JCP Online First, published on March 1, 2017 as 10.
1136/jclinpath-2016-204294
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1 plasmablastic features.
Department of Pathology,
West Virginia University,
Morgantown, West Virginia,
USA
2
Department of Internal
Medicine, West Virginia
University, Morgantown,
West Virginia, USA
Correspondence to
Dr Flavia G Rosado,
Department of Pathology, West
Virginia University, 1 Medical
Center Dr, Room 2146F/HSC
North, Morgantown, WV
26506, USA; fgrosado@hsc.
wvu.edu
Received 19 December 2016
Revised 2 February 2017
Accepted 7 February 2017
To cite: Ahn JS, Okal R,
Vos JA, et al. J Clin Pathol
Published Online First:
[please include Day Month
Year] doi:10.1136/jclinpath-
2016-204294
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd under licence.
Original article
Plasmablastic lymphoma versus plasmablastic
myeloma: an ongoing diagnostic dilemma
Janice S Ahn,1 Ryan Okal,1 Jeffrey A Vos,1 Matthew Smolkin,1 Abraham S Kanate,2
Flavia G Rosado1
ABSTRACT
Aims To determine the utility of clinical, morphological
and phenotypical features in the differential diagnosis of
plasmablastic lymphoma and myeloma with
Methods All plasmablastic neoplasms identified from a
15-year retrospective search were reviewed and classified
into ‘lymphoma’, ‘myeloma’ or ‘indeterminate’. The
classification was then compared with the previously
established clinical diagnosis. Lessons learned from this
review were used to design a diagnostic algorithm for
pathologists to use in the absence of known clinical
history.
Results The classification was possible in 10 of 11
cases, 8 lymphomas and 2 myelomas (n=2). No
distinctive morphological or phenotypical features were
identified. The most useful histopathological parameter
was a positive Epstein-Barr virus in situ hybridisation.
Presence of associated lymphadenopathy and/or oral
mass in the absence of complete myeloma-defining signs
was used to favour a diagnosis of lymphoma in 4 of 8
cases.
Conclusions The distinction between plasmablastic
lymphoma from plasmablastic myeloma warrants detailed
knowledge of clinical, radiological and laboratorial
findings. New studies identifying distinctive phenotypical
or genetic features are needed to improve the
histopathological differentiation of plasmablastic
neoplasms.
INTRODUCTION
Plasmablastic lymphoma (PBL) is an aggressive large
B-cell lymphoma initially described as an intraoral
tumour arising in association with Epstein-Barr
virus (EBV) infection in HIV-positive individuals.1
Following its initial description, the scope of
PBL has expanded to include extra-oral and
nodal tumours lacking EBV or HIV-infection
association.2–6 Morphologically, PBL shows a
diffuse infiltrate of immunoblastic-appearing plasma
cells termed plasmablasts admixed with cells with
more mature plasmacytic differentiation.2 Although
considered a type of B-cell lymphoma, PBL
expresses plasma cell markers CD138, CD38 and
MUM-1 while lacking expression of B-cell markers
CD20 and PAX-5.2 The identification of EBV,
anaplastic lymphoma kinase (ALK) or human
herpesvirus 8 (HHV-8) distinguishes PBL from
other rare lymphomas with similar features,
namely, ALK-positive large B-cell lymphoma, large
B-cell lymphoma in HHV-8-associated multicentric
Castleman disease and primary effusion
lymphoma.2 7
Ahn JS, et al. J Clin Pathol 2017;0:1–6. doi:10.1136/jclinpath-2016-204294
Included in the differential diagnosis of PBL are
plasma cell neoplasms (eg, multiple myeloma) that
contain plasmablasts. Depending on the site of
involvement, plasma cell neoplasms are histologi-
cally classified as extramedullary plasmacytoma or
plasma cell myeloma.8 Extramedullary plasmacy-
toma presents as an isolated tissue mass preferen-
tially in the head and neck region.8 Plasma cell
myeloma is a bone marrow-based neoplasm, clinic-
ally termed multiple myeloma on demonstration of
end-organ damage (CRAB: hyperCalcaemia, Renal
disease, Anaemia and Bone lesions) and/or high
tumour burden (>60% bone marrow plasmacytosis
or significantly altered free light chain ratio).9 The
term ‘plasmablastic myeloma’ (PBM) has been
applied to plasma cell neoplasms when there are
>30% plasmablasts.10–12 Nodal involvement, while
seen in up to 40% of advanced cases, is not a
typical presenting sign of plasma cell neoplasms.13
Furthermore, association with EBV or HIV infec-
tion is exceedingly rare.6 14–16
Despite these differences, the clinical and histo-
pathological distinction between PBL and PBM is
often difficult, particularly in EBV-negative
tumours arising in immunocompetent adults. Albeit
difficult, a timely and precise diagnosis of plasma-
blastic neoplasms is important, as their treatments
differ significantly. The recommended treatment
for PBL includes dose-intense chemotherapy regi-
mens such as etoposide, vincristine, doxorubicin,
with a bolus of cyclophosphamide and prednis-
one,17 or hyperfractionated cyclophosphamide, vin-
cristine, doxorubicin and dexamethasone with
alternating methotrexate and cytarabine.18 The use
of cyclophosphamide, doxorubicin, vincristine and
prednisone is no longer considered optimal first-
line therapy.18 Conversely, plasma cell neoplasms
are treated with various combinations of steroids,
proteasome inhibitors, immunomodulatory agents
and alkylators. High-dose therapy and autologous
stem cell transplantation is routinely considered in
eligible patients with myeloma, but its role in PBL
remains undefined.19
For pathologists, there are few available tools
that allow for a specific and definitive histopatho-
logical differentiation of PBL and PBM. Both show
the same morphological spectrum and identical
plasma cell phenotype. EBV-encoded RNA in situ
hybridisation study (EBER)-positivity can be
helpful, but is absent in up to 40% of PBL cases.2
A previously proposed algorithm to approach
tumours with plasmablastic morphology incorpo-
rates EBER, HHV-8 and ALK immunohistochemis-
try, as well as clinical features.7
1
 Original article
This retrospective review of tumours with plasmablastic
morphology aims to evaluate the usefulness of various para-
meters that differentiate PBL and PBM. In order to do so, we
classified cases with plasmablastic features as lymphoma or
myeloma based on review of all pertinent histopathological and
clinical materials. Based on the lessons learned from this review,
we propose a diagnostic algorithm for the classification of neo-
plasms with plasmablastic features.
MATERIALS AND METHODS
We retrospectively searched the electronic medical records for
all pathology reports containing the term ‘plasmablastic’ from
January 2000 through January 2015. Only cases with available
glass slides were included. The pre-existing H&E-stained tissue
sections were reviewed by three haematopathologists (MS, JAV
and FGR) for morphological categorisation into plasmablastic
(>60% plasmablastic cells), plasmacytic (<40% plasmablastic
cells) or mixed (approximate equal numbers of plasmablastic/
plasmacytic cells 40%–60%) groups (figure 1). We then
reviewed the available ancillary studies including flow cytometry,
immunohistochemistry, in situ hybridisation and cytogenetics.
Clinical data were extracted from electronic medical records by
independent study personnel. It comprised demographic infor-
mation, results of physical examination, pertinent radiological
findings and laboratory values.
Using the current knowledge of plasmablastic neoplasms pre-
viously reported,2 7 10 12 14 we classified cases into ‘PBL’, ‘PBM’
or ‘indeterminate’ categories. An unbiased and independent
classification was assured by having different study members
extract data from medical records and classify the cases. Cases
categorised as ‘indeterminate’ were those in which clinical
and/or histopathological data were insufficient for confident
classification. We then compared the classification results with
the documented clinical diagnosis. This study has been approved
by the institutional review board.
RESULTS
A total of 11 cases were included. Of these, eight (73%) were
classified as PBL and two (18%) as PBM. In one case (9%), the
Figure 1 Morphological spectrum of
plasmablastic neoplasms. (A) Example
of plasmablastic lymphoma with a
predominance of plasmablasts,
characterised as large cells with large
nuclei and prominent central nucleoli
( patient #4, H&E, ×400). (B) Variants
of plasmablastic lymphoma with more
plasmacytic appearance were also seen
( patient #10, H&E, ×400). (C) Example
of plasmablastic myeloma containing
plasmablasts admixed with cells
resembling centroblasts ( patient #3,
H&E, ×400). ALK, anaplastic
lymphoma kinase; EBER, Epstein-Barr
virus-encoded RNA; HHV-8, human
herpesvirus 8; LBCL, large B-cell
lymphoma.
2 Ahn JS, et al. J Clin Pathol 2017;0:1–6. doi:10.1136/jclinpath-2016-204294
available morphological and clinical features were not sufficient
for definitive classification as either PBL or PBM (classified as
‘indeterminate’). Cases classified as PBL received lymphoma
regimens, and the cases classified as PBM received therapy for
myeloma, indicating 100% concordance between the study clas-
sification and the original clinical diagnosis. The clinical and
morphological features of these 11 patients are described below
within the Results section, and summarised in tables 1 and 2.
Lessons learned from this review were used to design a diagnos-
tic algorithm depicted in figure 2.
Plasmablastic lymphoma
Of the eight PBL-classified patients, three were HIV-positive
(patients #2, #4 and #8). Of these, two ( patients #2 and #4)
had positive EBER in tissue from the oral cavity and oesopha-
gus, respectively. Although patient #8 had high EBV viraemia
by PCR (10 314 copies/mL), EBER was negative. Of the remain-
ing patients, four were HIV-negative ( patients #1, #3, #5 and
#6) and one had an unknown HIV status ( patient #7). Of the
HIV-negative cases, one was EBER-positive and three were
EBER-negative. The single HIV-negative EBER-positive case
(patient #1) was of a male aged 42 years with end-stage liver
disease presenting with ascites and plasmablastic cells in the
peritoneal fluid. A negative HHV-8 excluded primary effusion
lymphoma in this patient. The three EBER-negative
HIV-negative cases ( patients #3, #5 and #6) were from a
female aged 61 years with isolated posterior nasopharyngeal
soft tissue mass, and from a female aged 58 years and a male
aged 74 years, both presenting with diffuse lymphadenopathy.
Negative HHV-8 and/or ALK immunostains excluded the diag-
nosis of an HHV-8-associated neoplasm and/or ALK-positive
large B-cell lymphoma in patients #3 and #6, respectively.
Concomitant bone marrow involvement was seen in four
cases ( patients #3, #6, #7 and #8). In these patients, the pres-
ence of diffuse hypermetabolic lymphadenopathy and/or extra-
medullary presentation led to the classification of these cases as
PBL, despite the presence of at least one myeloma-defining sign
in four cases (table 1). For patient #7, whose HIV status,
history of immunosuppression and presence/absence of
 Original article

Table 1 Plasma cell neoplasms: clinical characteristics and Epstein-Barr virus (EBV) status
Age BM Free Bone Outcome
Case# Sex HIV EBER Site (%) LN LC M-spike CRAB Hb lesions Cr Ca Therapy (months)

Plasmablastic lymphoma
1 42 − + Ascites NA NA NA NA ± 8.4 − 1.15 7.9 Supportive Dead (<1)
M
2 35 + + Oral NA + − NA − 14.8 − 1.1 9.6 DA EPOCH Rx Alive (117)
M
3 74 − − Lymph node 40% + 17.2 + ± 10.6 − 0.9 9.5 EPOCH Alive (23)
M
4 49 F + + Oesophagus − + NA NA ± 8.9 − 0.71 8.6 DA-EPOCH Alive (15)
5 61 F − − Nasopharynx − − 0.8 − − 13.7 − 0.85 9.3 DA-EPOCH Alive (15)
Rx
6 58 F − − Lymph node >90% + 2.8 − ± 8.6 + 0.91 9.9 CHOP Dead (10)
7 54 NA + Testicle 30% + NA NA NA 15.4 NA NA NA Hyper-CVAD Dead (13)
M
8 55 + − Bone 80% + 3.45 + ± 8.5 + 0.7 8.1 EPOCH Dead (4)
M marrow
Plasmablastic myeloma
9 71 NA NA Bone >90% − 5.7 + + 10 + 5.8 12 DVD Dead (17)
M marrow
10 72 F NA NA Bone 80% − NA + ± 7.0 + 0.8 9.1 Radiation, Thal Dead (3)
marrow DA
Indeterminate
11 79 NA − Mandible NA NA NA NA NA NA NA NA NA NA NA
M
At time of presentation, the patients had incomplete CRAB signs, with normal creatinine levels (0.8 mg/dL).
BM (%), percentage of involvement at time of presentation; Ca, serum calcium, 8.9–10.1 mg/dL; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; Cr, creatinine, reference
0.4–1.2 mg/dL; CRAB, myeloma-defining signs (+: complete; −: absent; ±: incomplete); DA, dexamethasone; DVD,doxorubicin, vincristine, dexamethasone; EBER, Epstein-Barr
virus-encoded RNA; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; F, female; free LC, free light chain ratio, 0.26–1.65 mg/dL; Hb, haemoglobin, reference
12.5–16.3 (males) and 11.2–15.2 g/dL (females); hyper-CVAD, alternating doses of cyclophosphamide, vincristine, doxorubicin and dexamethasone with high-dose methotrexate and
cytarabine; LN, significant lymphadenopathy; M, male; M-spike, monoclonal immunoglobulin spike by serum and/or urine protein electrophoresis, or immunofixation electrophoresis; NA,
not available or performed; outcome, months of available follow-up data; Rx, radiation; Thal, thalidomide.

Table 2 Plasmablastic neoplasms: histopathological findings

Case# Morph CD45 CD20 PAX-5 MUM-1 CD138 HHV-8 ALK CD10 CD56 CD79a Cyclin D1 Light chain MYC Gene Ki-67

Plasmablastic lymphoma
1 PC − − − + + − − − − − NA Kappa NA NA >95%
2 PC − − NA NA + NA NA − NA Weak NA Lambda NA NL >95%
3 Mixed + − − + Var − − − − Var+ NA Kappa NA NL 80%
4 PB NA − NA NA + NA NA NA NA NA NA Lambda NA NL >95%
5 Mixed NA − − NA + NA NA NA NA NA NA Kappa NA NL 80%
6 PB Var+ − − + +† NA −* + − − − Kappa − NL 75%
7 PB − − NA NA + NA NA NA Weak + − NA Lambda −* NA >95%
8 Mixed NA − NA NA + NA NA NA + NA NA Kappa +* C >90%
Plasmablastic plasma cell myeloma
9 PB − − NA NA + NA NA NA NA − NA Lambda NA NL‡ NA
10 PC − − NA NA + NA NA NA NA NA NA Kappa NA NA 80%
Indeterminate
11 PC Weak+ − NA NA + NA − − NA + NA Lambda NA NA NA
All were immunohistochemical studies.
*Fluorescence in situ hybridisation, HHV-8, Var.
†Weakly positive.
‡One of 13 cells cultured had trisomy 11 and additional structural defects.
ALK, anaplastic lymphoma Kinase; C, complex cytogenetics; gene, genetics; HHV-8, human herpes virus-8; morph, morphology based on predominant cells type; NL, normal; PB,
plasmablastic; PC, plasmacytic; var, variable.

lymphadenopathy or tissue-based disease were unknown, the
positive EBER favoured the histological classification as PBL.
Morphologically, the eight tumours classified as PBL had vari-
able numbers of plasmablasts: three cases had a plasmablastic
morphology ( patients #4, #6 and #7), two were predomin-
antly plasmacytic ( patients #1 and #2) and three were mixed,
Ahn JS, et al. J Clin Pathol 2017;0:1–6. doi:10.1136/jclinpath-2016-204294
with approximately equal numbers of plasmablastic and plasma-
cytic cells (patients #3, #5 and #8). All cases were positive for
CD138 (weak in patient #6) and negative for CD20, indicating
a plasma cell differentiation. Two of four cases (50%) were posi-
tive for CD45. All cases demonstrated light chain restriction.
PAX-5, HHV-8 and ALK were negative in all evaluable cases
3
 Original article
Figure 2 Proposed diagnostic
algorithm for tumours with
plasmablastic morphology. EBER,
Epstein-Barr virus-encoded RNA;
HHV-8, human herpes virus-8
immunohistochemistry; ALK, anaplastic
lymphoma kinase by
immunohistochemistry or fluorescence
in situ hybridisation; complete CRAB,
presence of all myeloma-defining signs
(hyperCalcaemia, Renal disease,
Anaemia and Bone lesions);
incomplete CRAB, presence of one or
more, but not all, myeloma-defining
signs; suspicious lymphadenopathy,
unexplained, persistent
lymphadenopathy associated with
suspicious clinical and/or radiological
features; oral mass, soft tissue-based
lesions only.
(table 2). With exception of patient #7, all evaluable cases were
negative for CD56 (table 2). Ki-67 demonstrated a high prolifer-
ation rate in all evaluable cases, ranging from 75% to >95%.
The single CD10-positive case ( patient #6) coexpressed
MUM-1 and lacked PAX-5 and CD79a, with weak CD138
expression, negative CD79a and negative ALK and MYC altera-
tions by fluorescence in situ hybridisation (FISH). Of note, the
single MYC translocation-positive case ( patient #8) had a
complex karyotype by FISH.
Plasmablastic myeloma
The patients classified as myeloma ( patients #9 and #10) were
a male aged 71 years and a female aged 72 years, who presented
with isolated bone marrow disease (30% and 40% bone
marrow clonal plasma cells, respectively). Imaging excluded
soft-tissue masses and lymphadenopathy. Patient #9 presented
with complete myeloma-defining signs for the diagnosis of mul-
tiple myeloma. Patient #10, however, had incomplete myeloma-
defining signs at presentation with anaemia and bone lesions but
normal serum calcium and creatinine (table 1). Neither had a
history of immunosuppressive therapy or transplantation,
lymphadenopathy, extramedullary masses, splenomegaly or
body cavity effusions. HIV and EBV testing were not performed
on either patient, likely due to a low clinical suspicion for
lymphoma, that is, extramedullary disease or lymphadenopathy.
The morphological features of the PBM case were similar to
those classified as PBL (table 2). The immunohistochemical find-
ings of PBM also mirrored those of PBL; however, most studies
performed on PBL cases had not been performed on myeloma
cases. In both groups, the neoplastic cells were uniformly posi-
tive for CD138 and negative for CD20 and CD45. CD79a was
negative and proliferation rate by Ki-67 was 80% in the single
case evaluated for these markers. EBV-ISH, HHV-8, ALK and
MYC testing had not been performed.
Indeterminate
The single case that could not be categorised into lymphoma or
myeloma ( patient #11) was that of a male aged 79 years who
4 Ahn JS, et al. J Clin Pathol 2017;0:1–6. doi:10.1136/jclinpath-2016-204294
presented with an EBER-negative mandibular mass, without any
other information available in the medical records.
Histologically, plasmablastic cells were admixed with plasmacy-
tic cells as well as those resembling centroblasts. These cells
were positive for CD138, CD79a and CD45 (dim), while nega-
tive for CD20 and PAX-5. By in situ hybridisation, they were
lambda-restricted and EBER-negative. ALK immunohistochemis-
try was negative. Studies to assess for MYC rearrangement and
HHV-8 infection were not available. The clinical diagnosis,
treatment, follow-up data and imaging records describing
whether the lesion was soft tissue-based or bone-based were
also not available.
DISCUSSION
Using a combination of morphological, phenotypical and
selected clinical findings, we were able to classify 10 of 11 plas-
mablastic tumours into 8 PBLs and 2 PBMs, independent from
the previously established clinical diagnosis. Of note, the term
‘PBL’ in this study refers to the general category of lymphomas
with plasmablastic features, which may include
HHV-8-associated tumours and ALK-positive large B-cell
lymphoma. As a result of this study, we propose a diagnostic
algorithm to aid in the prospective classification of these
neoplasms.
The single most useful histopathological feature in this differ-
entiation was the detection of EBV-positivity by EBER in situ
hybridisation. Although the overall rate of EBER-positivity has
been reported to range from 60% to 73% of PBL cases,1–3
5 7 16 20
only a minority of our cases (4 of 8 evaluable cases,
50%; patients #1, #2, #4 and #7) were EBER-positive. This
difference may be related to specific characteristics of the popu-
lation included in this study, such as prevalence of
HIV-positivity.21 Although not frequently seen in this series, a
positive EBER determined the classification of a case as lymph-
oma, regardless of all other parameters, including HIV status,
presence of CRAB signs, concomitant bone marrow disease,
lytic lesions or lymphadenopathy. The high positive predictive
value of EBV-positivity for lymphoma is due to the infrequent

association of myeloma with EBV infection.6 While a positive
EBER in a plasmablastic neoplasm allows for the classification
of lymphoma, it does not discriminate PBL from primary effu-
sion lymphoma (PEL), which requires demonstration of
HHV-8-positivity.20–23 24
The importance of obtaining HHV-8 immunohistochemistry in
the setting of EBER-positive plasmablastic tumours has been
emphasised in previous diagnostic algorithms.7 Nevertheless, of all
four EBER-positive tumours described in this series, only the one in
the peritoneal fluid had an HHV-8 immunostain performed
(patient #1). In the instances of PEL that are positive for HHV-8,
but negative for EBV,24 25 26 the differential diagnosis may also
include large B-cell lymphoma arising in HHV-8-associated multi-
centric Castleman disease (Castleman-LBCL). Therefore, in the
algorithm proposed in this study, we recommend that an HHV-8
immunostain be performed to exclude PEL/Castleman-LBCL in all
plasmablastic tumours regardless of HIVand EBER status (figure 2).
In an EBER-negative plasmablastic neoplasm, a positive ALK
determines the diagnosis of ALK-LBCL,7 20 which otherwise
overlaps with PBL. In our series, ALK had been performed in
only three of eight plasmablastic cases ( patients #1, #3 and
#6), two of which were EBER-negative, suggesting that the
infrequent use of this study is a possible explanation for the
under-recognition of ALK-LBCL.27 Immunophenotypical fea-
tures may be helpful to guide the request for ALK studies.
ALK-LBCLs are usually negative for CD79a and CD30,20 unlike
other plasmablastic neoplasms, in which expression of CD79a
and/or CD30 is variable.2 8 22
MYC alterations (including MYC/IgH) are found in approxi-
mately 50% of PBL cases.19 28–30 However, the identification of
MYC rearrangement in 15% of plasma cell myeloma31 and up to
50% of MYC alterations PBM,14 limits its value in distinguishing
PBL from myeloma. In this study, only one of three cases classi-
fied as PBL had positive MYC rearrangement by FISH.
PBL and myeloma show significant morphological and pheno-
typical overlap, limiting the ability of a pathologist to render a
specific diagnosis in the majority of EBER-negative cases.
Although traditionally described as a tumour with a predomin-
ance of plasmablasts, PBL may be predominantly plasmacytic in
up to 41% of cases.2 6 16 In fact, two of eight cases in this study
(25%, patients #1 and #2) were plasmacytic. We demonstrate
that the number of plasmablasts is variable in both plasmablastic
and plasmacytic morphological variants, and mixed cases with
approximate equal number of both cell types also exist.
Interestingly, two cases in this series also showed cells resem-
bling centroblasts (figure 1), further contributing to morpho-
logical heterogeneity of plasmablastic neoplasms.
Phenotypically, as both PBL and PBM are of terminally differ-
entiated B-cells/plasma cells,3 6 7 16 32 both tumours are positive
for CD138 and MUM-1, while negative for CD20 and PAX-5,
as shown in our study (table 2). CD56, while originally thought
to favour myeloma,2 8 16 has since been demonstrated in up to
56% of PBL cases,6 thereby reducing its utility. In our study,
two of five (40%) cases were CD56 positive, one of which
stained weakly. CD10 expression has been reported in 29% of
PBM6 and in 41%–67% PBL cases3 6 16 32 (in this study one of
four PBL, 25%), and is therefore of little utility. A high Ki-67 is
unlikely to distinguish between PBL and PBM as both entities
usually demonstrate high rates of proliferation.6 32
Clinical correlation is essential to classify neoplasms with
plasmablastic morphology, as illustrated by the case classified as
‘indeterminate’ in this study ( patient #11). In this case,
although histological data were available, the lack of sufficient
clinical data and EBER-positivity precluded classification of this
Ahn JS, et al. J Clin Pathol 2017;0:1–6. doi:10.1136/jclinpath-2016-204294
Original article
case into either PBL or PBM. In the literature, a similar case was
diagnosed as a ‘neoplasm indiscriminate between lymphoma
and myeloma’.33
Lymphadenopathy and/or an isolated head and neck mass
were used to favour the diagnosis of PBL in four of four
EBER-negative/unknown cases, as plasmacytoma cannot be
excluded at this anatomical site (figure 2). In addition to lymph-
adenopathy, three of four EBER-negative cases also had incom-
plete myeloma signs, which were considered non-specific for
myeloma, regardless of bone marrow status. In such cases, the
diagnosis of PBL was favoured. Conversely, in the absence of
lymphadenopathy, plasma cell neoplasm/myeloma was favoured
in the presence of bone marrow disease and at least one
myeloma-defining sign (figure 2).
CONCLUSION
This review illustrates the difficulties associated with the clin-
ical and histopathological diagnosis of neoplasms with plasma-
blastic features. A specific histopathological diagnosis may only
be possible in those cases in which association with EBV,
HHV-8 and the rare expression of ALK can be demonstrated.
As such, EBER-negative cases are likely to be reported non-
specifically as ‘hematolymphoid neoplasm with plasmablastic
features’.
We show that in EBER-negative cases, distinction between
lymphoma and myeloma relies heavily on an extensive and
detailed knowledge of the clinical history. Our data suggest that
the diagnosis of lymphoma may be favoured in the presence of
significant lymphadenopathy or oropharyngeal soft tissue mass
at presentation, while the diagnosis of myeloma may be
favoured on demonstration of isolated bone marrow disease and
at least one myeloma-defining sign.
The diagnosis of lymphoma may be more easily established
on retrospective review of clinical and laboratorial data, as in
this study. However, prospectively, when complete medical
information is often unavailable or unknown, specific classifica-
tion of a plasmablastic neoplasm may be impossible. Future
studies are warranted in order to further characterise PBL and
PBM, as well as to determine histopathological markers to
better differentiate these two entities.
Take home messages
▸ Hematolymphoid neoplasms with plasmablastic morphology
( plasmablastic lymphoma (PBL), plasmablastic myeloma
(PBM), primary effusion lymphoma, large B-cell lymphoma
arising in human herpesvirus 8 (HHV-8)-associated
multicentric Castleman disease and anaplastic lymphoma
Kinase (ALK)-positive large B-cell lymphoma) may show
significant morphological and immmunophenotypical overlap.
▸ The differential expression of Epstein-Barr virus, HHV-8 and/
or ALK is useful in distinguishing neoplasms with
plasmablastic morphology in the absence of clinical history.
▸ When myeloma-defining signs are incomplete or absent, the
presence of significant lymphadenopathy and/or
oropharyngeal soft tissue mass favours the diagnosis of
lymphoma, regardless of bone marrow status.
▸ Future studies are warranted in order to determine
histopathological markers to differentiate PBL and PBM.
Handling editor Mary Frances McMullin
5
 Original article
Acknowledgements The authors thank Dr Jeffrey Stead for his contributions, and
Dana Gray and Ed Gray for their assistance.
Contributors All persons who meet authorship criteria are listed as authors, and
all authors certify that they have participated sufficiently in the work to take public
responsibility for the content, including participation in the concept, design, analysis,
writing or revision of the manuscript.
Competing interests None declared.
Ethics approval West Virginia University Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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