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ICCS e-Newsletter
CSI Spring 2013
David A Westerman, MBBS FRACP FRCPA
Department of Pathology
Peter MacCallum Cancer Centre
Melbourne, Australia
e-CSI - Clinical History:
• A 52 year Caucasian man presents with
pancytopenia for investigation, and a
previous history of “T cell lymphoma”.
e-CSI - Peripheral Blood:
• CBC
–
–
–
–
–
–
–
–
–
WBC:
RBC:
Hgb:
Hct:
MCV:
MCH:
MCHC:
RDW:
Plts:
Normal Range
0.5 x 109/l
2.86 x 1012/l
9.0 g/dl
27.0 %
95.0 fl
32.0 pg
32.9 g/dl
17.2%
25 x 109/l
(4.0 – 11.0)
(4.5 – 6.5)
(13.0 – 18.0)
(40.0 – 54.0)
(80.0 – 96.0)
(27.0 – 32.0)
(31.0 – 35.0)
(11.7 – 15.7)
(150 – 400)
e-CSI - Peripheral Blood:
• CBC Differential
– Granulocytes:
– Lymphocytes:
– Monocytes:
– Eosinophils:
75%
9%
11%
2%
e-CSI - Clinical History:
• Bone marrow aspirate and trephine biopsy
were performed.
• Flow cytometric immunophenotyping was
performed on the bone marrow aspirate and
the results from selected 8-color tubes are
provided for review.
e-CSI - Flow Cytometric Studies:
• Acquired FACS Canto II, analyzed with Kaluza
e-CSI - Flow Cytometric Studies:
Initial gating strategies
excluded doublets and
debris
Further gating to
include WBC’s and then
a more “targeted”
gated population based
on an unusual CD45 vs
SSC plot, in this case –
“mononuclear gate”
e-CSI - Flow Cytometric Studies:
56% of mononuclear cells gated are
CD2+, while T cells account for only
4%
An expanded monocytic
population is also identified
with weak (but normal) CD4
expression (green)
e-CSI - Flow Cytometric Studies:
CD2 vs CD3 allows
separation of the NK
cell population
(black) and
monocytes (green) in
this case.
Normal CD4+ and 8+
T cells can also be
seen (mustard colour
and blue)
e-CSI - Flow Cytometric Studies:
CD2+ and 16/56+ NK cells (black), monocytes in green,
residual T cells in mustard and light blue
e-CSI - Flow Cytometric Studies:
NK cells are CD94+bright,
26+bright, 4-, 27+

Normal T cells
e-CSI - Flow Cytometric Studies:
• Normal NK plot expressions
Normal expression of pooled normal donors
NK cells are in black, CD4+T cells mustard, CD8+ T cells in blue
e-CSI - Flow Cytometric Conclusion:
1. NK cells 56% of mononuclear gate expressing:
CD2+, 3-, 4-, 5 partial, 7-, 8-, 16/56+, 26+
bright, 27-, 94+ bright, TCR αβ- & γδ2. Monocytes –normal expression compared to
controls with this panel of markers but
expanded in number
e-CSI – cont.
• Correlation with morphology and
subsequently immunohistochemistry was
performed
e-CSI – morphology
The aspirate quality was poor. A trephine touch is depicted
showing numerous large, immature haematopoietic precursors
e-CSI – morphology
H & E section x 40 magnification
e-CSI – morphology
H & E section x 200 magnification; Effacement by an
undifferentiated population of large blast-like cells
e-CSI – morphology
CD2 demonstrates a dominant positive population,
including mitotic figures
e-CSI – morphology
CD3 shows cytoplasmic staining, in keeping with staining of CD3
epsilon chains of NK cells
e-CSI – morphology
TIA shows a significant positive population, while some granzyme
positivity was also seen (not shown), in keeping with the cytotoxic
function of NK cells
e-CSI – morphology
• EBV ISH is not a validated in our mercuric
chloride fixed trephines, so was not tested
• TP53 IHC (not shown) showed positivity in
about 20% of cells
• Insufficient material was available for
cytogenetics
• TCR gene rearrangement studies were
polyclonal
e-CSI – Diagnosis
• Aggressive NK-cell leukaemia
• Reactive monocytosis
e-CSI – Aggressive NK-cell leukaemia
• This is a rare disorder with a preponderance in
Asian and South American populations, and
young to middle aged
• There is a strong association with EBV
• Patients present with fever, cytopenias,
constitutional symptoms, leukaemic cells, DIC,
or
haemophagocytic
syndrome.
Skin
involvement is uncommon
e-CSI – Aggressive NK-cell leukaemia
• Morphologically: NK cells in this disorder vary
from typical large granular lymphocyte
morphology to atypical forms with folded
nuclei, and nucleoli to frank blasts
• The typical phenotype is CD2+ CD3- CD3ε+
CD56+ CD57- CD16+ CD11b+
• FAS ligand (CD95) is found on neoplastic cells,
and also in the serum
• T cell receptor genes are germline
e-CSI – Aggressive NK-cell leukaemia
• >90% cases are EBV positive
• Karyotypic anomalies vary and include 11q,
6q, 17p deletions
• The prognosis is poor and median survival
measureable in just a few months
• Typically the disease is refractory to aggressive
chemotherapy
e-CSI – References
• Chan JKC, Jaffe ES, Ralfkiaer E et al. WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues. 4TH edition, pp276-277.
• Dearden CE, Johnson R, Pettengell R et al. Guidelines for the
management of mature T-cell and NK-cell neoplasms (excluding
cutaneous T-cell lymphoma). Br J Haematol 2011; 153, 451–485.
• Kawa-Ha K, Ishihara S, Ninomiya T et al. CD3-negative
lymphoproliferative disease of granular lymphocytes containing
Epstein-Barr viral DNA. J Clin Inves 1989; 84: 51-55.
• Kwong YL, The Diagnosis & management of extranodal NK/T cell
lymphoma, nasal-type and aggreesive NK-cell leukemia. J Clin Exp
Hematopath. 2011; 51: 21-27.
• Suzuki R, Suzumiya J, Nakamura S et al. Aggressive natural killer-cell
leukemia revisited: large granular lymphocyte leukemia of cytotoxic
NK cells. Leukemia 2004; 18: 763–770.