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Diffuse large B-cell lymphoma and polycythemia vera discovered at the onset
– A rare association and its possible importance in lymphoma prognosis
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Rom J Morphol Embryol 2016, 57(1):313–318
ISSN (print) 1220–0522 ISSN (online) 2066–8279 CCAASSEE RREEPPOORRTT
Diffuse large B-cell lymphoma and polycythemia vera
discovered at the onset – a rare association and its
possible importance in lymphoma prognosis
VIOLA MARIA POPOV1), CAMELIA -MARIOARA DOBREA2), MIHAI POPESCU3), IANCU EMIL PLEȘEA4),
VALENTIN -TITUS GRIGOREAN5), RUXANDRA -DIANA SINESCU6), VICTOR DAN EUGEN STRÂMBU5)
1)Department of Hematology, “Colentina” Clinical Hospital, Bucharest, Romania
2)Laboratory of Pathology, Departme nt of Hematology, “Fundeni” Clinical Institute, Bucharest, Romania
3)Department of Neurosurgery, Emergency County Hospital, Pitesti, Romania;
Department of Medical Assistance an d Kinesiotherapy, Faculty of Sciences, University of Pitesti, Romania
4)Department of Pathology, University of Me dicine and Pharmacy of Craiova, Romania
5)Department of Surgery, “Carol Davila” University of Medicine and Pharma cy, Bucharest, Romania
6)Department of Plastic Surgery, “Car ol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Abstract
Diffuse large B-cell lymphoma (DLBCL) represent the most frequently non-Hodgkin’s lymphoma (NHL) (over 30%), especially in deve loping
countries. Many associations of NHL with another neoplasia were described following chemotherapy or radiotherapy regimens. The coexistence
of DLBCL with myeloproliferative neoplasms (MPNs) JAK2V617F positive at the onset was very rare reported in the literature. We describe a
clinical case of a 52-year-old man who presented both diagnoses at the onset – DLBCL and MPN – polycythemia vera (PV) type. The patient
was treated with two CHOP cycles (Cyclophosphamide, Hydroxydaunoru bicin, Oncovin, Prednisolone) followed by six R-CHOP (Rituxim ab-
CHOP) cycles, together with a platelet-reducing agent, achieving remission for 20 months, followed by a relapse which is under treatment.
The clonally expansion of an abnormal pluripotent hematopoetic stem cell could be responsible for both, PV and DLBCL. However, recent
reports suggested the possible involvement of two different clones. The clinical significance and the role of JAK2 mutation in the evolution
of patients with NHLs, including DLBCL are still unknown. Further genetic and clinical studies have to point out common gene mu tations
for the two diseases and their connection with the diseases behavior under the treatment. Conclusions : The coexistence of NHLs and
especially DLBCLs and MPNs JAK2 positive is very rare. Although DLBCL alone has good prognosis, other prognostic factors should be
checked when it is associated with PV. The presence of JAK2V617F seems to be a candidate but whose role in DLBCL evolution, nat ural
or under treatment has to be cleared up.
Keywords : JAK2 mutation, polycythemia vera, diffuse large B-cell lymphoma, prognosis.
 Introduction
Diffuse large B-cell lymphoma (DLBCL) represent
the most frequently non-Hodgkin’s lymphoma (NHL)
(over 30%), especially in developing countries [1, 2].
An alternative microarray technology (gene expression profiling – GEP) allowed the identification of three types
of DLBCL not otherwise spec ified (NOS): GEP profile
of germinal center B-cells (GCB-like), GEP profile of activated peripheral B-cell (ABC) and few cases that
cannot be classified in these categories (type 3 DLBCL).
The GEP classification is very important for prognosis of these patients: ABC-DLBCL patients have a worse
prognostic than GCB-DLBCL [3]. GCB-DLBCL subtype
is associated with amplifications of the REL loci, BCL-2 translocations and hypermutations of the immunoglobulins
loci; the other type, ABC-DLBCL is associated with
activation of the nuclear factor-kappa B (NF- κB) pathway.
The amplifications at 9p corresponding to JAK2 was
associated with DLBCL primar y mediastinal subtype [2].
Patients with myeloproliferative neoplasms (MPNs), especially patients with polycythemia vera (PV) have
JAK2V617F mutation (93% of patients with PV; 50% patients with primary myelofibrosis or essential thrombo-
cythemia) [4]. The presence of JAK2V617F mutation was
not implicated in evolution of other lymphoproliferative disease, like B-cell chronic lymphocytic leukemia (B-
CLL) [5]. In MPNs patients, this mutation plays a major
role in myeloid maturation induced by cytokines and grows factors signaling (including interleukin-3, erythropoietin,
granulocyte and granulocyte-macrophage colony-stimu-
lating factor, thrombopoietin). A few patients also have associated chromosomal abnormalities (9p or 20q deletion)
[6].
The association between NHLs and PV is rare [7, 8].
Although an infrequent event, the spectrum of clinical
situations gathers together no more than three different
forms: (a) either the two dis eases are coexisting from the
onset, especially in previously untreated patients [8–12],
(b) or, much more rarely, the myelodysplastic syndrome
is following the lymphoma and its therapy [13–15], (c) or lymphoma was reported subsequent to diagnosis of PV
[7, 16, 17]. We will present a clinical case of one patient
with simultaneously diagnosis of DLBCL and PV and will make a brief review of the other 18 cases about we could
find data reported in the literature. Written informed
R J M E
Romanian Journal of
Morphology & Embryology
http://www .rjme.ro/

Viola Maria Popov et al.
314
consent was obtained from the patient for publication of
this case report and the accompanying images.
 Case presentation
Patient’s status at admission
A 52-year-old male, without si gnificant medical history,
was admitted in the Emergency County Hospital, Pitesti,
Romania, for altered health state, nocturne sweats, weight
loss, lymphadenopathies. On clinical examination, the patient was afebrile, with good general state [performance
status ECOG 1 ( Eastern Cooperative Oncology Group )],
multiple peripheral mobile unpainful lymphadenopathies
(supraclavicular, axillar and inguinal), with a diameter of
1–3 cm; bloating, upper abdominal increased sensitivity,
and liver border at the 2 cm bellow costal margin, consis-tency moderately increased, rounded edge, spleen palpable
with bottom pole from 2–3 cm below costal border.
Clinical laboratory investigations
The white blood cell (WBC) count showed leukocytosis
(18 500/mm
3) with slight left shift deviation, without
blasts or promyelocytes but with basophils (3%), high platelet count (869 000/mm
3) with giant platelets and
platelet aggregates, but hem oglobin (Hb) and hematocrit
(Ht) in normal values (Hb 15.2 g/dL, Ht 41.9%). Blood
biochemistry was normal ex cept lactate dehydrogenase (LDH) level, which was mild elevated (250 IU/mL).
Serology was negative for he patitis viruses (HBV, HCV).
Serum erythropoietin (EPO) was very low (<1 U/mL). The
mutant homozygote status for JAK2V617F was determined by real-time polymerase chain reaction (RT-PCR).
Pathology and immunohistochemistry (IHC)
We performed a bone marrow trephine biopsy (BMB)
from posterior-superior iliac crest, after local anesthesia.
After fixation in 10% buffered formaldehyde, BMB sample
was decalcified for 3–4 hours in Na
2EDTA (Disodium
ethylenediaminetetraacetate) , processed and paraffin
embedded. The sections of 4 μm were stained with
Hematoxylin–Eosin (HE). The BMB histological exami-
nation revealed a hypercellular bone marrow, with pan-
myelosis (Figure 1a), normal myeloid:erythroid (M:E) ratio (3:1), moderate megakaryocytic hyperplasia with giant
hyperlobulated megakaryocytes, dispersed and in small peri-
vascular clusters (Figure 1b), without lymphoid infiltration.
We have also performed biopsy of an axillary lymph
node. The microscopic examination of the lymph node was
typical for a large cell NHL (l oss of normal architecture,
diffuse malignant infiltrate with large-sized atypical
lymphoid cells, round vesicular nucleus, 2–4 medium-sized
nucleoli, moderately basophilic cytoplasm) (Figure 2, a and b).

Figure 1 – Bone marrow biopsy: (a) Hypercellula rity, panmyelosis; (b) Clusters of large megakaryocytes. HE staining:
(a) ×100; (b) ×400.

Figure 2 – Lymph node biopsy: (a) Diffuse large cells lymphoid infiltrate; (b) Tumor cells ar e large lymphoid cells, with
vesicular nucleus and 2–3 nucleoli. HE staining: (a) ×100; (b) ×400.

Diffuse large B-cell lymphoma and polycythemia vera discovered at the onset – a rare association…
315

IHC staining was carried out on paraffin sections using
MaxPolymer Novolink (Leica, UK), in accordance with
the manufacturer’s protocol. We performed IHC stainings
with B-cell marker anti-CD20 (clone L26, 1:250 dilution,
Novocastra, Leica, UK) and T-cell marker anti-CD3 (clone LN10, 1:400 dilution, Novocastra, Leica, UK).
The tumor was diffusely positive for CD20 (Figure 3)
and CD3 negative.

Figure 3 – Lymph node biopsy: tumor cells are large
B-cells, CD20 positive. IHC staining for CD20, ×200.
The final diagnosis was DLBCL associated with MPN,
JAK positive homozygous, PV type.
Computed tomography (CT) scans performed for
DLBCL staging showed mild hepatomegaly (right hepatic
lobe 17.4 cm, left hepatic lobe 7 cm), moderate spleno-megaly (16.7 cm), two inguinal adenopathies (3.5/3.2 cm
and 3.2/3.6 cm) with homogenous structure, without pulmonary or mediastinal lesions, advocating for III B
clinical stage of DLBCL. Th e prognosis score, according
to the Revised International Prognostic Index (R-IPI)
was 2, meaning a good prognosis.
Patient outcome
The patient was treated with two CHOP cycles
[Cyclophosphamide, Hydroxydaunorubicin (Adriamycin),
Oncovin (Vincristine) and Prednisolone], followed by six cycles of CHOP with anti-CD20/Rituximab (R-CHOP)
chemotherapy. He has also rece ived Anagrelidum (a platelet-
reducing agent) 0.5 mg×2 daily.
The patient achieved hematological remission of
DLBCL, confirmed by positron emission tomography (PET)
scans, after eight months, but relapsed after 20 months with pleural effusion and mediastinal tumor. He was planned
for another chemotherapy schedule, R-ICE type (Rituximab,
Ifosfamid, Carboplatin and Etoposidum) and his treatment is ongoing.
 Discussion
The association between a MPN, especially PV and
a NHL at the time of diagnosis is rare, as we already mentioned above. We identified in the literature only
26 cases, including ours, in the last 50 years since Heinle
et al. [9] reported the first case with this association
(Table 1).
Table 1 – Synopsis of cases identified in th e accessible literature with non-H odgkin’s lymphoma and polycytemia vera
since the first case communicated in 1966 by Heinle et al. [9] (modified after P apageorgiou et al. [8] and Jeong et al.
[12] and extended)
No. Year Ref. Gender Age
[years] Type of NHL Therapy Outcome
Simultaneous at the onset
1 2016 [12] F 61 Follicular (grade 1) Local excision; radiation;
phlebotomy; Aspirin; HU NHL – CR; stabilization of
Hct; leukocytosis;
thrombocytosis
2 2014 [20] M 14 Mixed diffuse lymphocytic
kidney infiltration Chemotherapy (NoS) Favorable after
chemotherapy Improvement in renal
parameters
3 2002 [10] M 66 Follicle center cell (grade 1) m-BACOD; MIT + PDM; HU NHL – CR and reduction
of PV;
PV – recurrence of after four years of chemotherapy
withdrawal
4 1991 [19] M 20 Immature phenotype CHOP + VM26
CNS prophylaxis (MTX + DEX)
PDN + VCR + DNM + Asparaginase m-BACOD No response and
progression of NHL,
followed by close mortality
5 1988 [21] M 73 Plasmacytoid, colon Melphalan NoS
6 1985 [22] F 53 Large B-cell Chemotherapy (NoS) Favorable after
chemotherapy
7 1981 [23] NoS NoS Diffuse, lymphocytic RAMI RAMI
8 1966 [9] F 86 Lymphocytic Phlebotomy + radioactive
phosphorus RAMI
9 2016 OC M 52 DLBCL R-CHOP NHL – CR after eight
months and relapse after 20 months
Under treatment with new
scheme
NHL first at the onset
10(1) 2013 [15] M 72 DLBCL – brain
(three years before PV) RAMI RAMI

Viola Maria Popov et al.
316
No. Year Ref. Gender Age
[years] Type of NHL Therapy Outcome
11(2) 2011 [26] M 90 Follicular (24 years before PV) NoS NoS
12(3) 2006 [14] M 64 Small lymphocytic CTX + VCR + PDN and RXB Favorable post-
chemotherapy Hb and EPO normalized
13(4) 1996 [13] F 74 Diffuse centroblastic
(11 years before PV) ADM + VCR + PDN + MTX NHL – remission
PV – NoS
14(5) 1992 [24] M? NoS DLBCL
(4.5 years before PV) CTX and Procarbazine NHL in CR
PV – NoS
PV first at the onset
15(1) 2011 [26] M 75 DLBCL (10 years after PV) NoS NoS
16(2) 2011 [26] M 64 DLBCL (23 years after PV) NoS NoS
17(3) 2011 [26] M 79 DLBCL (9 years after PV) NoS NoS
18(4) 2009 [27] F 69.6 DLBCL (6.6 years after PV) NoS NoS
19(5) 2009 [27] M 65.6 Mantle cell (1.6 years after PV) NoS NoS
20(6) 2009 [27] M 79.9 NoS (10.9 years after PV) NoS NoS
21(7) 2006 [17] NoS NoS DLBCL RAMI RAMI
22(8) 2002 [7] F 61 DLBCL , high-grade
malignancy, oral cavity
(17 years after PV) m-BACOD
Local radiotherapy Oral lesion – CR
Favorable at 10 months
after treatment
23(9) 1995 [16] M? NoS Anaplastic B-cell (Ki-1) RAMI RAMI
24(10) 1994 [25] NoS NoS B-cell , high-grade malignancy RAMI RAMI
25(11) 1994 [25] NoS NoS B-cell , high-grade malignancy RAMI RAMI
26(12) 1994 [18] M 78 Cutaneous T-cell
(one year after PV) Phlebotomy
Photochemotherapy Resolution of skin lesion;
stabilization of Hct; leuko-cytosis; thrombocytosis
Ref: Reference; NHL: Non-Hodgkin’s lymphoma; F: Female; HU: Hydroxyurea; CR: Complete remission; Hct: Hematocrit; M: Male; NoS: Not
specified; m-BACOD: Second-generation combination chemotherapy regimen – Methotrexate (MTX), Bleomycin, Adriamycin/Doxorubicin
(ADM), Cyclophosphamide (CTX), Oncovin–Vincristine (VCR), Dexamethasone (DEX); MIT: Mitoxantrone; PDM: Prednimustine; PV: Poly-cythemia vera; CHOP: Regimen containing CTX, ADM, VCR and Predni sone (PDN); VM26: Teniposide; CNS: Central nervous system; DNM:
Daunomycin; RAMI: Restricted access to minimal information; OC: Our case; DLBCL: Diffuse large B-cell lymphoma; R-CHOP: Regimen
which combines CHOP with Rituximab (RXB); EPO: Erythropoietin.

Clinical morphological aspects
A first remark is concerning the sequence the two
diseases appeared in the patient’s life. The most numerous
group, gathering together al most half of the identified
cases, is the one including those cases with PV as the
first disease. At the opposite, the least numerous group,
including only five cases, was the one where the NHL
arose the first.
A second remark is concerning the NHL’s morphology.
More than 45% of the identified cases were B-cell
lymphomas and two-thirds of these belonged to the
group where PV was first at the onset.
Overall, the association between the two types of
proliferation was most frequently encountered in men,
with some differences. Thus, in the group with NHL at
the onset almost all cases were males whereas in the group
with both diseases discovered at the onset, one-third of
the cases were females. The males prevailed also in the
group with PV at the onset ev en one-quarter of the cases
had no gender specification. Finally, the males were
prevailing in the group with B-cell lymphomas too but in
one-quarter of cases, the patients’ gender was not specified.
The age range is also different from one group to
another. Thus, the group with NHL at the onset seems to be
the preserve of elderly people whereas in the group with
both diseases at the onset we found also young patients, of
14 and 20 years old. In the group with PV at the onset, two-
thirds of patients had the age specified and it was higher
than 60 years. In the group with B-cell lymphomas, patients
were adults over 50 years and elderly but, again, we have
to mention the lack of data in one-third of the cases. The therapeutic strategy was focused in most of the
cases and irrespective the group on the lymphoproli-
ferative disease. In only f our cases [9, 10, 12, 18] are
mentioned therapeutic procedures for PV. Unfortunately, we have to mention again that the restricted access to the published data (half of the cases) did not allow a
complete assessment of the applied therapy. If we do not
take into consideration the 15 cases with no data concerning the patient’s outcome, then in most of remaining cases the outcome was favorable first and foremost for the NHL. There was only one case [19] where the complex and sustained chemotherapy could not stop the progression
of the lymphoproliferative di sease and the patient died.
The prognosis of our patient was good (score IPI 2,
PET scan negative). Patient was treated by R-CHOP chemotherapy schedule for DLBCL, but he relapsed after 20 months with mediastinal determination.
To treat patients with diff erent concurrent cancers,
including lymphoproliferative and myeloproliferative neoplasms, is a difficult task. In the past, IPI score brought more information about the prognosis of DLBCL patients. In present, many investigations improve the prediction of
outcome for treatment of these patients. Fluorodeoxy-
glucose–positron emission to mography (FDG-PET) brings
an important role in predicting of outcome after completion of first-line therapy for DLBCL patients.
Patients who are PET negative have a 0% to 16%
probability of relapse, compared with 87% to 100% of PET-positive patients [28]. DLBCL patients with negative and mild metabolism PET/CT following first-line treatment had good prognosis, who needed no additional therapy [29].

Diffuse large B-cell lymphoma and polycythemia vera discovered at the onset – a rare association…
317
Pathogenic and genetic aspects
The nature of the relationship between NHL, especially
high grade, and PV is not clear [13]. The studies of last decades could not prove clearly a mechanism of coexistence
of the two diseases, without any previous cytotoxic or radiation exposure [8, 12] or of a mechanism by which one can induce other, taking into consideration that they
can be sequential at the onset. There are many hypotheses
concerning their mechanisms of appearance, both when
it happens sequentially or in the same time.
Thus, when we talk about coexistence: ▪ The coincidence cannot be excluded [13];
▪ Chromosomal abnormalities consisting in random
mutations that occur in distinct initiating cells in both
PV and NHL are suggesting th e possible involvement of
two different clones [12, 25, 30];
▪ Both malignancies may have evolved by clonal
expansion of the same abnormal pluripotent hematopoietic stem cell although the karyotypes were not studied [13,
16].
When we talk about sequence of the onsets: ▪ The genomic instability characteristic to myelo-
proliferative neoplasms may contribute to subsequent lymphoproliferative neoplasms occurrence [26, 27];
▪ PV could be secondary to the ectopic production of
erythropoietin by the lymphoma cells [14];
▪ PV could develop as a consequence of therapy for
the NHL. However, there are an increasing number of patients surviving long term after chemotherapy for the malignant lymphoproliferative disease [13].
The genetic investigations could represent further a
key tool in the elucidation of the relationship between the
two types of proliferation. A starting point was the study of tyrosine kinase gene JAK2 (Janus Kinase 2) mutations.
Thus, the JAK2V617F mutation, a point mutation in the JAK2 gene, has an important role in the pathogenesis of the MPNs. The JAK2 mutation induces the activation
of the JAK-STAT signaling pathway, and leads to
autonomous cell growth [31, 32].
The JAK2V617F was identified not only in MPNs
patients, but also in NHL patients. However, the detection of JAK2 mutation in NHL is rare. For instance, Wang et al. reported the presence of JAK2 V617F allele in only
three of 237 patients with lymphoid neoplasms [8, 31,
32]. Another study reported that patients with primary mediastinal DLBCL have a relative increase in JAK2 transcripts, but the JAK2 signaling in these cases was represented by mechanisms distinct from JAK2V617F or JAK2 exon 12 activating mutations, described in MPNs
[33].
Najfeld et al. showed that patients with Ph-negative
MPNs and non-MPNs have two types of JAK2 rearran-gements. Gain and amplification of JAK2 was primarily observed in patients that were JAK2V617F-positive; rearrangements of JAK2 were seen in patients who lacked the JAK2V617F mutation. There are many JAK2 rearran-gements, including a novel J AK2-NF-E2 interaction, JAK2
translocation to chromosomes 3, 4, 12, 14, and 21 and detection of TEL/ETV6-JAK2 translocation. In NHL
patients, the presence of JAK2 attracts multiple gene partners and may contribute to disease progression [34].
In other studies, the presence of JAK2V617F mutation was not found in normal B- and T-lymphocyte populations
and had no relevance in B-CLL patients because no
evidence that the proliferativ e behavior of B-CLL clone
is mediated through this mutation was found [35, 36].
The patterns of gene expression, as well as individual
genes have also had an important prognostic significance. Three genes (LMO2, BCL6 and FN1) were correlated with prolonged survival and three (BCL2, CCND2 and
SCYA3) were correlated with shorter survival. Expression
of bcl-6 and CD10 was associated with a favorable outcome compared with MUM1 or cyclin D2 expression.
However, the clinical si gnificance and the role of
JAK2 mutation in the evolution of patients with NHLs, including DLBCL are still unknown [32].
Our study revealed that the paucity of cases reported
in the literature and the lack or restricted access to the
data included in the identified reports could not offer solid arguments in favor of certain influence of PV on NHL prognosis. Further genetic and clinical studies who should gather together a significant number of cases have
to point out common gene mutations for the two diseases
and their connection with the diseases behavior under the treatment.
 Conclusions
The coexistence of NHLs and especially DLBCLs and
MPNs JAK2 positive is very rare. Although DLBCL alone
has good prognosis, other prognostic factors should be
checked when it is associated with PV. The presence of
JAK2V617F seems to be a candidate but whose role in
DLBCL evolution, natural or under treatment has to be
cleared up.
Conflict of interests
The authors declare that they have no conflict of
interests.
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Corresponding author
Mihai Popescu, Professor, MD, PhD, Department of Medi cal Assistance and Kinesiotherapy, Faculty of Sciences,
University of Pite ști; Department of Neurosurgery, Emergency County Hospital, 36 Aleea Spitalului, 110283 Pite ști,
Romania; Phone +40248–287 150, e-mail: mihaipopescu2000@yahoo.com

Received: April 8, 2015 Accepted: April 22, 2016
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