Introduction
Follicular lymphoma is an indolent B cell
lymphoproliferative disorder of transformed follicular center B
cells (1). Patients with follicular
lymphoma present with diffuse lymphadenopathy, bone marrow
involvement and splenomegaly; in rare cases, other extranodal sites
may also be involved (1). Follicular
lymphoma is one of the most common subtypes of non-Hodgkin lymphoma
(NHL) with an estimated incidence of 3.18 cases per 100,000
individuals in the USA (2).
Follicular lymphoma is the initial neoplasm for indolent lymphomas
and has a median overall survival of >10 years (1). Observation or radiation therapy is
adequate for asymptomatic and low tumor bulk disease cases
(3,4).
For patients needing therapy, the majority of patients are treated
with chemotherapy plus rituximab (5–7).
Myeloproliferative neoplasms are characterized by
terminal myeloid cell expansion in the peripheral blood, resulting
in various combinations of erythrocytosis, leukocytosis,
thrombocytosis, bone marrow hypercellularity/fibrosis and
splenomegaly (8). Polycythemia vera
is a Philadelphia-negative myeloproliferative disease associated
with JAK2 mutation characterized by erythrocytosis; patients are
treated by phlebotomy and/or cytotoxic drugs (9). Myeloproliferative neoplasms are
associated with lymphoproliferative disease following the
administration of cytotoxic drugs or exposure to radiation, but are
rarely observed prior to therapy (10,11).
In the present study, a case of a 61-year-old female
with a history of transient ischemic attack is reported. The
patient was simultaneously diagnosed with follicular lymphoma and
an unclassifiable myeloproliferative neoplasm. It is possible that
the coexistence of follicular lymphoma and an unclassifiable
myeloproliferative neoplasm prior to the administration of a
cytotoxic drug or exposure to radiation may involve 2 unrelated
clones of different lineages.
Case report
A 61-year-old Asian female visited the Ulsan
University Hospital (Dong-gu, Ulsan, Republic of Korea) in October
2013 with a painless but palpable left epitrochlear mass. The
patient had suffered a transient ischemic attack in August 2010,
and was prescribed aspirin (100 mg once per day) and cilostazol
(100 mg once per day) at the time. The 1.5-cm sized left
epitrochlear mass presented without systemic B symptoms, such as
fever, night sweat or unintentional weight loss. Laboratory
findings demonstrated leukocytosis [white blood cell (WBC) count,
16,040 cells/µl], erythrocytosis (hemoglobin, 17.5 g/dl;
hematocrit, 58.3%), thrombocytosis (platelet count, 782,000
cells/µl), reduced erythropoietin (6.26 mU/ml), elevated lactate
dehydrogenase (789 IU/l) and elevated serum β-2 microglobulin (2.8
mg/l). A computed tomography scan of the neck, chest and abdomen
identified an enlarged spleen, but no other lymphadenopathy. An
excisional lymph node biopsy demonstrated follicular lymphoma with
nodal growth pattern, which are closely packed and contained small
round cleaved cells and larger non-cleaved cells (grade 1)
(Fig. 1). The tumor cells were
positive for B-cell lymphoma 2 (Bcl-2), cluster of differentiation
(CD) 20, and negative for CD3 and cyclinD1. Positron emission
tomography identified a mild hypermetabolic lesion in the operation
bed of the left elbow, demonstrating post-surgery alteration.
Diffusely increased metabolism of the skeletal bone marrow was also
observed throughout the body. A biopsy of the bone marrow revealed
hypercellularity, with predominance of cells derived from the
erythroid series and large polylobated megakaryocytes with
increased mitotic figures. However, no evidence of lymphomatous
infiltration was observed (Fig. 2).
The V617F mutation in janus kinase 2 (JAK2) was also detected in
the cells of the bone marrow specimen. Based on these results, the
disease was considered to be at a clinical stage I, and the
follicular lymphoma international prognostic index score indicated
an intermediate risk (12). Following
local excision of the lymph node, radiation was delivered to the
involved field at a dose of 24 Gy in 12 fractions. A computed
tomography scan of the neck, chest and abdomen performed 3 months
later revealed no abnormalities. Following phlebotomy and plasma
apheresis, the patient was started on hydroxyurea (1 g twice per
day, orally) 2 weeks subsequent to the end of radiotherapy, and was
administered 500 mg twice per day of the drug as maintenance
therapy. On the sixth month of follow-up, the WBC count,
hemoglobin, hematocrit and platelet count were reduced to 7,430
cells/µl, 12.2 g/dl, 36.5% and 379,000 cells/µl, respectively, and
the patient was in a healthy condition at the time of
reporting.
Discussion
A small number of patients (<10%) diagnosed with
follicular lymphoma present stage I/II of the disease (13). In these cases, radiation therapy is
the treatment of choice, following which, the 10-year overall
survival rate is 60–80%, with a median survival time of ~19 years
(3). The therapies for polycythemia
vera are aimed at preventing the occurrence of thrombosis (19,20). The
initial therapy for patients at high risk of developing thrombosis
consists of phlebotomy plus a low dose of aspirin, supplemented
with a cytoreductive agent, such as hydroxyurea (21). In the present report, radiation was
delivered to the involved field, following local excision of the
lymph node in the left epitrochlear area. The patient was
administered hydroxyurea and aspirin subsequent to phlebotomy and
plasma apheresis.
Direct or indirect dysregulation of the tyrosine
kinase JAK2 signaling pathway, as a result of somatically acquired
mutations, is involved in the pathogenesis of myeloproliferative
neoplasms (22). JAK2 participates in
the signaling pathways initiated by the cytokine receptors that are
required for normal myelopoiesis, including those for
erythropoietin, thrombopoietin and granulocyte colony stimulating
factor (23). The JAK2 V617F variant
increases genomic instability by reducing apoptosis secondary to
DNA damage, and by altering the expression of a number of genes,
which in turn may increase the risk of genetic lesions that lead to
leukemic transformation (24).
The JAK2 V617F mutation is present in 95% of
patients with polycythemia vera and in ~50% of patients with
primary myelofibrosis or essential thrombocythemia (24,25). This
mutation has also been observed in patients affected by other
myeloid diseases, including 67% of patients with refractory anemias
and ring sideroblasts associated with thrombocytosis (26), 7.8% of patients with chronic
myelomonocytic leukemias and a low percentage of patients with
primary acute myeloblastic leukemias, myelodysplastic syndromes and
chronic myeloid leukemia (27).
However, to the best of our knowledge, the JAK2 V617F mutation has
not been detected in follicular lymphoma thus far. Furthermore, the
coexistence of follicular lymphoma and myeloproliferative neoplasm
is rare (14,28).
There are limited number of reports in the
literature that are relevant to the case described in the present
report (Table I). It is uncertain
whether there is a pathogenetic association between the
myeloproliferative and lymphoproliferative diseases: It is likely
that both are as a result of random mutations occurring in distinct
initiating cells. However, given the higher risk of
lymphoproliferative neoplasms development in myeloproliferative
neoplasms reported in larger studies, the genomic instability
characteristic to myeloproliferative neoplasms may contribute to
subsequent lymphoproliferative neoplasms occurrence (29,30). The
pathogenesis may be attributed to reduced immunocompetence and/or
anti oncogene suppression.
 | Table I.Review of the association between PV
and malignant lymphoma, prior to the administration of a cytotoxic
agent and/or exposure to radiation. |
Table I.
Review of the association between PV
and malignant lymphoma, prior to the administration of a cytotoxic
agent and/or exposure to radiation.
| Age
(years)/gender | Histological type of
lymphoma | Timing of
diagnoses | Treatment | Outcomes | Reference |
|---|
| 73/M | Plasmacytoid of the
colon | Simultaneous | Melphalan | Not available | (15) |
| 20/M | Immature T-cell | Simultaneous | CTX+ADM+VCR+VM26+PDN
plus CNS prophylaxis with MTX +DEX; PDN+VCR+DNM +asparaginase;
m-BACOD | No response and
progression of NHL, followed by close mortality | (16) |
| 78/M | Cutaneous T-cell | Sequential (PV
detected 1 year prior to NHL) | Phlebotomy;
photochemotherapy | Resolution of skin
lesion; stabilization of Hct; leukocytosis; thrombocytosis | (17) |
| 52/M | Hodgkin's | Sequential (PV
detected 9 months prior to NHL) | Phlebotomy; VLB;
CVPP | HL CR and reduction
of PV; recurrence of PV after 4 years of chemotherapy
withdrawal | (18) |
| 66/M | Follicle center cell
(grade 1) | Simultaneous | m-BACOD; MIT+PDM;
HU | NHL CR;
transformation of PV into secondary MMM | (14) |
| 61/F | Follicular (grade
1) | Simultaneous | Local excision;
radiation; phlebotomy; aspirin; HU | FL CR; stabilization
of Hct; leukocytosis; thrombocytosis | Present report |
In the present study, the JAK2 V617F mutation was
identified in the malignant cells of a patient with an
unclassifiable myeloproliferative neoplasm and coexisting
follicular lymphoma. This finding may indicate that the JAK2 V617F
mutation represents a secondary event to primary gene mutations in
the primitive stem cells, which leads to the development of a
follicular lymphoma and an unclassifiable myeloproliferative
neoplasm. Regardless, further studies using molecular and genetic
approaches may aid in the understanding of this rare occurrence of
neoplasms.
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