Case 2 -
Precursor T-cell Lymphoblastic Lymphoma with Eosinophils and Foci of Myeloid Differentiation
L. Jeffrey Medeiros, M.D.
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An 11-year-old girl developed abdominal pain and physical examination revealed enlarged cervical lymph
nodes. Biopsy of one lymph node was considered atypical paracortical hyperplasia without a specific
diagnosis rendered. Bone marrow examination showed hypercellularity, myeloid hyperplasia, and
eosinophilia. The patient was then referred to another hospital.
At time of transfer, the complete blood count showed normal hemoglobin and platelet counts and a
leukocyte count of 19,000 with 10% eosinophils. Imaging studies showed cervical and retroperitoneal
lymphadenopathy. A second cervical lymph node was biopsied at this time. In retrospect, the initial
lymph node biopsy specimen was also involved by the same process. Immunohistochemical studies were
performed and a number of markers were assessed with the following results: CD2+, CD4-, CD5+, CD7+,
CD8-, Ig-, CD19-, and CD20-. (Additional markers are illustrated.) Conventional cytogenetic analysis
was performed previously on bone marrow aspirate material and again on the second cervical lymph node
specimen. The results showed a normal karyotype, 46, XX, in both specimens.
Precursor T-cell lymphoblastic lymphoma with eosinophils and foci of myeloid differentiation.
PCR studies showed the presence of ZNF198-FGFR1 c/w t(8;13)(p11;q12)
The findings are consistent with the 8p11 myeloproliferative syndrome
Case 2 - Slide 1
The 8p11 myeloproliferative syndrome is a term coined by Macdonald in
1995 for a syndrome characterized by: 1) a myeloproliferative disease associated with eosinophilia; 2)
lymphadenopathy, usually involved by lymphoblastic lymphoma/leukemia; 3) frequent progression to acute
myeloid leukemia; and 4) reciprocal translocations involving chromosome 8p11. Another name for this
syndrome is stem cell leukemia/lymphoma syndrome. Lymphomas arising in this syndrome also have been
designated as pre-T lymphoblastic lymphoma with eosinophilia and recently bilineal lymphoma.
Approximately 40 cases of 8p11 myeloproliferative syndrome have been reported in the literature to date.
Patients with 8p11 myeloproliferative syndrome show a wide age range, from 3 to 84 years. The male to
female ratio is approximately 1.5 to 1. Most patients have systemic symptoms that include fever, weight
loss, night sweats, and lethargy. Lymphadenopathy is very common and hepatosplenomegaly occurs in 60-70%
of patients. Extranodal sites can be involved, but the mediastinum is not a common site of involvement.
The clinical course is aggressive and these patients have a high risk of developing acute myeloid
leukemia, most often within 1-2 years after initial presentation and diagnosis.
Histologic and Immunophenotypic Findings
Peripheral Blood and Bone Marrow
At time of initial diagnosis, the blood smear shows leukocytosis, often with increased neutrophils,
band forms, metamyelocytes, and myelocytes. Occasional blasts may be present. Eosinophilia is almost a
constant finding; these cells are usually mature. Basophils are usually not increased. The bone marrow
is hypercellular with increased granulocytic precursors.
As the disease evolves myeloblasts appear in the blood and accrue in the bone marrow. Depending on
the point of time of bone marrow examination, the process can resemble a
myelodysplastic/myeloproliferative disease or acute myeloid leukemia.
As lymph node biopsy is not always performed in these patients, the frequency of lymphoblastic
lymphoma/leukemia (LBL) in these patients is not clearly established. In a 2002 review by Macdonald and
colleagues, 19 of 27 (67%) patients underwent lymph node biopsy and 16 of these patients had LBL.
Histologically, the neoplastic cells are predominantly small lymphoblasts with dusty chromatin and a
high mitotic rate. However, in biopsy specimens numerous mature-appearing eosinophils are also admixed
within the neoplasm. In patients with the t(8;13)(p11;q12), cases of LBL also often have a second,
usually subtle component that tends to surround blood vessels and is composed of slightly larger cells
with more abundant, often eosinophilic cytoplasm. In the case presented here, this second component was
more prominent, particularly in the second lymph node biopsy specimen.
Immunophenotypic studies have shown that most cases of LBL in patients with 8p11 myeloproliferative
syndrome are of immature T-cell lineage. These neoplasms express TdT, often CD1a, and a variety of
T-cell and T-cell-associated antigens. This is also true for LBL associated specifically with the
t(8;13). However, the second component in these neoplasms often expresses myeloid-associated antigens,
such as MPO, CD68, CD117, or lysozyme. This led Vega et al to suggest that LBL associated with the
t(8;13) are, in fact, bilineal neoplasms. In ~10% of patients with the 8p11 myeloproliferative
syndrome, the LBL has been of immature B-cell lineage (at least 4 cases reported).
The defining feature of this syndrome is the presence of reciprocal translocations involving the FIBROBLAST GROWTH FACTOR RECEPTOR 1 (FGFR1) gene at chromosome 8p11. The most
common translocation is the t(8;13)(p11;q12), but a total of at least eight translocations with cloned
breakpoints have been reported in the 8p11 myeloproliferative syndrome (see Table). As a result of each
translocation, the N-terminal portion of the fusion protein is composed of the partner and the C-terminal
is composed of FGFR1. The partner protein contributes the ability to self-associate. A few other, rare
chromosomal translocations also have been reported in the 8p11 myeloproliferative syndrome, but at this
time the partner genes have not been identified.
As the t(8;13) is most common and most often associated with LBL, the following discussion is focused
on this abnormality. As a result of the t(8;13), the FGFR1 and ZNF198 genes are both disrupted and a novel ZNF198-FGFR1 fusion gene is created. Normally, ZNF198 protein is expressed in the
nucleolus of cells and it is thought to have role in ribosomal RNA transcription. FGFR1 is a tyrosine
kinase that is known to have a role in activating many cell signaling pathways. The t(8;13) is thought
to mimic normal ligand binding and therefore constitutively activate FGFR1.
The t(8;13)/ZNF198-FGFR1 and the t(8;22)(p11;q11)/BCR-FGFR1 have been shown to be oncogenic in mice and induce both T-cell lymphoma
and a myeloproliferative disorder mimicking the human 8p11 myeloproliferative syndrome. Dong and
colleagues have have shown that ZNF198-FGFR1 activates a number of cell signaling pathways (e.g.
phospholipase C g, AKT, and MAPK to name a few). Other, cooperating molecular abnormalities are likely
to be involved in progression to acute myeloid leukemia.
Table. Translocations and Fusions Genes in the 8p11 Myeloproliferative
|Translocation ||Partner Gene of FGFR1|
- Abruzzo LV, Jaffe ES, Cotelingam JD, et al. T-cell lymphoblastic lymphoma with eosinophilia
associated with subsequent myeloid malignancy [see Comments]. Am J Surg Pathol 1992; 16:236–245.
- Agerstam H, Lilljebjorn H, Lassen C, et al. Fusion gene-mediated truncation of RUNX1 as a potential
mechanism underlying disease progression in the 8p11 myeloproliferative syndrome. Genes Chromosomes
Cancer 2007; 46: 635-643.
- Dong S, Kang S, Gu TL, et al. 14-3-3-integrates prosurvival signals mediated by the AKT and MAPK
pathways in ZNF198-FGFR1-transformed hematopoietic cells. Blood 2007; 110: 360-369.
- Inhorn RC, Aster JC, Roach SA, et al. A syndrome of lymphoblastic lymphoma, eosinophilia, and myeloid
hyperplasia/ malignancy associated with t(8;13)(p11;q11): description of a distinctive clinicopathologic
entity [see Comments]. Blood 1995; 85: 1881–1887.
- Jabbar AL-Obaidi M, Rymes N, White P, et al. A fourth case of 8p11 myeloproliferative disorder
transforming to B-lineage acute lymphoblastic leukaemia. A case report. Acta Haematol 2002; 107:
- Macdonald D, Aguiar RC, Mason PJ, et al. A new myeloproliferative disorder associated with
chromosomal translocations involving 8p11: a review. Leukemia 1995; 9: 1628-1630.
- Macdonald D, Reiter A, Cross NCP. The 8p11 myeloproliferative syndrome: a distinct clinical entity
caused by constitutive activation of FGFR1. Acta Haematologica 2002; 107: 101-107.
- Reiter A, Sohal J, Kulkami S, et al. Consistent fusion of ZNF198 to the fibroblast growth factor
receptor-1 in the t(8;13)9p11;q12) myeloproliferative syndrome. Blood 1998; 92: 1735-1742.
- Roumiantsev S, Krause DS, Neumann CA, et al. Distinct stem cell myeloproliferative/T lymphoma
syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusions genes from 8p11 translocations. Cancer Cell
2004; 5: 287-298.
- Vega F, Medeiros LJ, Davuluri R, et al. t(8;13)-positive bilineal lymphomas: report of 6 cases. Am J
Surg Pathol 2008; 32: 14-20.