Lecture about the most commone Lymphoproliferative disorders

1. Lymphoproliferative
disorders

2. Lymphoproliferative disorders
Several clinical conditions in which lymphocytes are produced in excessive
quantities ( Lymphocytosis)
Lymphoma
Malignant lymphoid mass involving the lymphoid tissues (± other tissues e.g :
skin ,GIT ,CNS …)
Lymphoid leukemia
Malignant proliferation of lymphoid cells in Bone marrow and peripheral blood (±
other tissues e.g : lymph nods ,spleen , skin ,GIT ,CNS …)
Definition

3. Lymphoproliferative disorders
Autoimmune Infection Malignant

4. Lymphocytosis
1- Viral infection :
•Infectious mononucleosis ,cytomegalovirus
,rubella, hepatitis, adenoviruses, varicella….
2- Some bacterial infection:
(Pertussis ,brucellosis …)
3-Immune : SLE , Allergic drug reactions
4- Other conditions:, splenectomy,
dermatitis ,hyperthyroidism metastatic
carcinoma….)
5- Chronic lymphocytic leukemia (CLL)
6-Other lymphomas:
Mantle cell lymphoma ,Hodgkin lymphoma…

5. • An acute, infectious disease, caused by Epstein-Barr virus and
characterized by
• fever
• swollen lymph nodes (painful)
• Sore throat,
• atypical lymphocyte
• Affect young people ( usually)
Infectious mononucleosis

6. Infectious Mononucleosis
• EBV is herpesvirus transmitted through saliva cause IM and
implicated in the development of Burkitt's lymphoma and
Hodgkin's disease.
• After the virus enters the body it can take up to a month before
symptoms begin.

7. Infectious mononucleosis
1-Virus specific antibodies
• IgM : Develops early and last for few month
• IgG: Develops later and persists for life
2- Heterophile antibodies :
Antibodies produced as a result of the infection and react to antigens from
animal RBCs.
• Sheep RBCs agglutinate in the presence of heterophile antibodies and are the
basis for the Paul-Bunnell test.
• Agglutination of horse RBCs on exposure to heterophile antibodies is the
basis of the Monospot test.
Lab Investigation

8. • Self limiting disease ( 4-6 weeks)
• Unusual complication such hepatitis ,encephalitis and splenic
rupture may occur.
• Treatment :
1. Supportive
2. Rest
3. Analgesia
4. Steroid or Acyclovir in severe cases or at complication
Infectious Mononucleosis

9. ALL MM
CLL Lymphomas
Hematopoietic
stem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor
Myeloproliferative disorders
AML
Lymphoid
progenitor T-lymphocytes
Plasma
cells
B-lymphocytes
naïve

10. Malignant Lymphoproliferative disorders
Immature
ALL
Mature
Lymphoid leukemia
Lymphoma
CLL
Hairy cell leukemia
T- prolymphocytic
leukemia
Leukemic phase of
lymphoma
Hodgkin lymphoma
Non Hodgkin lymphoma
T- cell neoplasm
Adult T leukemia lymphoma
Sezary syndrome
Large anaplastic T lymphoma
B- cell neoplasm
Burkitt lymphoma
Diffuse large B lymphoma
Follicular lymphoma
Multiple myeloma
90% 10%

11. stem
cell
lymphoid
progenitor
progenitor-B
pre-B
plasma cell
Mature naïve B-cell
CD5
,CD23
IgM or IgD
CD34 &TDT
CD 19
CD20
Surface immunoglobin
CD38 ,CD138
IgG or IgA ,IgE
Germinal center
Mantle zone
GC blast Centroblas
t
Centrocyte
CD 5 CD10

12. CD5 ,CD23 ,IgM or IgD
CD34 &TDT
CD 19
CD20
Surface immunoglobin
CD38 ,CD138,
CD56
IgG or IgA or IgE
ALL
CLL t(11;14)
Cyklin D
Mantle lymphoma
CD 5 CD10
t(8;14)
C-myc
Burkitt lymphoma
t(3;14)
BCL-6
DLBCL
Follicular lymphoma
T(14;18)
BCL-2
Multiple myeloma

13. Chronic Lymphocytic Lymphoma
• Malignant conditions characterized by an increased number of
small, mature appearing lymphocytes in the blood (>5,000 ) and
bone marrow (± spleen and lymph node)
• The most common adult leukemia (~25% of adult leukemias)
• the median age is ~55 to 65 years. ( rare < 40 years).
• 1.5 to 2 times more common in men than women.

14. Features of CLL
40% of patients are asymptomatic at diagnosis

15. CLL Staging
Rai Staging Prognosis

16. For
reading

17. High-grade non-Hodgkin's B-cell lymphoma which is rapidly growing
and highly aggressive with extremely short doubling time (24 hrs)
Types of Burkitt's lymphoma
1-Endemic: associated with chronic malaria and EBV In equatorial
Africa . It particularly affects the jaw, other facial bone and breast.
Sporadic: occurs throughout the world and affects GIT.
Immunodeficiency-associated: associated with HIV infection or the
use of immunosuppressive drugs
Burkitt's lymphoma

18. Morphology
BMA Biobsy
Homogenous medium size cells with
round nuclei and deeply basophilic
and vacuolated cytoplasm
Diffuse infiltration with "starry sky”
(Macrophages engulfing the
apoptotic cells)

19. •There is a universal association between Burkitt’s lymphoma and
translocation of the c-MYC proto-oncogene at ch 8 to the
immunoglobulin gene at ch14 t(8;14)
• The c-MYC is nuclear transcription factor .
Burkitt’s lymphoma is the fastest growing tumor in humans.
Genetics of BL

20. After 25 D
of intensive
chemotherap
y
Clinical Presentation
Cure rate:
•90% at early phase
•70% at advance disease

21. • FL is malignant proliferation of germinal center B cells
centrocyte which has at least a partially follicular pattern.
• Due to overexpression o f Bcl2 caused by t(14;18) .
• Most common type of “indolent” lymphoma (25% ).
• Presented as Lymphadenopathy (100%), splenomegaly
(80%), BM involvement (60%) and blood involvement (40%).
• Indolent but incurable (some exceptions)
Follicular lymphoma

22. Immunophenotyping:
Positive for CD10,CD20 and Bcl2
Negative for CD5 ( in most cases)
CD10
BCL2
CD5
Diagnosis

23. •Median survival is around 10 years.
•Transformation to aggressive lymphoma (DLBCL) can occur.
Low grade FL FL in transformation
Aggressive
transformation (DLBCL)
Watch and weight
(most often)
Chemotherapy
Aggressive
Chemotherapy(± SCT)
Management

24. Malignant B neoplasm characterized by a triad of abnormalities:
• Accumulation of plasma cells in the bone marrow
•Lytic Bone lesions
• Production of a monoclonal immunoglobulin (Ig) or Ig fragments
Multiple Myeloma

25. For
reading
Pathogenesis of MM

26. Hodgkin lymphoma
Thomas Hodgkin
(1798-1866)

27. Classical Hodgkin Lymphoma
Indolent malignant lymphoma characterized by :
1- presence of few large binucleated cells (Reed-Sternberg ) surrounded by
reactive cells (lymphocytes, plasma cells ,eosinophils)
2- Involving cervical lymph nodes in young adults (most often )

28. germinal
centre
B cell
transforming
event(s)
loss of apoptosis
RS cell
inflammatory
response
EBV?
cytokin
es
A possible model of pathogenesis

29. CD 30 CD 15
Diagnosis of Hodgkin Lymphoma

30. Epidemiology
• Age: bimodal peak
age
–Third decade
–After 50
• Gender: male to

31. Etiology and
Risk Factors
• Unknown
• Possible etiologic
factor
–1) Familial factor
–2) Viruses - EBV

32. Signs and
Symptoms
• HD is a lymph node-based
malignancy
• Common = asymptomatic
lymphadenopathy
• Systemic symptoms
• Extranodal involvement

33. Location of
Lymphadenopathy
• 80% LN above the
diaphragm
–Anterior mediastinum
–Cervical,
supraclavicular,

34. Systemic
Symptoms
• 40% of patients ->
systemic symptoms
–B-symptom => Fever,
Night sweat, Weight loss
–Chronic pruritus

35. Extranodal
Involvement
• “E” lesion by direct
invasion
• Hematogenous
metastasis (Stage
IV): spleen, lungs,

36. Diagnosis
• Biopsy
• Pathology : “Reed -
Sternberg Cell”
–Diagnostic tumor cell
–Must be identified
–Large size, binucleated, large
eosinophilic nucleoli

37. Histology
• 1. Lymphocyte predominant (LP)
= few RS cells, good prognosis
• 2. Nodular sclerosis (NS) = the
most common, young adult,
female
• 3. Mixed cellularity (MC) =
generalized lymphadenopathy
• 4. Lymphocyte depletion (LD) =
numerous RS cells, poor

38. Staging : The Coltswolds
Classification for HD
• I: A single LN region or a lymphoid
structure (eg., spleen, thymus,
Waldeyer’s ring)
• II: Two or more LN regions on the
same side of the diaphragm
• III: LN regions or structures on both
sides of the diaphragm
–1: with/without involement of splenic, hilar,
celiac, or portal nodes

39. Designations applicable to
any disease stage
• A: No symptoms
• B: Fever, drenching sweats,
weight loss
• X: Bulky disease
–> 1/3 the width of the mediastinum
–> 10 cm maximal dimension of
nodal mass
• E: Involvement of a single

40. Prognostic
Factors
• Stage of disease: the most
important prognostic factor
• Number of sites of involvement
• Bulky disease ( particularly in
the mediastinum)
• B symptoms
• Age

41. Investigations
• 1. Imaging : CT scan of the chest/
abdomen
• 2. Lab tests: CBC, ESR, LDH
• 3. Bone marrow biopsy: B-symptoms
• 4. Staging laparotomy : consist of
–Splenectomy
–LN sampling:
celiac/splenic/hilar/paraaortic/paracaval/ili
ac nodes
–Wedge/needle biopsy of the liver
–open iliac crest Bone Marrow Biopsy

42. Treatment
• Stage I-II =
Radiotherapy
• Stage III-IV =
Chemotherapy

43. Radiotherapy
• Subtotal lymphoid irradiation =
Mantle + Paraaortic field
• Mantle field = base of mandible to
diaphragm
–Cover LN above diaphragm ->
submandibular, cervical,
supraclavicular, infraclavicular,
axillary, mediastinum, hilar

44. Side Effects of
Radiotherapy
• Acute
–N/V, Dermatitis, Fatigue
• Delay
–Pneumonitis
–Herpes zoster infection
–Subclinical hypothyroidism
–Infertility
–Secondary malignancies
• secondary solid tumors ( lung, breast)
• chemotherapy -> most common =
leukemia

45. Non-Hodgkin’s
Lymphoma
Heterogeneous group
of lymphoproliferative
malignancies

46. Epidemiology
• The incidence has
been increasing
worldwide.
• This increase is more
marked for older

47. Etiology and
Causative Factors
• The origin is UNCERTAIN.
• Causative factors with a
predisposition
–Immunosuppression
–Infectious agents (EBV,
HTLV-1, Herpes type 8,
H.pylori)

48. NHL
• Usually originates in
lymphoid tissues
• Can spread to other
organs
• Prognosis depends on the
histologic type, stage and

49. Clinical
Manifestations
• Asymptomatic LN enlargement (most
common presentation)
• 1) Location of lymphadenopathy
–most common = neck, inguinal, and
abdominal LNs
• 2) Systemic symptoms
–fever, weight loss, night sweats (
usually heralding more advanced
disease)

50. Staging Evaluation
• Pathologic diagnosed by an
experienced hematopathologist.
• Staging Evaluation includes:
–History + Physical Exam
–Lab : CBC, LDH
–Bone marrow biopsy
–Chest X-Ray
–CT abdomen and pelvis/chest
–Gallium scan

51. Histology: 2
prognostic groups
•Indolent lymphoma
•Aggressive
lymphoma

52. Staging: Ann Arbor System
(commonly used)
• I: A single nodal region (I) or single
extralymphatic site (IE)
• II: 2 or more nodal regions on the
same side of diaphragm(II) or a single
localized extralymphatic site and its
regional nodes on the same side of
diaphragm (IIE)
• III: Nodal regions on both sides of the
diaphragm

53. Designations
applicable to any stage
• A: No symptoms
• B: Weight loss, unexplained
fever, night sweats
• E: Localized involvement of
extralymphatic tissue
• S: Spleen involvement

54. Treatment
• Indolent Lymphoma
–Stage I + II = RT
–Stage III + IV = Chemotherapy +
RT
• Aggressive Lymphoma
–Stage I + II = combined modality (
Chemotherapy + RT)
–Stage III + IV = Chemotherapy (

55. Radiotherapy
• Involve-field RT:
–Involved region + first-echelon
adjacent LN region
• Extended field RT:
–involve field + second-echelon
adjacent LN region

56. Example

57. Radiation Dose:
• Indolent: 2,500 - 3,500
cGy
• Aggressive: 3,500 -
4,500 cGy

58. Late effects of
treatment
• Normal tissue
toxicity
• Secondary cancers

59. A practical way to think of lymphoma
Category Survival of
untreated
patients
Curability To treat or
not to treat
Non-Hodgkin
lymphoma
Indolent Years Generally
not curable
Generally
defer Rx if
asymptomatic
Aggressive Months Curable in
some
Treat
Very
aggressive
Weeks Curable in
some
Treat
Hodgkin
lymphoma
All types Variable –
months to
years
Curable in
most
Treat