Case report
A 70-year-old patient initially consulted his general physician because
of a persisting anal abscess that did not respond to a two-week
antibiotic treatment with amoxicillin and clavulanic acid. A blood test
to assess the patient’s response to this infection, unexpectedly showed
thrombocytopenia, macrocytic anemia and a normal white blood cell count
with a leukoerythroblastic presentation (Table 1 and Figure 1A).
Therefore, the patient was referred to the emergency department for
further examination. Careful anamnesis revealed extensive weight loss (±
20 kg) during the last couple of months, increasing fatigue, decreased
exercise tolerance and right hypochondrial discomfort. Additionally, the
patient reported no night sweats. Further physical examination revealed
hepatomegaly, which was later confirmed by ultrasound examination. No
lymphadenopathy nor other physical irregularities could be observed. The
patient’s medical history included hypercholesterolemia and poorly
controlled type 2 diabetes. His previous blood test, performed three
months earlier, did not show any hematological abnormalities
(Table 1 ) as well as a negative HIV status. Based on these
preliminary findings, the initial differential diagnosis included acute
leukemia, myelodysplastic syndrome (MDS) and myelofibrosis.
An examination of a bone marrow smear and trephine biopsy from the iliac
crest was performed. The aspirate was stained with Wright-Giemsa for
cytomorphologic evaluation and showed a markedly decreased megakaryo-,
erythro- and myelopoiesis as well as the presence of a large population
of blasts (75%) with a pleomorphic morphology. These cells displayed a
moderate nuclear-to-cytoplasmic ratio, one or more prominent nucleoli
and a rim of basophilic cytoplasm. Although the morphology of most of
these cells was compatible with monoblasts (50%) (Figure 1B ),
some cells displayed a perinuclear halo zone (25%) (Figure
1C ), more reminiscent of plasmablasts. Due to the peculiar morphologic
presentation of the blastic cells, the differential diagnosis was
adjusted to the following entities: plasmablastic myeloma, plasmablastic
lymphoma, plasma cell leukemia, and acute leukemia. Plasma cell leukemia
was excluded since only 2% plasma cells were detected by flow
cytometry, far below the 20% diagnostic criterium. Other laboratory
findings (Table 1 ) included a mildly increased lactate
dehydrogenase (LDH) and C-reactive protein (CRP), no significant
hypercalcemia, a normal kidney function and a markedly elevated
β2-microglobulin level. IgG and IgA levels were mildly
decreased whilst IgM was not detectable. Serum free light chains were
within normal values and displayed a normal κ/λ ratio. Moreover, serum
electrophoresis and immunofixation could not detect a monoclonal
fraction of IgG, IgA, IgM, IgD, IgE, kappa or lambda. The latter
experiments were repeated at 37°C to exclude precipitation of
cryoglobulins, as well as with β-mercaptoethanol pretreatment to rule
out polymerization of a monoclonal M-protein; all yielding the same
result.
Flow cytometry was performed according to the EuroFlow protocols
(Euroflow.org) to distinguish acute leukemia from a plasma cell
neoplasm.1 The acute leukemia orientation tube (see
details at euroflow.org) showed a large population with a distinctive
high forward scatter (FSC) without a blastic phenotype: CD45-,
CD19dim, CD34-, myeloperoxidase (MPO)-, cytoplasmic
CD3-, cytoplasmic CD79a- and CD7-. Subsequently, the plasma cell
disorder panel confirmed the presence of neoplastic cells with a typical
plasma cell immunophenotype: CD45-, CD19dim,
CD38bright, CD138+, CD28-, and CD56-. Interestingly, no
cytoplasmic or surface light chain expression could be demonstrated in
two independent analyses. Lack of CD56 expression along with the forward
scatter properties allowed us to exclude a blastic plasmacytoid
dendritic cell neoplasm.
Microscopic evaluation of the bone marrow trephine biopsy showed a
limited presence of the three lineages and a striking invasion of
neoplastic cells with plasmablastic aspect (Figure 2A ). The
reticulin staining corresponded to a myelofibrosis grade 1.
Immunohistochemistry (IHC) confirmed bone marrow invasion by CD38+ and
CD138+ neoplastic cells (Figure 2B ). Additional staining showed
MUM1 and cyclin D1 expression and absence of pan-B markers (PAX5, CD79a
and CD20). Analogous to flow cytometry, no kappa or lambda expression
could be demonstrated. IHC staining of IgG, IgA and IgM showed no clear
positive expression, with the exception of a weak reaction, possibly
aspecific, for IgG in combination with a high background staining. The
weak IgG expression at diagnosis was confirmed in a second trephine
biopsy in follow-up. Other analyzed markers (HHV-8, LMP-1 and MYC) were
negative. Chromogenic in situ hybridization or EBV-encoded RNA
transcript (EBER) could not be performed since only decalcified material
was available.
G-banding analysis showed a complex karyotype. Fluorescence in situ
hybridization (FISH) was performed on CD138 isolated cells and revealed
the presence of a t(11;14)(q13;q32) without evidence for the presence of
t(4;14), t(14;16) or MLL rearrangements. Shallow whole genome
sequencing, also performed on DNA from CD138 isolated cells, showed the
presence of segmental copy number gains and losses, as well as numerical
chromosome aberrations. Multiplex polymerase chain reaction showed a
clonal signal for the IgH and IgK light chains, thereby confirming the
presence of a clonal B-cell neoplasm. The t(11;14)(q13;q32)
translocation is commonly observed in plasmablastic myeloma, whereas
plasmablastic lymphoma is typically associated with a MYC-rearrangement.
PET-CT was compatible with the presentation of a disseminated myeloma
invasion showing a diffuse invasion pattern of the bone marrow with
multiple osteolytic lesions, without any extranodal localizations.
Although there are no definite criteria to differentiate non-secretor
plasmablastic myeloma from plasmablastic lymphoma, this case is most
compatible with a non-secretor myeloma based on the clinical
presentation, disseminated bone marrow involvement and lytic lesions
without extranodal involvement, along with extensive laboratory
investigations.
The patient was treated with a combination of velcade, endoxan and
dexamethasone (VCD) and further antibiotic treatment was sufficient to
cure the anal abscess.2 After two VCD cycles, the bone
marrow biopsy revealed a drop in plasmablastic cells from 75% to 15%
and PET-CT showed one residual metabolically active region in the right
4th rib. Two additional VCD cycles were given and
evaluation of a bone marrow biopsy showed a slightly elevated plasma
cell count (5-10%) with atypical morphology. Despite the poor
prognosis, the patient has a very good partial response (VGPR) after
four VCD cycles and an autologous stem cell transplant is planned in the
near future. The patient gave an informed consent for this case report.