammatory diseases; may remain localized; indolent
Follicular Lymphoma
Older adults w/ generalized lymphadenopathy and marrow involvement; indolent
Mantle cell lymphoma
Older males with disseminated disease; moderately aggressive
Small lymphocytic lymphoma/ chronic lymphocytic leukemia
Older adults with bone marrow, lynph nodes, spleen and liver disease; most have peripheral blood involvement; autoimmune involvement and thrombocytopenia in a minority; indolent
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 671

26. SALIENT CLINICAL FEATURES Anaplastic large cell lymphoma
TYPE
SALIENT CLINICAL FEATURES
Anaplastic large cell lymphoma
children and young adults, usually with lymph node and soft tissue disease; aggressive
Hairy cell leukemia
Older males with pancytopenia and splenomegaly; indolent
Mycosis fungioides/ Sézary syndrome
Adult patients with cutaneous patches, plaques, nodules or generalized erythema; indolent
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 671

27. Lymphoid neoplasia can be suspected from all the clinical features but histological examination of lymph nodes or other involved tissues is required for the diagnosis
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 668

28. Staging evaluation for NHL
Ann Arbor Staging system is applicable to both Hodgkin’s disease and NHL

29. Ann Arbor Staging System
PATIENT: 70 y.o. Male
Gradual weight loss
Low grade fever
Anorexia
Body Weakness
Bilateral Cervical Lymph Nodes
Right Axillary Mass
Largest: 3x2cm
Discrete, nontender, movable
Palpable spleen 3cm below L subcostal margin MCL
Stage
Definition I
Involvement of a single LN region or lymphoid structure (eg. Spleen, thymus, Waldeyer’s ring) II
Involvement of ≥2 LN regions on the same side of the diaphragm (the mediastinum is a single site; hilar LN should be considered as “lateralized” and, when involved on both sides, constitute stage II disease)
III
Involvement of LN regions or lymphoid structures on both sides of the diaphragm
III1
Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes
III2
Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1 IV
Involvement of extranodal site(s) beyond that designated as “E”
>1 extranodal deposit at any location
Any involvement of liver or bone marrow
Source: p. 691

30. Ann Arbor Staging System
Stage
Definition A
No symptoms B
- Unexplained weight loss of >10% of the body weight during the 6 months before staging investigation
- Unexplained, persistent, or recurrent fever with temperatures >38°C during previous month
- Recurrent drenching night sweats during the previous month E
Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow
PATIENT: 70 y.o. Male
Gradual weight loss
Low grade fever
Anorexia
Body Weakness
Bilateral Cervical Lymph Nodes
Right Axillary Mass
Largest: 3x2cm
Discrete, nontender, movable
Palpable spleen 3cm below L subcostal margin MCL
Staging for our patient:
Stage III1B
Source: p. 691

31. Ancillary procedures for Primary staging
CBC
ESR
LDH
ß2- microglobulin
Serum protein electrophoresis
Chemistry studies reflecting major organ function
CT scans (chest, abdomen, pelvis)
Bone marrow biopsy
Source: p. 692

32. International Prognostic Index (IPI) for NHL
A powerful predictor of outcome in all subtypes of NHL
Scoring: based on presence or absence of
5 adverse prognostic factors
may have none or all 5 of these
Source: p. 692

33. ECOG PERFORMANCE STATUS*
Grade
ECOG
Fully active, able to carry on all pre-disease performance without restriction 1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5
Dead
PATIENT: 70 y.o. Male
Gradual weight loss
Low grade fever
Anorexia
Body Weakness
Bilateral Cervical Lymph Nodes
Right Axillary Mass
Largest: 3x2cm
Discrete, nontender, movable
Palpable spleen 3cm below L subcostal margin MCL

34. KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA
Able to carry on normal activity and to work; no special care needed.
  100  
Normal no complaints; no evidence of disease. 90
Able to carry on normal activity; minor signs or symptoms of disease. 80
Normal activity with effort; some signs or symptoms of disease.
Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed. 70
Cares for self; unable to carry on normal activity or to do active work. 60
Requires occasional assistance, but is able to care for most of his personal needs. 50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly. 40
Disabled; requires special care and assistance. 30
Severely disabled; hospital admission is indicated although death not imminent. 20
Very sick; hospital admission necessary; active supportive treatment necessary. 10
Moribund; fatal processes progressing rapidly.
Dead
PATIENT: 70 y.o. Male
Gradual weight loss
Low grade fever
Anorexia
Body Weakness
Bilateral Cervical Lymph Nodes
Right Axillary Mass
Largest: 3x2cm
Discrete, nontender, movable
Palpable spleen 3cm below L subcostal margin MCL

35. International Prognostic Index (IPI) for NHL
Five clinical Risk Factors
Age ≥ 60 years
Serum lactate DH levels elevated
Performance status ≥ 2 (ECOG) or ≤ 70 (Karnofsky)
Ann Arbor stage III or IV
> 1 site of extranodal involvement
Patients are assigned a number for each risk factor they have
Patients are grouped differently based upon the type of lymphoma
For diffuse large B cell lymphoma
0, 1 factor
2 factors
3 factors
4, 5 factors
Low risk
Low-intermediate risk
High-intermediate risk
High risk
35% of cases; 5-yr survival 73%
27% %
22% %
16% %
For diffuse large B cell lymphoma treated with R-CHOP
0 factor
1, 2 factors
3, 4, 5 factors
Very good
Good
Poor
10% of cases; 5-yr survival 94%
45% %
45% %
PATIENT: 70 y.o. Male
Gradual weight loss
Low grade fever
Anorexia
Body Weakness
Bilateral Cervical Lymph Nodes
Right Axillary Mass
Largest: 3x2cm
Discrete, nontender, movable
Palpable spleen 3cm below L subcostal margin MCL
Source: p. 692

36. IPI for Patient (Pre treatment)
Age ≥ 60 years
Stage III1B
Serum LDH levels elevated
2 factors
Low-intermediate risk
27% of cases;
5-yr survival 51%
3 factors
High-intermediate risk
22% of cases;
5-yr survival 43%

37. Treatment of Non- Hodgkin’s Lymphoma

38. Precursor B cell Lymphoblastic Leukemia
Remission induction with combination therapy
Consolidation phase:
High dose systemic therapy
Treatment to eliminate CNS disease
Continuing therapy: prevent relapse and effect cure
Combination therapy used:
Rituximab- fludarabine- cyclophosphamide
Associated with grade III or IV neutropenia
Cyclophophamide- vincristine- prednisone
Cyclophosphamide- doxorubicin- vincristine- prednisone
Combination therapy: cyclophosphamide + doxorubicin + vincristine + prednisone (CHOP)/ chlorambucil, fludarabine, etoposide

39. B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia
Chlorambucil: orally; few immediate side effects
Chosen in elderly patients who require therapy
Fludarabine: IV; with significant immune suppression
more active agent; with significant incidence of complete remission
Regimens inclusive of this drug is chosen for young patients presenting with leukemia requiring therapy
Second line agent for patients with tumors unresponsive to chlorambucil
Combination

40. B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia
Rai stage O and Binet stage A (no manifestations of disease other than BM involvement and lymphocytosis
Followed without a specific therapy
With adequate number of circulating normal blood cells, asymptomatic
Require treatment for the first few years of follow up
Rai stage III or IV or Binet stage C (Bone Marrow failure)
Require initial therapy
Immune manifestations should be managed independently of antileukemic therapy

41. MALT Lymphoma Radiation and Surgery Eradication of H. pylori infection
Because it is often localized
Eradication of H. pylori infection
With more extensive diseases: Chlorambucil

42. Mantle Cell Lymphoma
With disseminated disease: aggressive combination chemotherapy regimens+ autologous/ allogeneic BM transplantation
Localized diseases: combination chemotherapy + radiotherapy
Asymptomatic, elderly patient: observation + single- agent chemotherapy
Combination chemotheray used: HyperC- Vad: cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytaribine and methotrexate); CHOP+ RITUXIMAB

43. Follicular Lymphoma
Asymptomatic patient, older patient: watchful waiting
For those who require treatment: single- agent chlorambucil or cyclophosphamide or combination therapy with CVP or CHOP
For patients with localized follicular lymphoma: radiotherapy
Most responsive to chemotherapy and radiotherapy
Active therapies:
Fludarabine
Interferon α: prolong survival in patients on doxorubicin- containing combination therapies
Monoclonal antibodies with or without radionuclides
Lymphoma vaccines

44. Diffuse Large B Cell Lymphoma
Initial Treatmant: combination chemotherapy regimen= CHOP + Rituximab
Stage I or non bulky stage II: 3-4 cycles + field radiotherapy
Bulky stage II, stage III, stage IV: 6-8 cycles or 4 cycles then reevaluate -> complete remission -> 2 more cycles, then therapy discontinued
IPI : predict favorable responses
Score 0-1: 5 year survival >70 %
Score 4-5: 5 year survival ~20%
For refractory cases or relapse
Salvage therapy
Alternative combination therapy
Autologous bone marrow transplantation

45. Burkitt’s Lymphoma Treatment should begin 48 hrs after diagnosis
High doses of Cyclophosphamide
Prophylactic therapy to CNS mandatory

46. Other B Cell Lymphoid Malignancies
Hairy cell leukemia: Cladribine
Splenic marginal zone lymphoma: splenectomy, chlorambucil
Lymphoplasmacytic lymphoma: Chlorambucil, fludarabine and cladribine
Nodal marginal zone lymphoma: treatment same as follicular lymphoma

47. Precursor T Cell Lymphoblastic Leukemia
Very intensive remission induction and consolidation regimens
Leukemia- like regimens: for older children and young adults
With high levels of LDH or BM, CNS involvement: BM transplantation

48. Anaplastic Large T/ Null Cell Lymphoma
Treatment regimens same as for other aggressive lymphomas (diffuse large B cell lymphoma)
Rituximab is omitted

49. Mature/Peripheral T Cell Disorders
Mycoises Fungoides
Localized early stage: radiotherapy- total skin electron beam irradiation
More advanced disease: topical glucocorticoids, topical nitrogen mustard, phototherapy, psoralen with PUVA, electron beam radiation, IFN, Antibodies, fusion toxins and systemic cytotoxic therapy
Adult T Cell Lymphoma/ Leukemia
Combination chemotherapy regimens

50. THANK YOU!