CLL is one of the most common blood cancer in adults. Most of the patients are asymptomatic.

1. Slide Presentation
HEMATOLOGY
Sansar Babu Tiwari, MBBS, PGY I
Department of Pathology
TUTH
3rd June 2020
1

2. Single Wright-stained Peripheral Blood Smear
50 year old male
WBC: 3,83,570
Hb: 7.4 g/dl
Plt: 1,86,000
SLIDE PRESENTATION
2

3. Single Wright-stained Peripheral Blood Smear
WBC MORPHOLOGY:
1. Neutrophils (5%)
Segmented nucleus with pink granules in cytoplasm
2. Lymphocytes(92%)
Deep purple nucleus almost covering cell and sky blue cytoplasm
3. Monocytes(2%)
Indented dark purple nucleus with blue-grey cytoplasm
SLIDE PRESENTATION
3

4. WBC MORPHOLOGY:
4. Eosinophils (1%)
Segmented nucleus with orange granules in cytoplasm
SLIDE PRESENTATION
4

5. RBC MORPHOLOGY:
Normochromic Normocytic
Parasites not seen
PLATELET MORPHOLOGY:
Adequate and normal in morphology
SLIDE PRESENTATION
5

6. Olympus, X40
6

7. Olympus, X100
7

8. Olympus, X200
8

9. Olympus, X400
9

10. Olympus, 1000x
10

11. Olympus, 1000x
11

12. Olympus, 1000x
12

13. Chronic lymphoproliferative
Disorder (CLPD)
-CLL
PROVISIONAL DIAGNOSIS
13

14. Case
A 50-year-old man
Fatigue and 5-kg weight loss over the past 6 months
PE shows hepatosplenomegaly and diffuse, nontender lymphadenopathy.
Hemoglobin concentration of 7.4 g/dL
Leukocyte count of 3,83,570/mm3
Platelet count 1,86,000
PBS awaited
A direct antiglobulin (Coombs) test is positive.
14

15. 15
Case

16. Case
PBS report:
There are plenty of small looking lymphocytes along
with increased number of smudge cells. So, in view of
consideration of CLL/SLL, further flowcytometry can
confirm the condition and cytogenetic analysis is
suggested if there is progressive enlargement of the
lymph node and hepatosplenomegaly.
16

17. • Flow cytometry showed CD5, CD19, CD20,
CD23 positive cells.
• Cytogenetics showed del(17p13).
• Rai Staging classified this patient into Stage III.
• Binet Classification Stage C.
17
Case

18. • Bone marrow biopsy done
• Patient started on Fludarabine,
cyclophosphamide and rituximab (FRC)
• Did not improve on medications
• Considered for bone marrow transplantation.
18
Case

19. 19
Case

20. Case
20

21. 21
Case

22. Chronic lymphocytic leukemia
• Epidemiology:
– Most common leukemia in adults
– Median age: 70 years but can be seen even in 30-
39 age group
– Male:Female = 1.3:1 to 1.7:1
– Caucasians > African americans > Asians
– No effect with migration. Japanese who settled in
Hawai donot have higher incidence in comparison
to their native counterparts.
22

23. Chronic lymphocytic leukemia
• Epidemiology:
– Unlike other cancers, even atom bomb survivors
donot have increased risk of CLL
– Environmental exposure to benzene, rubber are at
increased risk
– Even multiple episodes of pneumonia is
associated with development of CLL later.
23

24. Chronic lymphocytic leukemia
• Clinical features:
– Mostly incidental on PBS
– Sometimes patient presents with painless cervical
lymphadenopathy that waxes and wanes but not
disappear completely
– Rarely 5-10 % presents with typical B symptoms of
lymphoma
• Unintentional weight loss ≥10% in the last 6 months
• Fever >100.5 f for ≥ 2 weeks without evidence of infection
• Drenching night sweats
• Extreme fatigue
24

25. Chronic lymphocytic leukemia
• Clinical features:
– Occasionally, recurrent infections like pneumonia,
autoimmune complications like hemolytic anemia,
thrombocytopenia or pure red cell aplasia, or
exaggerated reactions to mosquito bites.
25

26. Chronic lymphocytic leukemia
• Clinical features:
– Lymphadenopathy: 50-90%
• Cervical, supraclavicular or axillary
• Firm, rounded, discrete, non-tender, and freely mobile upon
palpation.
• Unsual lymph nodes when there is rapid enlargement
– Splenomegaly: 25-55%
• Painless and nontender
– Hepatomegaly: 15-25%
• Mildly enlarged and non-tender
– Skin: Leukemia cutis in face
– Rarely Waldeyers ring, GI mucosa and even meningeal
leukemia is reported.
– MPGN, MCD and amyloidosis.
26

27. Chronic lymphocytic leukemia
• Laboratory findings:
– Lymphocytosis:
• Threshold: >5000/microL absolute blood lymphocytes
• If the count is increased above 2,50,000 it is time to maintain
hydration and stop diuretics to prevent from hyperviscosity
syndromes like CVA and MI.
• In patients with CLL, lymphocyte count may be normal or only mildly
elevated. They have ALC <5000/microL at the time of diagnosis.
– Neutropenia, anemia and thrombocytopenia
• Due to AIHA, Pure red cell aplasia, ITP, rarely agranulocytosis
– Hypogammaglobinemia: G, A, M. Risk of infection.
In a study of 109 patients whose free light chain ratio, M-protein
and hypogammaglobinemia were collected prediagnostically, their
prevalences were found to be 38, 13 and 3 respectively. In 40% of
these patients these abnormal value were detected 10 years
before the actual onset of disease.
27

28. Chronic lymphocytic leukemia
• PBS
– Lymphocytosis:
• The majority of thee leukemic cells are typically small,
mature-appearing lymphocytes with a darkly stained
nucleus, partially condensed chromatin and indiscernible
nucleoli. There is a narrow rim of slightly basophilic
cytoplasm.
• A proportion of cells may be comprised of intermediate-
sized lymphocytes with large oval or notched nuclei, lacy-
appearing nuclear chromatin, and prominent, single,
centrally placed nucleoli. These are prolymphocytes.
• Smudge cells or basket cells are mechanically disrupted cells
due to their increased fragility.
• When complicated by AIHA, spherocytes may also be
prominent.
28

29. 29

30. 30

31. 31

32. Chronic lymphocytic leukemia
• Immunophenotypic findings:
– Basically three characteristic findings:
• Expression of the B cell-associated antigens CD19, CD20
and CD23. The staining intensity of CD20 is usually
low/dim.
• Expression of CD5, an antigen expressed on T cells and
subsets of mature B cells.
• Low levels of surface membrane immunoglobulins (i.e
SmIg weak). IgM or IgD or both, single light chain only
These cells express HLA-DR and are negative for CD10
and cyclin D1.
32

33. 33

34. 34

35. Chronic lymphocytic leukemia
• Bone marrow findings:
– Generally not required for the
diagnosis. Usually when done,
>30% lymphocytes
– Previously helpful for
prognostic value with pattern
study in trephine biopsy.
• Three patterns: Non-
diffuse(Nodular and interstitial)
and diffuse. Advanced disease
have diffuse pattern
• Sometimes overlap between
nodular and other two patterns
is seen.
35

36. 36
Pseudofollicle

37. Chronic lymphocytic leukemia
• Lymph node and Spleen:
– Diffuse effacement of nodal architecture with
scattered residual naked germinal centers.
– Large lymphoid cells (prolymphocytes and
paraimmunoblasts) with more prominent nucleoli
are always present.
– These large lymphoid cells are usually clustered in
pseudofollicles (proliferation centers), a finding
pathognomonic of CLL/SLL.
– Spleen shows infiltration of both red and white
pulp with predominance of white pulp
involvement.
37

38. 38

39. Chronic lymphocytic leukemia
• Diagnosis:
– International workshop on CLL 2018 suggests CLL
can be diagnosed when both of the following
criteria are met.
• Absolute B lymphocyte count in the PBS ≥5000/microL
sustained for at least 3 months with preponderant
population of morphologically mature-appearing
lymphocytes
• Clonality of the circulating B lymphocytes should be
confirmed by flow cytometry of the peripheral blood
demonstrating Ig light chain, light chain clonality,
expression of B cell antigen and T cell antigen.
39

40. Chronic lymphocytic leukemia
• Diagnosis:
– International workshop on CLL 2018 suggests CLL
can be diagnosed when both of the following
criteria are met.
• Classification in case of ALC<5000/microL depends on
number and type of the following disease
manifestations.
– Patients with none of these disease manifestations are
diagnosed with monoclonal B cell lymphocytosis
– Patients with one or more cytopenias due to bone marrow
infiltration with typical CLL cells are diagnosed with CLL
regardless of the ALC or the presence of lymphadenopathy
– Patient with nodal, splenic or other extramedullary
involvement, without cytopenias due to bone marrow
infiltration are diagnosed with SLL.
40

41. Chronic lymphocytic leukemia
• Staging and Diagnosis:
– Rai System:
– Binet System:
41

42. 42

43. Chronic lymphocytic leukemia
• Prognostic factors:
– Lymphocyte doubling time: Measured in months
• The shorter the LDT the more progressive the course.
• The longer the LDT the more indolent is the course.
• Short LDT warrants aggressive therapy.
– Genetic abnormalities:
• Del11q
• Trisomy 12
• Del13q
• Del17p
43
Favourable prognosis

44. Chronic lymphocytic leukemia
• Prognostic factors:
– B2M
• Increasing level
associated with
poorer prognosis.
• It may be
increased with
renal dysfunction.
• Regulated by IL-6,
which is released
from vascular
endothelium.
– ZAP-70
• Usually not
expressed by B
cells, but increase
in CLL associated
with poorer
prognosis.
44

45. Chronic lymphocytic leukemia
• Histological transformation:
– Two to five fold increased risk of second lymphoid
malignancy.
– 60% related to original B-CLL cell
– 40% separate cell of origin
• Aggressive or highly aggressive lymphoma (Richter’s
trabsformation) - 3 to 7%
• Prolymphocytic leukemia (PLL) - 2%
– Vs Prolymphocytoid transformation
• Hodgkin Lymphoma - 0.5 to 2%
• Multiple myeloma- 0.1%
45

46. 46

47. Chronic lymphocytic leukemia
• Histological transformation:
– AML
• When AML occurs in a patient with CLL, it is most likely
tobe therapy-related myeloid neoplasm
Or
• De novo AML
But not
• Likely to be developed from CLL clone.
47

48. Chronic lymphocytic leukemia
• Treatment:
– Not all patients with CLL require treatment at the
time of diagnosis.
• It is a heterogenous disease with certain subsets having
survival rates similar to that of normal population
• CLL cannot be treated completely by the current
options unless HCT is done.
• RCT between immediate vs delayed treatment dint
show significant difference in the overall survival.
• Rarely spontaneous regression is observed.
48

49. Chronic lymphocytic leukemia
• Treatment:
– Patients with active disease
49

50. Chronic lymphocytic leukemia
• Treatment:
– Patients with active disease
• Median survival 1.5 to 3 years without treatment
• With therapy increased upto 5 to 15 years
• No single frontline treatment
• Should be customized taking into account the clinical
features and the adverse effects of the therapy
50

51. 51

52. Chronic lymphocytic leukemia
• Treatment:
– Patients without active disease: Median survival
greater than 10 years
• Rai 0,1 and 2
• Binet A or B
– Localized SLL
– Observation:
• Blood count and clinical exam at 3 month interval
• If patient develop active disease: Treat
52

53. Chronic lymphocytic leukemia
• Response criteria:
– Usually every patient relapse at some point in
their treatment, even of they show complete or
partial response initially.
– Asymptomatic relapse does not require
treatment.
53

54. 54

55. • Thankyou!!!
55