19 October 2011 (Wednesday) - Lymphoproliferation

A colleague has prepared a case study for staff to use for CPD purposes. I was dead keen to try this out for myself….
Haemoglobin                14.9  g/dl   (11 to 15)
White Blood Cells          14.3  10^9/l (4 to 11)
Platelets                  124   10^9/l (150 to 400
Red Blood Cells            5.06  10^12/l(3.8 to 4.8)
Haematocrit                0.449 ratio  (0.36 to 0.46)
Mean Cell Volume           88.7  fl     (80 to 100)
Mean Cell Haemoglobin      29.4  pg     (27 to 32)
Mean Cell Haemoglobin Con  33.2  g/dl   (32 to 36)
Neutrophils                2.6   10^9/l (2 to 7.5)
Lymphocytes                11.2  10^9/l (1.5 to 4)
Monocytes                  0.4   10^9/l (0.2 to 1)
Eosinophils                0.0   10^9/l (0.02 to 0.5)
Basophils                  0.0   10^9/l (0 to 0.1)
 ESR                        1     mm/h   (1 to 20)
Referred to consultant haematologist:

Lymphocytosis with mature lymphoid cells with clumped chromatin. smear cells seen.  c/w  Lymphoproliferative disorder, most probably CLL.

Question 1: Discuss what is meant by Lymphoproliferative Disorder?

Lymphoproliferative disorders (LPDs) refer to several conditions in which lymphocytes are produced in excessive quantities. They are sometimes equated with "immunoproliferative disorders", because of the natural function of lymphocytes, but this classification is arguable.
Examples include;
  • follicular lymphoma
  • chronic lymphocytic leukemia
  • acute lymphoblastic leukemia
  • hairy cell leukemia
  • lymphomas
  • multiple myeloma
  • Waldenstrom's_macroglobulinemia
  • Autoimmune lymphoproliferative syndrome
Question 2: Illustrate the Immunophenotyping Markers to differentiate between the different Lymphoproliferative disorders.

Disorder/cell type

B-cell malignancies/Pan-B-cell antigens
CD19, CD20, CD22, CD79b, Igm, Igd, Igk, Igl
Precursor B-cells
CD1d, CD10, CD34, CD45, CD58, TdT, NG2,
Chronic lymphocytic leukaemia
CD5, CD23, CD38, CD52{, ZAP70
Hairy cell leukaemia
CD11c, CD25, CD103
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
CD5, CD10
Burkitt’s lymphoma
CD10, TdT

T-cell malignancies/Pan-T-cell antigens
CD2, CD3, CD4, CD5, CD7, CD8, ab TCR, cd TCR
Precursor T cells
CD1a, TdT, Myeloid markers
T-prolymphocytic leukaemia
CD26, CD52
T-large granular lymphocyte leukaemia
CD16, CD56, CD57
Se´zary syndrome/Mycosis fungoides
Adult T-cell leukaemia/lymphoma

Natural killer cell antigens (and natural
killer cell malignancies)
CD2, CD7, CD8, CD16, CD56, CD57

Question 3: Discuss the CLL score.

The CLL score is as described in:

CLL immunophenotype scoring system (Delgado, et al 2003)
Score points
1 0
CD22 or CD79b
Weak Strong
Positive Negative
Positive Negative
Negative Positive
Weak Strong
Score = or > 4 in 92% of cases of CLL
If <= 3 then exclude mantle cell lymphoma by one or both of:
(i) Immunostaining of bone marrow trephine sections or lymph node for nuclear cyclin D1
(ii) FISH for t(11:14) using blood, BM or lymph node.
Other lymphoproliferative disorders such as marginal zone, follicular and lymphoplasmacytic lymphomas can usually be distinguished by their immunophenotype. In problematic cases, lymph node or other tissue biopsy may be appropriate if the distinction is clinically important.

A score of four or above is obtained in over 90% of cases of CLL. A lower score should be treated with suspicion, but the diagnosis of CLL cannot be ruled out.
However CD5 positivity is present in most (90%+) cases. If this is absent, then alternative diagnoses should be considered.
CLL scoring should not be confused with clinical staging:

Median survival
Lymphocytosis (>15,000/mm3)
150 months
(12.5 years)
Lymphocytosis plus nodal involvement
node groups
101-108 months
(8.5-9 years)
Lymphocytosis plus organomegaly
node groups
60-71 months
(5-6 years)
Anemia (RBCs)
Hgb <11 g/dL

Hgb <10 g/dL         
19-24 months
(1.5-2 years)
Lymphocytosis plus thrombocytopenia
PLT <100
 PLT <100,000/mm3

Question 4: Discuss the prognosis of patient of being diagnosed with CLL with reference to Lymphocyte doubling time

Lymphocyte Doubling Time is defined as the period of time needed for lymphocytes to double in number the amount found at diagnosis.
http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19871201)60:11%3C2712::AID-CNCR2820601122%3E3.0.CO;2-1/pdf  quotes that it appears to predict the progression of the disease. Specifically it (and other sources) feel that a doubling in less than a year is of worse prognosis than that of more than a year.

However it doesn’t take long to find doubt cast on the validity of these findings. After all, active therapy will reduce the lymphocyte mass, and consequently prolong the lymphocyte doubling time.

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