good lecture

1. Lymphoma
By.Hayelom.k

2. Normal lymph node architecture
Cortex
Medulla
Plasma cells
Paracortex
T-cells
Lymphoid
Follicle
B-cells
Lymphocyte constantly recirculate

3. Lymphoid follicle (B-Cell region)
Germinal center
Centroblasts, centrocytes
Mantle and marginal
zones

4. Small centrocyte-arrowhead, large centrocyte-arrow, centroblast - thick arrow
Mitosis – curved arrow
Germinal center cells

5. LYMPHADENOPATHY
BENIGN
NEOPLASTIC
PRIMARY:
LYMPHOMA
SECONDARY:
METASTASIS
Summary of lymph node pathology

6. Clinical manifestations of lymph node
diseases
-Enlarged
-Tender/non tender
-Systemic symptoms

7. LYMPHADENOPATHY
BENIGN
NEOPLASTIC
PRIMARY:
LYMPHOMA
SECONDARY:
METASTASIS
Summary of lymph node pathology

8. reactive changes in the nodes

9. Follicular hyperplasia
Rheumatoid arthritis, Toxoplasmosis

10. Follicular hyperplasia
tingible body macrophages
Resting
lymphocytes in
the mantle
zone

11. Interfollicular/paracortical hyperplasia
T-cell response, acute viral infections(mononucleosis)

12. Sinus histiocytosis
Dilated sinusoids, increased number and size of cells lining the sinusoids

13. Toxoplasmosis pink, epitheloid macrophages, follicular hyperplasia
Mixed type lymphadenopathy

14. Necrotizing lymphadenitis
Microabscesses Bartonella Henselae
(silver stain) cats scratch

15. Granulomatous lymphadenitis

16. Lymphadenopathy
LYMPHADENOPATHY
BENIGN
NEOPLASTIC
PRIMARY:
LYMPHOMA
SECONDARY:
METASTASIS

17. Metastatic adenocarcinoma

18. Lymphadenopathy (cont)
LYMPHADENOPATHY
BENIGN
NEOPLASTIC
PRIMARY:
LYMPHOMA
SECONDARY:
METASTASIS

19. ·Willis (1948)
“… nowhere in pathology has a chaos of
names so clouded clear concepts as in
the subject of lymphoid tumors ….”
•Hopwood (1957)
“… the urge to classify is a fundamental
human instinct: like a predisposition to
sin, it accompanies us into the world at
birth and stays with us to the end …”

20. Lymphoma classification
Rappaport
1966
Lukes Collins
1974
Working formula
1982
Kiel
1988
REAL
1994
WHO
2001
2008
Is this the REAL
thing…..?
WHO ……knows!

21. WHO Classification of lymphomas
At least 30 types of lymphoma are recognized
3 broad flavors
- B-cell lymphomas
Precursor (immature),
peripheral (“mature”)
- T-cell lymphomas
- Hodgkin lymphoma ( bona fide lymphoma)
~ 85% in North America and Europe are B-cell
· two types account for > 50% of lymphomas
- diffuse large B-cell lymphoma (~ 30 - 40%)
- follicular lymphomas (~ 25 - 30%)
·

22. Etiology of lymphomas
Translocations involving the IgH are
requent

23. Etiology of lymphomas
Inherited genetic factors-genomic instability:
-Down syndrome, NF type I
Autoimmune disorders: Sjogren, Hashimoto
Viruses: EBV, HTLV1 and herpes virus
Environmental agents:
-Chronic inflammation, Helicobacter Pylori and MALT
lymphoma
-Gluten sensitive enteropathy and intestinal lymphoma
Iatrogenic:
-Radiotherapy
-Chemotherapy

24. Diagnosing lymphomas

25. Diagnosing lymphoid neoplasias
HOW ?
WHY ?
Flow cytometry
Immunohistochemistry
Karyotyping
Diagnosis
Monitoring
Prognosis

27. Diagnosing lymphomas
CD 20 antibody staining B lymphocytes

28. Diagnosing lymphoid neoplasias
• T-cell markers
– CD3 mature T cells
– CD4 – helper T cell
– CD5 – T cell, small
subset of B cells
– CD8 – cytotoxic T cell
• B cell markers
– CD19 - mature B cell
– CD20 - mature B cell
– CD23 - activated
mature B cell
– CD10
– Bcl-6

29. Lymphoid leukemia versus lymphoma
Somewhat arbitrary, distinctions for
lymphoid neoplasias
Lymphoid leukemia presents with mainly
bone marrow and blood involvement
Lymphoma presents with nodal or
extranodal mass with minimal
blood/marrow involvement
Many diseases overlap or evolve from one
another

30. Signs and symptoms
Lymphoid leukemias present with signs and
symptoms related to bone marrow
involvement
Anemia, thrombocytopenia, leukopenia
Lymphomas present as nontender mass (>2
cm)
Extranodal- skin, GI tract, brain,
Fever, weight loss, night sweats (B-symptoms)
Patients may have any combination of the
above

31. Origin of B-cell lymphomas
Marginal zone
Mantle zone
Germinal center
Naive B-cell
Mantle cell
lymphoma
Follicular lymphoma
Burkitt lymphoma
Large cell lymphoma
Memory B-cell
CLL/SLL
Marginal zone
lymphoma
Plasma cell
Myeloma

32. Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma
CLINICAL
•commonest leukemia
•CLL often picked up on routine CBC
•typically indolent (but not always!)
•rare less than 40 years
•complications:
• autoimmune (10-15%) (ITP, AIHA)
• hypogammaglobulinemia
• transformation (DLBCL)
PATHOLOGY
•diffuse growth pattern
Spleen is frequently involved

33. proliferation center-mitotically active cells=this is
where the tumor cells grow
Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma

34. MORPHOLOGY
- small, mature lymphocytes >4000/mm3
- smudge cells characteristic
IMMUNOPHENOTYPE
CD19, CD20, CD23, CD5
GENETICS
13q deletion (good prognosis)
trisomy of 12
11q deletion (bad prognosis)
Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma

35. Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma
Nucleated erythrocyte Spherocytes Smudge cells Small lymphocytes

36. 3.Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma
TRANSFORMATION
1. LARGE CELL LYMPHOMA
(Richter)
- 10%
2.Prolymphocytic lymphoma
-15-30%
average survival 1 year

37. FOLLICULAR LYMPHOMA
15-20 000/year, less common in Europe, Asia
-Middle age patient’s
-Most common indolent lymphoma
-Peripheral blood 10%
-Bone marrow 85% involved
-Spleen and liver also commonly involved
-Can undergo transformation into large cell lymphoma

38. Follicular lymphoma
Classic low power view
- back-to-back follicles
- loss of interfollicular
zones
- extranodal follicles
- uniform size of follicles

39. Follicular lymphoma
Back to back, uniform follicles, attenuated mantle
zone, no tingible body macrophages

40. Follicular lymphoma
diagnostic hallmark t(14;18)
Translocates the bcl-2 gene
next to IgH
over expression of bcl-2 prevents
apoptosis
Bcl-2 +
Bcl-2 – staining in normal
Lymphoid follicle

41. APOTOSIS (Hippocratic Greek) APOPTOSIS (modern Greek)

42. Follicular lymphoma
centrocyte:
-cleaved/notched/twisted
-raisin
-buttock
50% transforms into large cell
lymphoma

43. Follicular lymphoma
Centroblasts- important in grading

44. Splenic involvement in follicular lymphoma

45. Origin of B-cell lymphomas
Marginal zone
Mantle zone
Germinal center
Naive B-cell
Mantle cell
lymphoma
Follicular lymphoma
Burkitt lymphoma
Large cell lymphoma
Memory B-cell
CLL/SLL
Marginal zone
lymphoma
Plasma cell
Myeloma
CB/CC

46. Diffuse Large B-cell Lymphoma
Most common non Hodgkin lymphoma(~40%)
- 25, 000 new cases/year
- median age 6th decade - all age
groups
- typically present with a single rapidly
enlarging mass
- often (~ 40%) extranodal
Variable clinical outcome
aggressive, has to be treated immediately

47. Diffuse Large B-cell lymphoma
Etiology and clinicopathologic subtypes
- de novo
-BCL-6 mutation freezes the differentiation of cells in the
germinal center + blocks the effect of p53
-can occur anywhere in the body
- transformed from either follicular lymphoma (t14;18) or CLL/SLL
- immunosuppressed patients
- transplant patients, AIDS patients
- KSHV, EBV, HHV-8 infection

48. Diffuse Large B-cell Lymphoma
Note the population of large tumor cells, diffuse growth pattern, variation in size
and shape of cells, cells with vesicular nucleus and cleaved cells

49. Origin of B-cell lymphomas
Marginal zone
Mantle zone
Germinal center
Naive B-cell
Mantle cell
lymphoma
Follicular lymphoma
Burkitt lymphoma
Large cell lymphoma
Memory B-cell
CLL/SLL
Marginal zone
lymphoma
Plasma cell
Myeloma
CB/CC

50. Burkitt’s lymphoma
Extremely aggressive, high grade lymphoma
T(8;14) activates c-myc oncogene
Clinical-genetic classification
- endemic
- sporadic
- immunodeficiency-associated

51. Extremely aggressive high grade lymphoma
T(8-14) activates c-myc oncogene
Endemic Non-endemic Immunodeficiency
children and young adults
Site Jaw/Facial Ileocecal area Systemic/non-CNS
EBV ~ 100% ~ 15-20% ~ 25%
BM not involved can be can be
Cure rate high high ?
Burkitt lymphoma

52. t(8;14) which activates c-myc oncogene

53. Burkitt lymphoma endemic variant

54. Burkitt lymphoma
small round cells in a “starry sky” pattern created by macrophages
engulfing cellular debris, mitoses

55. Clinically:
- typically presents in elderly males
- frequently extranodal:
- leukemic phase
- GI: lymphomatous polyposis
- much more aggressive than other
- poor response to conventional
chemotherapy
- median survival 3 - 4 years
Mantle cell lymphoma

56. •classic cytogenetics [~ 90%]:
t(11;14)(q13;q32)
upregulates cyclinD1
expression, dysregulates
cell cycle
immunohistochemically:
intranuclear cyclin D1
Origin: CD5 positive, naïve cells of
the mantle zone
CD19+, CD20+, CD23 -
Mantel cell lymphoma

57. Origin of B-cell lymphomas
Marginal zone
Mantle zone
Germinal center
Naive B-cell
Mantle cell
Lymphoma
CLL/SLL
Follicular lymphoma
Burkitt lymphoma
Large cell lymphoma
Memory B-cell
CLL/SLL
Marginal zone
lymphoma
4.Plasma cell
Myeloma
CC/CB

58. Extra-nodal marginal zone lymphoma,
MALToma
• Pathogenesis:
– Autoimmune disorders: thyroid(Hashimoto), salivary glands
(Sjogren)
– Chronic infection: stomach, lung, skin, conjunctiva
– Begins as a polycloncal reactive process, over time becomes a
monoclonal B cell lymphoma
– In stomach, highly associated with helicobacter pylori
• monocytoid B cells, plasma cells, germinal centers,
lymphoepithelial lesions
• Survival: indolent in early stages
• Cell of origin: marginal zone B cell

59. MALTOMA
Gastric MALToma

60. Origin of B-cell lymphomas
Marginal zone
Mantle zone
Germinal center
Naive B-cell
Mantle cell
lymphoma
Follicular lymphoma
Burkitt lymphoma
Large cell lymphoma
Memory B-cell
CLL/SLL
Marginal zone
lymphoma
4.Plasma cell
Myeloma
CC/CB

61. typically presents as:
- male in 6th decade
- splenomegaly
- no lymphadenopathy
- CBC:
- pancytopenia
- marked monocytopenia
•splenic disease:
- red pulp (unique )
Hairy cell leukemia

62. Hodgkin lymphoma
Incidence
- ~ 1% of all new cancers in USA
- ~ 7,500 new cases/year
- constant recent increase
Age
- bimodal age-curve (unique in
cancer)
- 15 - 35
- > 50
Sex
- M:F = ~ 4:3 (except nodular
sclerosis)

63. Hodgkin Lymphoma
• Painless lymphadenopathy
- cervical ~ 70%
- axillary ~ 15%
- inguinal ~ 10%
• Constitutional symptoms
- fever
- night sweats
- weight loss
• Infections: fungal, TB

64. unique amongst
cancers: rarity of
the neoplastic
cell in involved
tissue
DIAGNOSTIC
REED-STERNBERG
CELL or variants
Pleomorphic cellular
infiltrate:
- lymphocytes
- macrophages
- plasma cells
- eosinophils
- fibroblasts
- neutrophils
• predominate
• vary according to
classification
• reactive
Hodgkin lymphoma

65. LYMPHOCYTE
PREDOMINANT
nodular sclerosis
mixed cellularity
lymphocyte
depletion
lymphocyte rich
95% 5%
Hodgkin lymphoma

66. Hodgkin lymphoma
Classic Reed-Sternberg cell

67. Hodgkin lymphoma
A B
C D
A. Classic B. Mononuclear variant C. Lacunar variant D. Lympho-histiocytic variant

68. Hodgkin Lymphoma
CD15 and CD30 antibodies are used to stain
Reed Sternberg cells

69. Nodular sclerosing
Clinical:
-adolescent and young adult,
-females > males
-usually lower cervical,
supraclavicular, or mediastinal
LN
Histology:
- occasional R-S cells,
Lacunar cells, inflammatory
cells, bands of sclerosis
Survival: Excellent

70. Hodgkin lymphoma, nodular sclerosing

71. NS MC LD LR
Frequency ~70% ~20% <1% ~5%
Usual age 15-30 any/middle >50 any
middle
Clinically females abdominal advanced early
mediastinal splenic marrow stage
5yr survival ~80% ~60% ~30% ~90%
Hodgkin lymphoma features

72. Staging of HL
• I: Single LN region or extra-nodal site
• II: 2 or more LN regions on same side of diaphragm
• III: LN on both sides of diaphragm, may include spleen
• IV: Multiple or disseminated foci
• Further divided into absence (A) or presence (B) of fever,
night sweats, unexplained weight loss of >10% body
weight

73. •clinically:
- adults
- Mycosis fungoides
patch, plaque, tumor
- Sezary Syndrome
- erythroderma
- generalized adenopathy
- circulating tumor cells
- MF: indolent but progressive
- SS: unfavorable (10-20%/5
year survival)
•pathologically:
- classic epidermotropism
- papillary dermal fibrosis
- cerebriform nuclei
•immunophenotype: CD4
T-cell lymphomas

74. Mycosis fungoides
Plaque phase tumor phase

75. Sezary syndrome
Generalized exfoliative erythroderma

76. Reference
Robbins 10th edition
Ackerman histopathology text book 11th edition
Deciy text book of hematology