BMV30: 79 YEAR-OLD MAN WITH ANEMIA, A MONOCLONAL PROTEIN, AND
SPLENOMEGALY.
Rajeev Balasubramaniam1 and Dita Gratzinger1
1.Stanford Hospital, Pathology, Stanford, Ca, USA
ditag@stanford.edu
Clinical history: 79 years-old male with several month history of anemia, weight loss and recently discovered
monoclonal protein in the serum. CT scan reveals an enlarged spleen.
Hb 9.5 g/dL (14.0-17.0 g/dL), WBC 1.1 K/uL (4.5 - 11.0 K/uL), Plt 185 K/uL (150-400K/uL).
Other lab. parameters: Serum monoclonal protein; IgA, 1030 mg/dL (70-400 mg/dL)
Biopsy fixation: The core biopsy is immediately placed in Bouin’s solution for 45 minutes, then rinsed, and
transferred to decalcification for one hour.
Microscopy: The core biopsy is hypercellular for age (95%) and contains a marked increase
megakaryocytes, including numerous clusters of atypical large hyperchromatic forms in a background of
streaming fibrosis. Scattered blasts are present interstitially and in small clusters. No patent sinusoids or
intrasinusoidal hematopoiesis is seen. There is a normal-appearing small mature lymphocytic infiltrate in some
areas. Residual hematopoiesis is nearly absent, with decreased erythroids and markedly decreased myeloids.
Trabecular bone is normal. The aspirate smears are hemodilute with minimal spicules. Erythroid precursors
are reduced, with normal maturation. Myeloid precursors are markedly reduced to absent. An atypical
population of medium-sized agranular blasts accounts for 30% of nucleated cells on a 200-cell differential.
Numerous small mature lymphocytes are also seen. Megakaryocytes are increased in number with atypical
monolobate forms and abnormal large platelet fragments.
Immunophenotype/immunohistochemistry: Immunostaining for CD34 shows increased blasts in a patchy
distribution, with clusters in some areas and approximately 20% involvement overall. Flow cytometry reveals a
CD34+ blast population accounting for 45% of all leukocytes. These blasts express CD38, CD13 (partial),
CD33, CD56, HLA-DR, CD11c (partial), CD2 (partial), CD4 (partial), CD5 (partial), CD7 (partial), and TdT
(partial), with a subset showing abnormal co-expression of CD15/CD117. They are negative for MPO, CD14,
CD64, CD3, CD19, and CD20.
B-cells and plasma cells are polyclonal. No aberrant antigen expression is detected on T-cells.
Cytogenetics: Deletion 20q is detected in 20 of 20 metaphases examined. A myeloma FISH panel is
negative.
Molecular analysis: JAK-2 mutational analysis performed on the peripheral blood is negative.
Proposed diagnosis
Acute Leukemia, Unclassifiable, possibly arising out of an undiagnosed Jak-2-negative chronic
myeloproliferative disorder.
Interesting feature(s) of the submitted case
The immunophenotype of the blasts shows some myeloid antigen expression (CD13, CD33, CD117) in the
absence of MPO reactivity. Similarly, numerous T-antigens (CD2, CD5, CD7) are expressed without CD3 to
definitively support T-lymphoblastic differentiation. According to the WHO 2008 classification scheme, the
diagnosis is therefore acute unclassifiable leukemia.
The clusters of atypical megakaryocytes and 4+ reticulin fibrosis raise the possibility of an underlying Jak-2negative myeloproliferative disorder. Absent iron stores masking a polycythemia may be considered. This
condition would more commonly be associated with progression to an acute myeloid leukemia (versus an
acute lymphoid leukemia). Isolated del(20q) also supports a myeloid neoplasm.
Unfortunately the patient passed away one week after presentation. The post-mortem examination revealed
widespread organ involvement, including liver, spleen, lung and dura mater, by both the acute leukemia
(confirmed by CD34 immunostaining) and the unclassified myeloproliferative disorder. In our experience
multiple solid organ involvement by both and acute leukemia and a chronic myeloproliferative neoplasm is
extremely unusual.
Cytogenetic studies revealed an isolated deletion 20q. This recurrent cytogenetic abnormality is commonly
seen in myeloid disorders, including chronic myeloproliferative diseases, however the prognostic significance
of this finding in such cases remains unclear. 1 Interestingly, this abnormality has also been reported in
patients with plasma cell disorders and monoclonal serum proteins (as was seen in this patient). 2,3
In addition to the acute leukemia and atypical megakaryocytes, the biopsy contained a lymphoid infiltrate that
was shown to be heterogeneous without aberrant antigen expression by immunophenotyping. Peripheral
blood B- and T- lymphocytes have been shown to be clonally related to the myeloid neoplasm in primary
myelofibrosis.4
References:
1. Panani AD. Cytogenetic and molecular aspects of Philadelphia negative chronic myeloproliferative disorders:
clinical implications. Cancer Lett. 2007 Sep 18;255(1):12-25.
2. Nilsson, T et al. MDS/AML-associated cytogenetic abnormalities in multiple myeloma and monoclonal gamopathy
of undetermined significance: Evidence for frequent de novo occurrence and multipotent stem cell involvement of
del (20q). Genes, Chromosomes and Cancer. 41: 223-31 (2004).
3. Liu, YC et al. Deletion (20q) as the sole abnormality in Waldenstrom macroglobulinemia suggests a distinct
pathogenesis of 20q11 abnormality.
4. Reeder TL, Bailey RJ, Dewald GW, Tefferi A. Both B and T lymphocytes may be clonally involved in
myelofibrosis with myeloid metaplasia. Blood. 2003 Mar 1;101(5):1981-3. Epub 2002 Oct 24.